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Abstract Fusarium wilt, caused by (Fusarium udum Butler), is a significant threat to pigeonpea crops worldwide, leading to substantial yield losses. Traditional approaches like fungicides and resistant cultivars are not practical due to the persistent and evolving nature of the pathogen. Therefore, native biocontrol agents are considered to be more sustainable solution, as they adapt well to local soil and climatic conditions. In this study, five isolates of F. udum infecting pigeonpea were isolated from various cultivars and characterized morphologically and molecularly. The isolate from the ICP 8858 cultivar displayed the highest virulence of 90%. Besides, 100 endophytic bacteria, 100 rhizosphere bacteria and three Trichoderma spp. were isolated and tested against F. udum isolated from ICP 8858 under in vitro conditions. Out of the 200 bacteria tested, nine showed highest inhibition, including Rb-4 (Bacillus sp.), Rb-11 (B. subtilis), Rb-14 (B. megaterium), Rb-18 (B. subtilis), Rb-19 (B. velezensis), Eb-8 (Bacillus sp.), Eb-11 (B. subtilis), Eb-13 (P. aeruginosa), and Eb-21 (P. aeruginosa). Similarly, Trichoderma spp. were identified as T. harzianum, T. asperellum and Trichoderma sp. Notably, Rb-18 (B. subtilis) and Eb-21 (P. aeruginosa) exhibited promising characteristics such as the production of hydrogen cyanide (HCN), cellulase, siderophores, ammonia and nutrient solubilization. Furthermore, treating pigeonpea seedlings with these beneficial microorganisms led to increased levels of key enzymes (POD, PPO, and PAL) associated with resistance to Fusarium wilt, compared to untreated controls. In field trials conducted for four seasons, the application of these potential biocontrol agents as seed treatments on the susceptible ICP2376 cultivar led to the lowest disease incidence. Specifically, treatments T2 (33.33) (P. aeruginosa) and T3 (35.41) (T. harzianium) exhibited the lowest disease incidence, followed by T6 (36.5) (Carbendizim), T1 (36.66) (B. subtilis), T4 (52.91) (T. asperellum) and T5 (53.33) (Trichoderma sp.). Results of this study revealed that, P. aeruginosa (Eb-21), B. subtilis (Rb-18) and T. harzianum can be used for plant growth promotion and management of Fusarium wilt of pigeonpea.

Multicellular organisms are constantly subjected to pathogens that might be harmful. Although insects lack an adaptive immune system, they possess highly effective anti-infective mechanisms. Bacterial phagocytosis and parasite encapsulation are some forms of cellular responses. Insects often defend themselves against infections through a humoral response. This phenomenon includes the secretion of antimicrobial peptides into the hemolymph. Specific receptors for detecting infection are required for the recognition of foreign pathogens such as the proteins that recognize glucans and peptidoglycans, together referred to as PGRPs and βGRPs. Activation of these receptors leads to the stimulation of signaling pathways which further activates the genes encoding for antimicrobial peptides. Some instances of such pathways are the JAK-STAT, Imd, and Toll. The host immune response that frequently accompanies infections has, however, been circumvented by diseases, which may have assisted insects evolve their own complicated immune systems. The role of ncRNAs in insect immunology has been discussed in several notable studies and reviews. This paper examines the most recent research on the immune regulatory function of ncRNAs during insect-pathogen crosstalk, including insect- and pathogen-encoded miRNAs and lncRNAs, and provides an overview of the important insect signaling pathways and effector mechanisms activated by diverse pathogen invaders.

cAMP signalling is critical for memory consolidation and certain forms of long-term potentiation (LTP). Phosphodiesterases (PDEs), enzymes that degrade the second messengers cAMP and cGMP, are highly conserved during evolution and represent a unique set of drug targets, given the involvement of these enzymes in several pathophysiological states including brain disorders. The PDE4 family of cAMP-selective PDEs exert regulatory roles in memory and synaptic plasticity, but the specific roles of distinct PDE4 isoforms in these processes are poorly understood. Building on our previous work demonstrating that spatial and contextual memory deficits were caused by expressing selectively the long isoform of the PDE4A subfamily, PDE4A5, in hippocampal excitatory neurons, we now investigate the effects of PDE4A isoforms on different cAMP-dependent forms of LTP. We found that PDE4A5 impairs long-lasting LTP induced by theta burst stimulation (TBS) while sparing long-lasting LTP induced by spaced four-train stimulation (4 × 100 Hz). This effect requires the unique N-terminus of PDE4A5 and is specific to this long isoform. Targeted overexpression of PDE4A5 in area CA1 is sufficient to impair TBS-LTP, suggesting that cAMP levels in the postsynaptic neuron are critical for TBS-LTP. Our results shed light on the inherent differences among the PDE4A subfamily isoforms, emphasizing the importance of the long isoforms, which have a unique N-terminal region. Advancing our understanding of the function of specific PDE isoforms will pave the way for developing isoform-selective approaches to treat the cognitive deficits that are debilitating aspects of psychiatric, neurodevelopmental and neurodegenerative disorders. KEY POINTS: Hippocampal overexpression of PDE4A5, but not PDE4A1 or the N-terminus-truncated PDE4A5 (PDE4A5Δ4), selectively impairs long-term potentiation (LTP) induced by theta burst stimulation (TBS-LTP). Expression of PDE4A5 in area CA1 is sufficient to cause deficits in TBS-LTP. Hippocampal overexpression of the PDE4A isoforms PDE4A1 and PDE4A5 does not impair LTP induced by repeated tetanic stimulation at the CA3-CA1 synapses. These results suggest that PDE4A5, through its N-terminus, regulates cAMP pools that are critical for memory consolidation and expression of specific forms of long-lasting synaptic plasticity at CA3-CA1 synapses., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Gastric malignancy is one of the most common malignancies diagnosed worldwide. Over the past many decades, extensive research has been made into the risk factors, pathogenesis and prognosis of gastric adenocarcinoma. However, gastric adenocarcinoma of the fundic gland (GA-FG) has been recently defined, and not much is known about its risk factors and pathogenesis. Since the first case, which was reported in 2007, only 195 cases have been described in the literature to date. The rarity of the lesion is the cause of unawareness of this entity among reporting pathologists, often leading to its misdiagnosis. Existing literature shows that the risk factors, pathogenesis and even the prognosis of GA-FG are remarkably different from gastric adenocarcinoma. Hence, early and correct diagnosis can have a significant impact on patient management and outcomes., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-α, Il-1β, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-κB phosphorylation, and a dose-dependent decrease in IκBα levels. BPA-induced NF-κB nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1β) established an inflammatory milieu. Perturbations in hepatic AMPKα phosphorylation, SIRT1, and PGC-1α, along with elevated p38 MAPK phosphorylation and ERα expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-κB-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ERα expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-κB/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPKα/PGC-1α and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The use of visible light to drive chemical transformations has a history spanning over a century. However, the development of photo-redox catalysts to efficiently harness light energy is a more recent advancement, evolving over the past two decades. While ruthenium and iridium-based photocatalysts dominate due to their photostability, long excited-state lifetimes, and high redox potentials, concerns about sustainability and cost have shifted attention to first-row transition metals. Luminescent Cu(I) complexes have emerged as promising alternatives, offering open-shell reactivity and tunable photoelectrochemical properties. This review (i) provides an overview of the structural, photophysical, and electrochemical properties governing copper(I) complexes; (ii) highlights advances in Cu(I)-BINAP catalysis for carbon-carbon and carbon-heteroatom bond formations under mild conditions; and (iii) analyzes the trajectory of this catalytic system, addressing challenges and identifying opportunities for further development.

Sleep disturbances are a significant concern in individuals with dementia, affecting their overall health and quality of life, as well as that of their family members and caregivers. Dementia, a progressive neurodegenerative condition marked by cognitive decline, often coexists with various comorbidities such as cardiovascular disease, diabetes, obesity, anxiety/depression and thyroid disorders. These comorbidities can further impair cognitive function and complicate the clinical management of dementia, making it essential to address them in a holistic manner. This review critically examines the complex interplay between dementia and its associated comorbidities, with a special focus on the prevalence and impact of sleep disturbances. Sleep problems in dementia patients are not only common but also contribute to a faster progression of cognitive decline and increased burden on caregivers. The article explores the mechanisms by which these comorbidities, including cardiovascular conditions and metabolic disorders, exacerbate sleep disturbances and cognitive impairment in dementia patients. By synthesizing recent research findings, the review highlights the importance of identifying and managing modifiable risk factors for sleep disturbances in dementia. Integrated treatment approaches that address both cognitive and sleep-related challenges are essential for improving patient outcomes. The review also underscores the need for further research to develop targeted interventions that can effectively manage sleep disturbances in dementia, thereby enhancing the quality of life for both patients and caregivers. Understanding the relationship between dementia, comorbidities, and sleep disturbances is crucial for the development of comprehensive care strategies. This review aims to inform healthcare professionals about the current state of knowledge and encourage the implementation of evidence-based practices in dementia care.

Findings from clinical trials have led to advancement of care for patients with gynecologic malignancies. However, restrictive inclusion of patients into trials has been widely criticized for inadequate representation of the real-world population. Ideally, patients enrolled in clinical trials should represent a broader population to enhance external validity and facilitate translation of outcomes across all relevant groups. Specifically, there has been a systematic lack of data for underrepresented groups, with many studies failing to report or differentiate study participants based on sociodemographic domains, such as race and ethnicity. As such, the impact of treatment in these underrepresented groups is poorly understood, and clinical outcomes according to various sociodemographic factors are infrequently assessed. Inclusion of diverse trial participants, with different racial and ethnic background, is essential for the understanding of factors that may impact clinical outcomes. Therefore, we conducted a multi-national meeting of clinical trial groups and industry with the goal of increasing equity, diversity, and inclusion in gynecologic cancer clinical trials and to address barriers to recruitment, participation, and harmonization of data collection and reporting. These Gynecologic Cancer Intergroup (GCIG) statements present recommendations and strategies for the gynecologic cancer research community to improve equity, diversity, and inclusion in gynecologic cancer clinical trials., Competing Interests: Competing interests: Alison Brand reports grants/contracts from the Australian Government Department of Health and Aged Care Medical Research Future Fund, Australia and New Zealand Gynaecological Oncology Group (ANZGOG); and is Director ANZGOG, Chair GCIG. Michael Bookman reports consultancy fees paid to the institution from Immunogen independent DSMB. Sabrina Chiara Cecere reports travel support from AstraZeneca, Clovis, GSK, MSD; honoraria from AstraZeneca, Clovis, GSK, MSD; participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, Clovis, GSK, MSD. Paul A. Cohen reports grants/contracts from the Australian Government Department of Health and Aged Care Medical Research Future Fund, Cancer Council Western Australia, Australia and New Zealand Gynaecological Oncology Group (ANZGOG); honoraria and educational events from AstraZeneca, MSD; advisory boards with AstraZeneca, Reliis; non-remunerated leadership roles as Director ANZGOG, Chair Research Advisory Committee ANZGOG, Education Committee Chair, International Gynecological Cancer Society, Expert Advisory Group Australian Centre for Prevention of Cervical Cancer, Editorial Board Member International Journal Gynecological Cancer; stock in Reliis Ltd. Jennifer Croke reports honoraria from American Society of Radiation Oncology (Member, Sexual and Gender Minority Affinity Working Group), Canadian Association of Radiation Oncology (Annual Scientific Meeting lead), Merck. Josie Ethier reports consultancy fees from AstraZeneca; honoraria from AstraZeneca, GSK, Merck; advisory board participation with AstraZeneca, Eisai, GSK, Merck. Franziska Geissler reports grants/contracts from International Research Fellowship, Swiss Cancer Research Foundation & Swiss Cancer League and Research Fund for Excellent Junior Researchers University of Basel 2024. Rosalind Glasspool reports grants/contracts from Clovis Oncology; consultancy fees from Clovis Oncology, GSK, Novartis; honoraria from GSK; travel support from GSK, MSD; participation on a Data Safety Monitoring Board or Advisory Board from IDMC Matao trial; leadership or fiduciary roles at IGCS Advocacy committee chair, IGCS board member, Chair of Scottish Gynaecological Cancer Trials Group; receipt of equipment, materials, drugs, medical writing, gifts or other services from AstraZeneca, GSK, Novartis; other financial or non-financial interests with Allarity Therapeutics, AstraZeneca, Immunogen, GSK. Philipp Harter reports grants/contracts from AstraZeneca, Clovis, Genmab, GSK, Immunogen, Novartis, Roche, Seagen; consultancy fees from Miltenyi; honoraria from Amgen, AstraZeneca, Clovis, Daiichi Sankyo, Eisai, Exscientia, GSK, Immunogen, Karyopharm, Mersana, MSD, Roche, Sotio, Stryker, Zai Lab; travel support from AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board at AstraZeneca, Clovis, Eisai, GSK, Immunogen, MSD, Miltenyi, Novartis, Roche. Chee Khoon Lee reports grants/contracts from Amgen, AstraZeneca, Merck, Roche; honoraria from Amgen, AstraZeneca, Gilead, GSK, Janssen, Merck, Merck kGA, Novartis, Roche, Takeda. Kristina Lindemann reports grants/contracts from GSK (research funding paid to institution); honoraria, consultancy fees, or advisory board fees from AstraZeneca, Eisai, GSK, MSD, Nycode; part of the Data Safety Monitoring Committee for Karyopharm.Ainhoa Madariaga reports honoraria from AstraZeneca, Clovis, GSK, MSD, Pharma & PharmaMar; travel support from AstraZeneca, GSK, MSD; participation on a Data Safety Monitoring Board or Advisory Board from AbbVie, AstraZeneca, GSK, MSD. Asima Mukhopadhyay reports grants/contracts from the Indian Council of Medical Research for the IPIRIC academic study which endorses the principles of EDIM; honoraria from KGOG; advisory board at CannariaBio; Secretary KolGoTrg, Executive Board Member GCIG; part funding support for the IPIROC trial for drug procurement from BDR Pharma. Amit Oza reports grants/contracts from Amgen, AstraZeneca; consultancy fees from BMS; advisory board participation with AstraZeneca and GSK; other financial or non-financial interests with AstraZeneca, GSK. Elisa Piovano reports travel support from AstraZeneca, GSK. Bhavana Pothuri reports grants/contracts from Agenus, Alkermes, AstraZeneca, Acrivon, Celgene, Celsion/Immunon, Clovis Oncology, Duality Bio, Eisai, Immunogen, Incyte, Imab, InxMed, Karyopharm Therapeutics, Lily, LOXO/Lily, Merck, Mersana, Novocure, Onconova, NRG Oncology, Roche/Genentech, Seagen, Sutro, Takeda, Tesaro/GSK, Toray, VBL Therapeutics, Xencor; consultancy fees from AstraZeneca, Celsion, Duality Bio, Eisai, GOG Foundation, Imvax Inc, Incyte Corporation, InxMed, Lily, Onconova Therapeutics, Regeneron, SeaGen, Signatera, Sutro Biopharma, Tesaro/GSK; honoraria from Albert Einstein-Montefiore, Bioascend, Colorado University, Curio, Lankenau Hospital, OncLive, PERS, PeerView, Vanium, Yale University; travel support from GOG Partners; advisory boards with AstraZeneca, Celsion/Immunon, GOG Foundation, Imab, Imvax, Incyte, InxMed, Lily, Merck, Mersana, Nuvation, Sutro, Tesaro/GSK; leadership or fiduciary roles in GOG Partners, NYOB Society VP, SGO Board of Directors, SGO Clinical Practice Committee Chair, SGO COVID-19 Taskforce co-chair. Jose Alejandro Rauh-Hain reports grants/contracts from NIH, Department of Defense, American Cancer Society; support for the present manuscript from Guidepoint Consulting, Sago. Ora Rosengarten reports consultancy fees from AstraZeneca, Medison, MSD, Neopharm; travel support from AstraZeneca, MSD; lecture honoraria from AstraZeneca. Jalid Sehouli reports grants/contracts from AstraZeneca, Eisai, GSK, Merck, MSD, Novocure, Roche, Tesaro; consultancy fees from AstraZeneca, Clovis, Eisai, GSK, Immunogen, Incyte, MSD, Novocure; honoraria from AstraZeneca, Bristol Myers Squibb, Clovis, Eisai, GSK, Immunogen, Incyte, MSD, Novartis, Novocure; travel support from AstraZeneca, Eisai, GSK, Immunogen, Incyte, MSD, Novocure, Roche; advisory boards with AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, GSK, Immunogen, Incyte, MSD, Novocure, PharmaMar; leadership or fiduciary roles at AGO, ASCO, Deutsche Stiftung Eierstockkrebs, ENGAGE, ESGO, GCIG, Medical writing (MSD). David Tan reports receiving research funding from the National Medical Research Council (NMRC) Clinician Scientist Award Senior Investigator Grant (CSASI21jun-0003), the Pangestu Family Foundation Gynaecological Cancer Research Fund; and product samples from AstraZeneca, Eisai, MSD (non-financial interest) for research trials. Institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics, Roche; personal fees for advisory board membership from AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Genmab, GSK, MSD, PMV Pharma, Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, Takeda; travel support from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, Takeda; current non-renumerated role as protocol chair of Asia Pacific Gynecologic Oncology Trials Group (APGOT); previous non-renumerated role as Chair of the Asia Pacific Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; ownership of stocks/shares of Asian Microbiome Library (AMiLi). Toon Van Gorp reports consultancy fees (via institution) from AbbVie, AstraZeneca, BioNTech, Cancer Communications and Consultancy Ltd, Eisai, GSK, ImmunoGen, Incyte, Karyopharm, MSD/Merck, OncXerna Therapeutics, Seagen, Tubulis, Zentalis; corporate sponsored research (via institution) from Amgen, AstraZeneca, Roche; honoraria for lectures (via institution) from AstraZeneca, Eisai, GSK, ImmunoGen, MSD; travel support from AstraZeneca, ImmunoGen, MSD, PharmaMar; grants/contracts from Amgen, AstraZeneca, Roche; chair of the Belgian and Luxembourg Gynaecological Oncology Group. Stephen Welch reports honoraria from AstraZeneca, Eisai, GSK, Merck; advisory boards with Eisai, Incyte, GSK, Roche, Takeda.All other authors declare no conflict of interest., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Ethnic and socioeconomic disparities in cancer outcomes are exacerbated by clinical trial underrepresentation. This study aims to identify inequalities in ethnicity and socioeconomic features among ovarian cancer clinical trial participants in two London cancer centres., Methods: All ovarian cancer patients treated between 2017 and 2022 were included. Patients participating in clinical trials were classified as the trial population (TP); the remainder were considered the non-trial population (NTP). Data on disease characteristics and sociodemographic features, including ethnicity and Indices of Multiple Deprivation (IMD) deciles, were accessed from electronic patient records., Results: Of the 892 patients, 212 (24%) were enrolled in trials: 87 in Phase II, 103 in Phase III, and 21 in prospective, non-investigational medicinal product trials. The TP were more likely to be of White ethnicity (72.6% vs. 57.5%; p < 0.001), younger (mean age 58 vs. 60; p = 0.003), living in less deprived areas (most deprived tercile: 21.2% vs. 34.0%; p = 0.004), and English-speaking (95.8% vs. 90.9%; p = 0.041). In the multivariate analysis, White ethnicity ( p < 0.0001), age ( p = 0.003), IMD decile ( p = 0.007), and interpreter requirement ( p = 0.037) were independent predictors of trial participation., Conclusions: Ethnic and socioeconomic inequalities affect trial participation, potentially worsening health disparities in ovarian cancer patients. Strategies to overcome trial recruitment barriers for underserved groups are needed to improve the equity of care.

Direct electrical stimulation has been used for decades as a gold standard clinical tool to map cognitive function in neurosurgery patients 1-8 . However, the molecular impact of electrical stimulation in the human brain is unknown. Here, using state-of-the-art transcriptomic and epigenomic sequencing techniques, we define the molecular changes in bulk tissue and at the single-cell level in the human cerebral cortex following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Direct electrical stimulation surprisingly had a robust and consistent impact on the expression of genes related to microglia-specific cytokine activity, an effect that was replicated in mice. Using a newly developed deep learning computational tool, we further demonstrate cell type-specific molecular activation, which underscores the effects of electrical stimulation on gene expression in microglia. Taken together, this work challenges the notion that the immediate impact of electrical stimulation commonly used in the clinic has a primary effect on neuronal gene expression and reveals that microglia robustly respond to electrical stimulation, thus enabling these non-neuronal cells to sculpt and shape the activity of neuronal circuits in the human brain., Competing Interests: Competing interests T.A. is a scientific advisor to Aditum Bio and Radius Health and serves on the scientific advisory board of Embark Neuro. The other authors declare no conflicting interests.

Sleep is established as an essential physiological need that impacts physical, emotional, and cognitive functions profoundly. Physiologically, inadequate sleep weakens immune function, heightening susceptibility to infections and chronic illnesses such as obesity, diabetes, and cardiovascular diseases. Hormonal disruptions due to sleep loss further exacerbate metabolic dysregulation, contributing to weight gain and other health complications. Emotionally, sleep deprivation leads to mood disturbances, including increased irritability, heightened stress responses, and a greater likelihood of mood disorders like depression and anxiety. These effects are compounded by cognitive impairments such as reduced alertness, impaired memory consolidation, and compromised decision-making abilities, akin to the impairments caused by alcohol consumption. Motor skills and coordination also suffer, elevating the risk of accidents, particularly in high-stress environments. For older adults, sleep quality is closely linked to cognitive function and overall longevity. Optimal sleep patterns are associated with slower brain aging and improved health outcomes. However, sleep disorders exacerbate existing conditions such as epilepsy and asthma, necessitating interventions like cognitive behavioral therapy (CBT) and medications such as melatonin to mitigate their impact. Education emerges as a crucial tool in promoting healthier sleep habits across all age groups. Addressing misconceptions about sleep and integrating sleep health into public health policies are essential steps toward improving overall well-being. Additionally, lifestyle factors such as diet and physical activity play significant roles in regulating sleep patterns, further emphasizing the interconnectedness of sleep with broader health outcomes. In summary, the articles underscore the intricate mechanisms through which sleep influences physiological functions and advocate for comprehensive approaches to enhance sleep hygiene and mitigate the adverse effects of sleep deprivation on human health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

1,2-Difunctionalization of styrenes, adding two distinct functional groups across the C═C double bond, has emerged as a powerful tool for enhancing molecular complexity. Herein, we report the development of a regioconvergent β-acyloxylation-α-ketonylation of styrenes through bromo/acyloxy transposition (BrAcT) and excited-state copper catalysis. This approach is amenable to gram-scale synthesis and tolerates a wide range of functional groups and complex molecular frameworks, including derivatives of natural products and marketed drugs. Our experimental and computational studies suggest a unique mechanism featuring a dynamic, ionic BrAcT process and excited-state copper-catalyzed redox reactions. We anticipate that this BrAcT process could serve as a broadly applicable and versatile strategy for β-acyloxylation-α-functionalization of styrenes, creating valuable intermediates for preparing new pharmaceuticals, agrochemicals, and functional materials.

Dementia, a prevalent condition in the United States, affecting millions of individuals and their families, underscores the importance of healthy cognitive ageing, which involves maintaining cognitive function and mental wellness as individuals grow older, promoting overall well-being and quality of life. Our original research study investigates the correlation between lifestyle factors and brain atrophy in individuals with mild cognitive impairment (MCI) or Alzheimer's disease (AD), as well as healthy older adults. Conducted over six months in West Texas, the research involved 20 participants aged 62-87. Findings reveal that sleep deprivation in MCI subjects and AD patients correlate with posterior cingulate cortex, hippocampal atrophy and total brain volume, while both groups exhibit age-related hippocampal volume reduction. Notably, fruit/vegetable intake negatively correlates with certain brain regions' volume, emphasizing the importance of diet. Lack of exercise is associated with reduced brain volume and hippocampal atrophy, underlining the cognitive benefits of physical activity. The study underscores lifestyle's significant impact on cognitive health, advocating interventions to promote brain health and disease prevention, particularly in MCI/AD cases. While blood profile data showed no significant results regarding cognitive decline, the study underscores the importance of lifestyle modifications in preserving cognitive function., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest with the scientific contents of this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In a study conducted in India, 50 Fusarium isolates were collected from pigeonpea growing regions and extensively examined for their cultural and morphological characteristics. These isolates exhibited significant variations in traits including growth rate, mycelial growth patterns, color, zonation, pigmentation, spore size, and septation. Subsequently, 30 isolates were chosen for pathogenicity testing on eight pigeonpea genotypes. Results showed distinct reactions, with four genotypes displaying differential responses (ICP8858, ICP8859, ICP8862, and BDN-2), while ICP9174 and ICP8863 consistently exhibited resistance and ICP2376 and BAHAR remained susceptible to wilt disease. To study the interaction between Fusarium isolates and pigeonpea host differentials (HDs), an additive main effects and multiplicative interaction analysis was conducted. The majority of disease incidence variation (75.54%) was attributed to HD effects, while Fusarium isolate effects accounted for only 1.99%. The interaction between Isolates and HDs (I × HD) contributed 21.95% to the total variation, being smaller than HD but larger than I. Based on HD reactions, isolates were classified into nine variants, showing varying distributions across pigeonpea growing states, with variants 2 and 3 being prevalent in several regions. This diversity underscores the need for location-specific wilt-resistant pigeonpea cultivars. Furthermore, genetic analysis of 23 representative isolates, through internal transcribed spacer region of ribosomal DNA and translation elongation factor 1-α gene sequencing, revealed three major clusters: Fusarium udum, Fusarium solani, and Fusarium equiseti. These findings hold potential for developing location-specific wilt-resistant pigeonpea cultivars and enhancing disease management strategies., (© 2024 Wiley‐VCH GmbH.)

Graceful healthy ageing and extended longevity is the most desired goal for human race. The process of ageing is inevitable and has a profound impact on the gradual deterioration of our physiology and health since it triggers the onset of many chronic conditions like dementia, osteoporosis, diabetes, arthritis, cancer, and cardiovascular disease. However, some people who lived/live more than 100 years called 'Centenarians" and how do they achieve their extended lifespans are not completely understood. Studying these unknown factors of longevity is important not only to establish a longer human lifespan but also to manage and treat people with shortened lifespans suffering from age-related morbidities. Furthermore, older adults who maintain strong cognitive function are referred to as "SuperAgers" and may be resistant to risk factors linked to cognitive decline. Investigating the mechanisms underlying their cognitive resilience may contribute to the development of therapeutic strategies that support the preservation of cognitive function as people age. The key to a long, physically, and cognitively healthy life has been a mystery to scientists for ages. Developments in the medical sciences helps us to a better understanding of human physiological function and greater access to medical care has led us to an increase in life expectancy. Moreover, inheriting favorable genetic traits and adopting a healthy lifestyle play pivotal roles in promoting longer and healthier lives. Engaging in regular physical activity, maintaining a balanced diet, and avoiding harmful habits such as smoking contribute to overall well-being. The synergy between positive lifestyle choices, access to education, socio-economic factors, environmental determinants and genetic supremacy enhances the potential for a longer and healthier life. Our article aims to examine the factors associated with healthy ageing, particularly focusing on cognitive health in centenarians. We will also be discussing different aspects of ageing including genomic instability, metabolic burden, oxidative stress and inflammation, mitochondrial dysfunction, cellular senescence, immunosenescence, and sarcopenia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fusarium wilt, caused by (Fusarium udum Butler), is a significant threat to pigeonpea crops worldwide, leading to substantial yield losses. Traditional approaches like fungicides and resistant cultivars are not practical due to the persistent and evolving nature of the pathogen. Therefore, native biocontrol agents are considered to be more sustainable solution, as they adapt well to local soil and climatic conditions. In this study, five isolates of F. udum infecting pigeonpea were isolated from various cultivars and characterized morphologically and molecularly. The isolate from the ICP 8858 cultivar displayed the highest virulence of 90%. Besides, 100 endophytic bacteria, 100 rhizosphere bacteria and three Trichoderma spp. were isolated and tested against F. udum isolated from ICP 8858 under in vitro conditions. Out of the 200 bacteria tested, nine showed highest inhibition, including Rb-4 (Bacillus sp.), Rb-11 (B. subtilis), Rb-14 (B. megaterium), Rb-18 (B. subtilis), Rb-19 (B. velezensis), Eb-8 (Bacillus sp.), Eb-11 (B. subtilis), Eb-13 (P. aeruginosa), and Eb-21 (P. aeruginosa). Similarly, Trichoderma spp. were identified as T. harzianum, T. asperellum and Trichoderma sp. Notably, Rb-18 (B. subtilis) and Eb-21 (P. aeruginosa) exhibited promising characteristics such as the production of hydrogen cyanide (HCN), cellulase, siderophores, ammonia and nutrient solubilization. Furthermore, treating pigeonpea seedlings with these beneficial microorganisms led to increased levels of key enzymes (POD, PPO, and PAL) associated with resistance to Fusarium wilt, compared to untreated controls. In field trials conducted for four seasons, the application of these potential biocontrol agents as seed treatments on the susceptible ICP2376 cultivar led to the lowest disease incidence. Specifically, treatments T2 (33.33) (P. aeruginosa) and T3 (35.41) (T. harzianium) exhibited the lowest disease incidence, followed by T6 (36.5) (Carbendizim), T1 (36.66) (B. subtilis), T4 (52.91) (T. asperellum) and T5 (53.33) (Trichoderma sp.). Results of this study revealed that, P. aeruginosa (Eb-21), B. subtilis (Rb-18) and T. harzianum can be used for plant growth promotion and management of Fusarium wilt of pigeonpea., (© 2024. The Author(s).)

The ovulatory response involves diverse molecular determinants, the interplay between which remains less investigated in fish. This study explores the temporal changes in the follicular microenvironment, regulatory factors, and underlying signaling events during ovulation in female zebrafish subjected to 14L:10D at 28 ± 1 °C in vivo vis-à-vis in hCG-stimulated full-grown (FG) follicles in vitro. Congruent with reduced GSH levels, SOD, and GPx activity, a graded increase in follicular free radicals, Nox4, and p38 MAPK phosphorylation in the morning hour groups (05:00 and 06:30) correlates positively with the ovulatory surge in inflammatory mediators (Tnf-α, Il-1β, Il-6, Nos2, and Cox-2). Further, elevated Pgr expression and its nuclear translocation, congruent with follicular lhcgr, star, and hsd20b2 upregulation in vivo, corroborates well with the transcriptional activation of genes (pla2g4aa, ptgesl, ptger4b, mmp9, adamts9), triggering ovulation in this species. Mechanistically, an elevated ovulatory response in hCG-treated FG follicles in vitro involves the upregulation of inflammatory mediators, pgr and ovulation-associated genes in a manner sensitive to PKA- and MAPK3/1-mediated signaling., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dementia is a major health concern in society, particularly in the aging population. It is alarmingly increasing in ethnic minorities such as Native Americans, African Americans, Hispanics/Latinos, and to some extent Asians. With increasing comorbidities of dementia such as diabetes, obesity, and hypertension, dementia rates are expected to increase in the next decade and beyond. Understanding and treating dementia, as well as determining how to prevent it, has become a healthcare priority across the globe for all races and genders. Awareness about dementia and its consequences such as healthcare costs, and caregiver burden are immediate needs to be addressed. Therefore, it is high time for all of us to create awareness about dementia in society, particularly among Hispanics/Latinos, Native Americans, and African Americans. In the current article, we discuss the status of dementia, cultural, and racial impacts on dementia diagnosis and care, particularly in Hispanic populations, and possible steps to increase dementia awareness. We also discussed factors that need to be paid attention to, including, cultural & language barriers, low socioeconomic status, limited knowledge/education, religious/spiritual beliefs and not accepting modern medicine/healthcare facilities. Our article also covers both mental & physical health issues of caregivers who are living with patients with dementia, Alzheimer's disease, and Alzheimer's disease-related dementias. Most importantly, we discussed possible measures to create awareness about dementia, including empowering community advocacy, promoting healthy lifestyle choices, education on the impact of nutrition, encouraging community participation, and continued collaboration and evaluation of the success of dementia awareness., Competing Interests: The authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Ovarian cancer (OC) is the most lethal gynaecologic malignancy, attributed to its insidious growth, non-specific symptoms and late presentation. Unfortunately, current screening modalities are inadequate at detecting OC and many lack the appropriate specificity and sensitivity that is desired from a screening test. Nearly 70% of cases are diagnosed at stage III or IV with poor 5-year overall survival. Therefore, the development of a sensitive and specific biomarker for early diagnosis and screening for OC is of utmost importance. Currently, diagnosis is guided by CA125, the patient's menopausal status and imaging features on ultrasound scan. However, emerging evidence suggests that a combination of CA125 and HE4 (another serum biomarker) and patient characteristics in a multivariate index assay may provide a higher specificity and sensitivity than either CA125 and HE4 alone in the early detection of OC. Other attempts at combining various serum biomarkers into one multivariate index assay such as OVA1, ROMA and Overa have all shown promise. However, significant barriers exist before these biomarkers can be implemented in clinical practice. This article aims to provide an up-to-date review of potential biomarkers for screening and early diagnosis of OC which may have the potential to transform its diagnostic landscape., Competing Interests: MM declares no conflict of interests related to this work. MM is a Novartis employee and shareholder., (© The Author(s), 2024.)

Nitro(hetero)arene derivatives are essential commodity chemicals used in various products, such as drugs, polymers, and agrochemicals. In this study, we leverage the excited-state reactivities of copper catalysts and nitro(hetero)arenes, and the Umpolung reactivity of acyl radicals to convert readily available nitro(hetero)arenes directly to valuable 2-aminophenol derivatives, which are important scaffolds in many top-selling pharmaceuticals. This reaction is applicable to a variety of nitro(hetero)arenes, acyl chlorides, and late-stage modifications of complex molecules, making it a useful tool for the discovery of new functional molecules. Mechanistic studies, including radical trapping experiments, Stern Volmer quenching studies, light ON/OFF experiments, and 18 O-labeling studies, suggest a reaction mechanism involving photoexcitation of a copper complex, diradical couplings, and an in-cage contact ion pair (CIP) migration. Our findings offer a streamlined protocol for synthesizing essential pharmacophores from nitro(hetero)arenes while simultaneously advancing knowledge in excited-state and radical chemistry and stimulating new reaction design and development., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Objectives: To date, studies have not provided definitive answers regarding whether previous immune checkpoint inhibitor (ICI) treatment alters outcomes for cancer patients with COVID-19., Methods: The OnCovid registry (NCT04393974) was searched from February 27, 2020, to January 31, 2022, for patients who received systemic anti-cancer therapy in the 4 weeks before laboratory-confirmed COVID-19 diagnosis. Propensity-score matching using country, vaccination status, primary tumor type, sex, age, comorbidity burden, tumor stage, and remission status investigated differences in predefined clinical outcomes comparing those who had or had not received ICIs., Results: Of 3523 patients screened, 137 ICI-only and 1378 non-ICI met inclusion criteria. Before matching, ICI patients were older, male, enrolled at centers in Italy, and had histories of smoking, thoracic cancers, advanced cancer stages, and active malignancies (P ≤0.02). After matching, there were 120 ICI and 322 non-ICI patients. ICI patients had no differences (odds ratio: 95% CI) in presenting COVID-19 symptoms (0.69: 0.37-1.28), receipt of COVID-specific therapy (0.88: 0.54-1.41), 14-day (0.95: 0.56-1.61), or 28-day (0.79: 0.48-1.29) mortalities. However, ICI patients required less COVID-19-related hospitalization (0.37: 0.21-0.67) and oxygen therapy (0.51: 0.31-0.83) and developed fewer complications (0.57: 0.36-0.92)., Conclusion: In this propensity-score matched analysis, previous ICI therapy did not worsen and potentially improved COVID-19 outcomes in patients with cancer., Competing Interests: Declarations of competing interest Alessio Cortellini received consulting fees from MSD, BMS, AstraZeneca, Roche; and speakers’ fees from AstraZeneca, MSD, Novartis, and Eisai. Matteo Lambertini acted as a consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, and Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work. Alessandra Gennari has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, Eisai, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: Eisai, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis, and Roche. Joan Brunet has declared consulting/advisory role for MSD and Astra Zenec, and support for attending meetings and/or travel for GSK. Josep Tabernero reports personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource (PER). Lorenza Rimassa reports receiving consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; and institutional research funding from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. David J Pinato received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, Eisai, Roche, DaVolterra, and Astra Zeneca; research funding (to institution) from MSD and BMS. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neuronal activity-dependent transcription directs molecular processes that regulate synaptic plasticity, brain circuit development, behavioral adaptation, and long-term memory. Single cell RNA-sequencing technologies (scRNAseq) are rapidly developing and allow for the interrogation of activity-dependent transcription at cellular resolution. Here, we present NEUROeSTIMator, a deep learning model that integrates transcriptomic signals to estimate neuronal activation in a way that we demonstrate is associated with Patch-seq electrophysiological features and that is robust against differences in species, cell type, and brain region. We demonstrate this method's ability to accurately detect neuronal activity in previously published studies of single cell activity-induced gene expression. Further, we applied our model in a spatial transcriptomic study to identify unique patterns of learning-induced activity across different brain regions in male mice. Altogether, our findings establish NEUROeSTIMator as a powerful and broadly applicable tool for measuring neuronal activation, whether as a critical covariate or a primary readout of interest., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: To date, limited evidence exists on the impact of COVID-19 in patients with soft tissue sarcoma (STS), nor about the impact of SARS-CoV-2 vaccines and recent chemotherapy on COVID-19 morbidity and mortality in this specific population., Methods: We described COVID-19 morbidity and mortality among patients with STS across 'Omicron' (15 December 2021-31 January 2022), 'Pre-vaccination' (27 February 2020-30 November 2020), and 'Alpha-Delta' phase (01 December 2020-14 December 2021) using OnCovid registry participants (NCT04393974). Case fatality rate at 28 days (CFR 28 ) and COVID-19 severity were also described according to the SARS-CoV-2 vaccination status, while the impact of the receipt of cytotoxic chemotherapy within 4 weeks prior to COVID-19 on clinical outcomes was assessed with Inverse Probability of Treatment Weighting (IPTW) models adjusted for possible confounders., Results: Out of 3820 patients, 97 patients with STS were included. The median age at COVID-19 diagnosis was 56 years (range: 18-92), with 65 patients (67%) aged < 65 years and most patients had a low comorbidity burden (65, 67.0%). The most frequent primary tumor sites were the abdomen (56.7%) and the gynecological tract (12.4%). In total, 36 (37.1%) patients were on cytotoxic chemotherapy within 4 weeks prior to COVID-19. The overall CFR 28 was 25.8%, with 38% oxygen therapy requirement, 34% rate of complications, and 32.3% of hospitalizations due to COVID-19. CFR 28 (29.5%, 21.4%, and 12.5%) and all indicators of COVID-19 severity demonstrated a trend toward a numerical improvement across the pandemic phases. Similarly, vaccinated patients demonstrated numerically improved CFR 28 (16.7% versus 27.7%) and COVID-19 morbidity compared with unvaccinated patients. Patients who were on chemotherapy experienced comparable CFR 28 (19.4% versus 26.0%, p = 0.4803), hospitalizations (50.0% versus 44.4%, p = 0.6883), complication rates (30.6% versus 34.0%, p = 0.7381), and oxygen therapy requirement (28.1% versus 40.0%, p = 0.2755) compared to those who were not on anticancer therapy at COVID-19, findings further confirmed by the IPTW-fitted multivariable analysis., Conclusion: In this study, we demonstrate an improvement in COVID-19 outcomes in patients with STS over time. Recent exposure to chemotherapy does not impact COVID-19 morbidity and mortality and SARS-CoV-2 vaccination confers protection against adverse outcomes from COVID-19 in this patient population., Competing Interests: AC received consulting fees from MSD, BMS, AstraZeneca, and Roche; speakers’ fee from AstraZeneca, MSD, Novartis, and Eisai. AG has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis, and Roche. JB has declared a consulting/advisory role for MSD and Astra Zeneca. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra, and Astra Zeneca; research funding (to institution) from MSD and BMS. All remaining authors have declared no conflicts of interest., (© The Author(s), 2024.)

Bisphenol A (BPA) is a widely used plastic monomer that potentially interferes with ovarian neuroendocrine, endocrine, and autocrine/paracrine factors, causing reproductive dysfunction. However, the influence of BPA on redox balance, estrogen receptor (ER) expression vis-à-vis meiotic cell cycle progression, and intra-oocyte signalling events has not been extensively investigated. The present study examines the impact of BPA on reproductive toxicity in female Labeo bata (Order Cypriniformes, Family Cyprinidae), a freshwater teleost preferred as a food fish in the Indian subcontinent. Our results show that while ovarian weight (gonadosomatic index, GSI) and dynamics of follicular growth undergo pronounced changes during the annual reproductive cycle, chronic BPA exposure at environmentally relevant concentrations promotes follicular atresia concomitant with reduced GSI during the spawning phase, the highest response being observed due to low-dose (0.1 μg/L, 0.438 nM) BPA exposure in vivo. Furthermore, BPA perturbation of ovarian StAR expression and ERα/ERβ homeostasis corroborates with elevated oxidative stress in BPA-treated ovary, FG follicles, and follicular cells. A sharp increase in ROS accumulation and nitric oxide (NO) levels in BPA-treated full-grown (FG) follicles coupled with loss of redox balance, elevated follicular cell death, and activation of apoptotic markers (caspase -8, -9, -3, Bax) indicate poor oocyte health and reproductive toxicity. Importantly, maturational steroid (MIS, 17,20β-P)-induced cyclin B-p34cdc2 activation and elevated GVBD (germinal vesicle breakdown) response require protein kinase A (PKA) inhibition and participation of Mos/MAPK- and cdc25-mediated signalling events. While the adenylate cyclase activator forskolin (FK) abrogates, priming with a PKA inhibitor (H89) promotes the meiotic G2-M1 transition, confirming the role of PKA in meiotic cell cycle progression in this species. Furthermore, the negative influence of BPA priming on 17,20β-P-induced oocyte maturation involves elevated PKAc phosphorylation (activation) and significant alteration in Mos/MAPK signalling, indicating derailed meiotic maturational competence and disrupted oocyte quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Memory consolidation involves discrete patterns of transcriptional events in the hippocampus. Despite the emergence of single-cell transcriptomic profiling techniques, mapping the transcriptomic signature across subregions of the hippocampus has remained challenging. Here, we utilized unbiased spatial sequencing to delineate transcriptome-wide gene expression changes across subregions of the dorsal hippocampus of male mice following learning. We find that each subregion of the hippocampus exhibits distinct yet overlapping transcriptomic signatures. The CA1 region exhibited increased expression of genes related to transcriptional regulation, while the DG showed upregulation of genes associated with protein folding. Importantly, our approach enabled us to define the transcriptomic signature of learning within two less-defined hippocampal subregions, CA1 stratum radiatum, and oriens. We demonstrated that CA1 subregion-specific expression of a transcription factor subfamily has a critical functional role in the consolidation of long-term memory. This work demonstrates the power of spatial molecular approaches to reveal simultaneous transcriptional events across the hippocampus during memory consolidation., (© 2023. Springer Nature Limited.)

Multicellular organisms are constantly subjected to pathogens that might be harmful. Although insects lack an adaptive immune system, they possess highly effective anti-infective mechanisms. Bacterial phagocytosis and parasite encapsulation are some forms of cellular responses. Insects often defend themselves against infections through a humoral response. This phenomenon includes the secretion of antimicrobial peptides into the hemolymph. Specific receptors for detecting infection are required for the recognition of foreign pathogens such as the proteins that recognize glucans and peptidoglycans, together referred to as PGRPs and βGRPs. Activation of these receptors leads to the stimulation of signaling pathways which further activates the genes encoding for antimicrobial peptides. Some instances of such pathways are the JAK-STAT, Imd, and Toll. The host immune response that frequently accompanies infections has, however, been circumvented by diseases, which may have assisted insects evolve their own complicated immune systems. The role of ncRNAs in insect immunology has been discussed in several notable studies and reviews. This paper examines the most recent research on the immune regulatory function of ncRNAs during insect-pathogen crosstalk, including insect- and pathogen-encoded miRNAs and lncRNAs, and provides an overview of the important insect signaling pathways and effector mechanisms activated by diverse pathogen invaders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mahanta, Bhoi, Komal, Samal, Nikhil, Paschapur, Singh, Kumar, Desai, Ahmad, Singh, Majhi, Mukherjee, Singh, Saini, Shahanaz, Srinivasa and Yele.)

A leiomyoma is a remarkably rare cause of a benign, one-side tonsillar enlargement. The diagnosis is essentially histologic and will not normally be suspected clinically. Immunohistochemistry is needed for substantiation of the morphology and confirmation. We submit this illustrative case report., Competing Interests: None

Solitary fibrous tumors (SFTs) are mesenchymal neoplasms with variable clinical behavior depending on age, tumor site, and size, and pathologic factors such as mitoses and necrosis. Imaging features on computed tomography (CT) or magnetic resonance imaging (MRI) are not specific, and the diagnosis relies on histopathology with immunohistochemistry. SFTs arising from seminal vesicles is rare and reported in only eight earlier cases. We discuss the clinical, histopathologic and positron emission tomography (PET) imaging characteristics of a 54-year-old patient with SFT of the seminal vesicle. The patient was treated with robot-assisted seminal vesiculotomy and is doing well on follow-up at two years.

Purpose: Although representing the majority of newly diagnosed cancers, patients with breast cancer appear less vulnerable to COVID-19 mortality compared with other malignancies. In the absence of patients on active cancer therapy included in vaccination trials, a contemporary real-world evaluation of outcomes during the various pandemic phases, as well as of the impact of vaccination, is needed to better inform clinical practice., Methods: We compared COVID-19 morbidity and mortality among patients with breast cancer across prevaccination (February 27, 2020-November 30, 2020), Alpha-Delta (December 1, 2020-December 14, 2021), and Omicron (December 15, 2021-January 31, 2022) phases using OnCovid registry participants (ClinicalTrials.gov identifier: NCT04393974). Twenty-eight-day case fatality rate (CFR 28 ) and COVID-19 severity were compared in unvaccinated versus double-dosed/boosted patients (vaccinated) with inverse probability of treatment weighting models adjusted for country of origin, age, number of comorbidities, tumor stage, and receipt of systemic anticancer therapy within 1 month of COVID-19 diagnosis., Results: By the data lock of February 4, 2022, the registry counted 613 eligible patients with breast cancer: 60.1% (n = 312) hormone receptor-positive, 25.2% (n = 131) human epidermal growth factor receptor 2-positive, and 14.6% (n = 76) triple-negative. The majority (61%; n = 374) had localized/locally advanced disease. Median age was 62 years (interquartile range, 51-74 years). A total of 193 patients (31.5%) presented ≥ 2 comorbidities and 69% (n = 330) were never smokers. In total, 392 (63.9%), 164 (26.8%), and 57 (9.3%) were diagnosed during the prevaccination, Alpha-Delta, and Omicron phases, respectively. Analysis of CFR 28 demonstrates comparable estimates of mortality across the three pandemic phases (13.9%, 12.2%, 5.3%, respectively; P = .182). Nevertheless, a significant improvement in outcome measures of COVID-19 severity across the three pandemic time periods was observed. Importantly, when reported separately, unvaccinated patients from the Alpha-Delta and Omicron phases achieved comparable outcomes to those from the prevaccination phase. Of 566 patients eligible for the vaccination analysis, 72 (12.7%) were fully vaccinated and 494 (87.3%) were unvaccinated. We confirmed with inverse probability of treatment weighting multivariable analysis and following a clustered robust correction for participating center that vaccinated patients achieved improved CFR 28 (odds ratio [OR], 0.19; 95% CI, 0.09 to 0.40), hospitalization (OR, 0.28; 95% CI, 0.11 to 0.69), COVID-19 complications (OR, 0.16; 95% CI, 0.06 to 0.45), and reduced requirement of COVID-19-specific therapy (OR, 0.24; 95% CI, 0.09 to 0.63) and oxygen therapy (OR, 0.24; 95% CI, 0.09 to 0.67) compared with unvaccinated controls., Conclusion: Our findings highlight a consistent reduction of COVID-19 severity in patients with breast cancer during the Omicron outbreak in Europe. We also demonstrate that even in this population, a complete severe acute respiratory syndrome coronavirus 2 vaccination course is a strong determinant of improved morbidity and mortality from COVID-19.

In this work, the possible mechanisms for the reactions of CO 2 with various positional isomers of methylpiperidines (MPs) (N-MP, 2-MP, 3-MP, and 4-MP) including the effect of aqueous solvation have been explored using quantum chemical methods. The major pathways investigated for CO 2 capture in aqueous amines are carbamate formation, its hydrolysis, and the bicarbonate formation (CO 2 + H 2 O + MP) reaction. The calculations indicate that an axial orientation for the methyl group and an equatorial for the COO - group could be energetically ideal in the carbamate product of MPs. The proton abstraction step in the carbamate pathway is almost barrierless for the zwitterion-amine route, while a much higher energy barrier is observed for the zwitterion-H 2 O route. During carbamate hydrolysis, the addition of even two explicit water molecules does not exhibit any notable effect on the already high energy barrier associated with this reaction. This indicates that bicarbonate formation is less likely to occur via carbamate hydrolysis. The calculations suggest that, although the carbamate pathway is kinetically favored, the MP carbamate could still be a minor product, especially for sterically hindered conformations, and the bicarbonate pathway should be predominant in aqueous MPs.

Background: COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2., Methods: OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974., Findings: At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [50·7%] of 1902 patients with sex data were female and 938 [49·3%] were male). Overall, 317 (16·6%; 95% CI 14·8-18·5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the pre-vaccination phase (191 [19·1%; 95% CI 16·4-22·0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16·8%; 13·8-20·3] of 653 patients, p=0·24), but significantly lower in the omicron phase (16 [6·2%; 3·5-10·2] of 256 patients, p<0·0001). In the alpha-delta phase, 84 (18·3%; 95% CI 14·6-22·7) of 458 unvaccinated patients and three (9·4%; 1·9-27·3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7·4%; 95% CI 3·5-13·5] of 136 boosted patients, 18 [9·8%; 5·8-15·5] of 183 patients who had two vaccine doses vs 277 [18·5%; 16·5-20·9] of 1489 unvaccinated patients, p=0·0001), respiratory sequelae (six [4·4%; 1·6-9·6], 11 [6·0%; 3·0-10·7] vs 148 [9·9%; 8·4-11·6], p=0·030), and prolonged fatigue (three [2·2%; 0·1-6·4], ten [5·4%; 2·6-10·0] vs 115 [7·7%; 6·3-9·3], p=0·037)., Interpretation: Unvaccinated patients with cancer remain highly vulnerable to COVID-19 sequelae irrespective of viral strain. This study confirms the role of previous SARS-CoV-2 immunisation as an effective measure to protect patients from COVID-19 sequelae, disruption of therapy, and ensuing mortality., Funding: UK National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust., Competing Interests: Declaration of interests AC has received consulting fees from MSD, Bristol Myers Squibb, AstraZeneca, and Roche, and speakers' fee from AstraZeneca, MSD, Novartis, and Eisai. ML acted as a consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, and Seagen, and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen, and Sandoz outside the submitted work. AG declares consulting or advisory roles for Roche, MSD, Eli Lilly, Pierre Fabre, Eisai, and Daichii Sankyo; speakers' fees for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, AstraZeneca, Celgene, and Daichii Sankyo; and research funds from Eisai, Eli Lilly, and Roche. CM-V has received travel grants and other honoraria from Bristol Myers Squibb, MSD, Novartis, and Roche. JB has declared consulting or advisory roles for MSD and AstraZeneca, and support for attending meetings and travel from GlaxoSmithKline. OM reports personal fees from Grupo Pacifico, Kyowa Kirin, Roche, and ROVI, and travel support from Almirall, Kyowa Kirin, and Sanofi. JT reports personal financial interest in the form of scientific consultancy roles for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; stocks in Oniria Therapeutics; and educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource. LRi reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, and Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi, and Servier; travel expenses from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks. AD'A has received educational support for congress attendance and consultancy fees from Roche. DJP has received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, and the Falk Foundation; travel expenses from Bristol Myers Squibb and Bayer Healthcare; consulting fees for Mina Therapeutics, Eisai, Roche, DaVolterra, and Astra Zeneca; and institutional research funding from MSD and Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

C -Glycosides are important carbohydrate mimetics found in natural products, bioactive compounds, and marketed drugs. However, stereoselective preparation of this class of glycomimetics remains a significant challenge in organic synthesis. Herein, we report an excited-state palladium-catalyzed α-selective C -ketonylation strategy using readily available 1-bromosugars to access a range of C -glycosides. The reaction features excellent α -selectivity and mild conditions that tolerate a wide range of functional groups and complex molecular architectures. The resulting α-ketonylsugars can serve as versatile precursors for their β-isomers and other C -glycosides. Preliminary experimental and computational studies of the mechanism suggest a radical pathway involving the formation of palladoradical and glycosyl radical that undergoes polarity-mismatched coupling with silyl enol ether, affording the desired α-ketonylsugars. Insight into the reactivity and mechanism will inspire new reaction development and provide straightforward access to both α- and β- C -glycosides, greatly expanding the chemical and patent spaces of glycomimetics., Competing Interests: Conflict of Interest There is no conflict of interest to report.

Synthesis of α,β-unsaturated-γ-lactams continue to attract attention due to the importance of this structural motif in organic chemistry. Herein, we report the development of a visible-light-induced excited-state copper-catalyzed [4 + 1] annulation reaction for the preparation of a wide range of γ-H, -OH, and -OR-substituted α,β-unsaturated-γ-lactams using acrylamides as the 4-atom unit and aroyl chlorides as the 1-atom unit. This modular synthetic protocol features mild reaction conditions, broad substrate scope, and high functional group tolerance. The reaction is amenable to late-stage diversification of complex molecular architectures, including derivatives of marketed drugs. The products of the reaction can serve as versatile building blocks for further derivatization. Preliminary mechanistic studies suggest an inner-sphere catalytic cycle involving photoexcitation of the Cu(BINAP) catalyst, single-electron transfer, and capture of radical intermediates by copper species, followed by reductive elimination or protonation to give the desired γ-functionalized α,β-unsaturated-γ-lactams.

Background: As management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer., Methods: In a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19., Findings: The study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR 30 ) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR 30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p<0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19 complication rate (11.9% vs 34.6%, p=0.0040), with a reduced need for COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse probability of treatment weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted OR, aOR 0.08, 95% CI 0.01 to 0.69).Overall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13-48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR 30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 10 9  cells/L, p=0.0098)., Conclusion: Anti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2., Competing Interests: Competing interests: KJH declares research funding from AstraZeneca, Boehringer-Ingelheim, MSD, Replimune and advisory board fees/honoraria from Arch Oncology, AstraZeneca, BMS, Boehringer-Ingelheim, Codiak Biosciences, Inzen Therapeutics, Merck-Serono, MSD, Pfizer, Replimune. DA reports consultation/advisory role for AstraZeneca, Bristol Myers Squibb, Merck Sharp reports speaker’s engagement from AstraZeneca, Bristol Myers Squibb, Merck Sharp reports serving as local PI for Bristol Myers Squibb, Pierre Fabre Pharma and coordinating PI for OncoLytics; reports grant funding from AbbVie; reports being/been DSMB chair of Sanofi (Genzyme); reports being/been a steering committee member of Roche. Olivier Michielin reports personal fees from Bristol-Myers Squibb, MSD, Novartis, Roche, Amgen, NeraCare, outside the submitted work. JR received speaker or advisory fees from Roche, Astra Zeneca, Merck, Ferrer, Persan Farma, Teva Pharma, Leo Pharma, Fresenius kabi, MSD, BMS. Travel expenses support from BMS, MSD, RocheUrania Dafni reports honorarium as Member of the Tumor Agnostic Evidence Generation Working Group of Roche, outside the submitted work. GP reports grants from Amgen, Lilly; grants, personal fees and nonfinancial support from Merck; grants and non-financial support from AstraZeneca; grants and personal fees from Roche, Bristol Myers Squibb, MSD, Novartis, outside the submitted work. Solange Peters reports consultation/advisory role for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol- Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody; talk in a company’s organized public event for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda; receipt of grants/research supports from being a (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. Emanuela Rromano reports investigator-initiated trial (funds paid to the institution) supported by Astra-Zeneca, BMS; serves on the consultancy/advisory board for Astra-Zeneca, Merck, Roche, Pierre Fabre. ML acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work.Alessandra Gennari has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis and Roche. Joan Brunet has declared consulting/advisory role for MSD and Astra Zeneca. Aleix Prat has declared personal honoraria from Pfizer, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations, and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb. Mark Bower received speakers’ fee from EISAI pharma, Gilead Sciences, Merck and ViiV. JT reports consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; speaker’s fees from Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and institutional research support from Amgen, Array Biopharma, AstraZeneca Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp and has had leadership roles in the European AIDS Clinical Society, UNAIDS, WHO, and The European Hematology Association/ European Society of Medical Oncology. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS. AC received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers’ fee from AstraZeneca, MSD, Novartis and Eisai. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Arginine deprivation has gained increasing traction as a novel and safe antimetabolite strategy for the treatment of several hard-to-treat cancers characterised by a critical dependency on arginine. Small cell lung cancer (SCLC) displays marked arginine auxotrophy due to inactivation of the rate-limiting enzyme argininosuccinate synthetase 1 (ASS1), and as a consequence may be targeted with pegylated arginine deiminase or ADI-PEG20 (pegargiminase) and human recombinant pegylated arginases (rhArgPEG, BCT-100 and pegzilarginase). Although preclinical studies reveal that ASS1-deficient SCLC cell lines are highly sensitive to arginine-degrading enzymes, there is a clear disconnect with the clinic with minimal activity seen to date that may be due in part to patient selection. Recent studies have explored resistance mechanisms to arginine depletion focusing on tumor adaptation, such as ASS1 re-expression and autophagy, stromal cell inputs including macrophage infiltration, and tumor heterogeneity. Here, we explore how arginine deprivation may be combined strategically with novel agents to improve SCLC management by modulating resistance and increasing the efficacy of existing agents. Moreover, recent work has identified an intriguing role for targeting arginine in combination with PD-1/PD-L1 immune checkpoint inhibitors and clinical trials are in progress. Thus, future studies of arginine-depleting agents with chemoimmunotherapy, the current standard of care for SCLC, may lead to enhanced disease control and much needed improvements in long-term survival for patients., Competing Interests: Dr Szlosarek reports grant research support from Polaris Group. The remaining authors report no other conflicts of interest., (© 2022 Carpentier et al.)

Histone deacetylases (HDACs) are enzymes that play a role in chromatin remodeling and epigenetics. They belong to a specific category of enzymes that eliminate the acetyl part of the histones' -N-acetyl lysine, causing the histones to be wrapped compactly around DNA. Numerous biological processes rely on HDACs, including cell proliferation and differentiation, angiogenesis, metastasis, gene regulation, and transcription. Epigenetic changes, specifically increased expression and activity of HDACs, are commonly detected in cancer. As a result, HDACi could be used to develop anticancer drugs. Although preclinical outcomes with HDACs as monotherapy have been promising clinical trials have had mixed results and limited success. In both preclinical and clinical trials, however, combination therapy with different anticancer medicines has proved to have synergistic effects. Furthermore, these combinations improved efficacy, decreased tumor resistance to therapy, and decreased toxicity. In the present review, the detailed modes of action, classification of HDACs, and their correlation with different cancers like prostate, breast, and ovarian cancer were discussed. Further, the different cell signaling pathways and the structure-activity relationship and pharmaco-toxicological properties of the HDACi, and their synergistic effects with other anticancer drugs observed in recent preclinical and clinical studies used in combination therapy were discussed for prostate, breast, and ovarian cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pramanik, Kumar Halder, Mukherjee, Kumar, Dey and R.)

Background: Fifteen percent of patients with cancer experience symptomatic sequelae, which impair post-COVID-19 outcomes. In this study, we investigated whether a proinflammatory status is associated with the development of COVID-19 sequelae., Methods: OnCovid recruited 2795 consecutive patients who were diagnosed with Severe Acute Respiratory Syndrome Coronavirus 2 infection between February 27, 2020, and February 14, 2021. This analysis focused on COVID-19 survivors who underwent a clinical reassessment after the exclusion of patients with hematological malignancies. We evaluated the association of inflammatory markers collected at COVID-19 diagnosis with sequelae, considering the impact of previous systemic anticancer therapy. All statistical tests were 2-sided., Results: Of 1339 eligible patients, 203 experienced at least 1 sequela (15.2%). Median baseline C-reactive protein (CRP; 77.5 mg/L vs 22.2 mg/L, P < .001), lactate dehydrogenase (310 UI/L vs 274 UI/L, P = .03), and the neutrophil to lymphocyte ratio (NLR; 6.0 vs 4.3, P = .001) were statistically significantly higher among patients who experienced sequelae, whereas no association was reported for the platelet to lymphocyte ratio and the OnCovid Inflammatory Score, which includes albumin and lymphocytes. The widest area under the ROC curve (AUC) was reported for baseline CRP (AUC = 0.66, 95% confidence interval [CI]: 0.63 to 0.69), followed by the NLR (AUC = 0.58, 95% CI: 0.55 to 0.61) and lactate dehydrogenase (AUC = 0.57, 95% CI: 0.52 to 0.61). Using a fixed categorical multivariable analysis, high CRP (odds ratio [OR] = 2.56, 95% CI: 1.67 to 3.91) and NLR (OR = 1.45, 95% CI: 1.01 to 2.10) were confirmed to be statistically significantly associated with an increased risk of sequelae. Exposure to chemotherapy was associated with a decreased risk of sequelae (OR = 0.57, 95% CI: 0.36 to 0.91), whereas no associations with immune checkpoint inhibitors, endocrine therapy, and other types of systemic anticancer therapy were found., Conclusions: Although the association between inflammatory status, recent chemotherapy and sequelae warrants further investigation, our findings suggest that a deranged proinflammatory reaction at COVID-19 diagnosis may predict for sequelae development., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe., Methods: In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing., Findings: As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57-77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19-0·61) and 28 days (0·34 [0·16-0·79]), complications due to COVID-19 (0·26 [0·17-0·46]), and hospitalisation due to COVID-19 (0·17 [0·09-0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15-0·34]) and oxygen therapy (0·24 [0·14-0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase., Interpretation: Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19., Funding: National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust., Competing Interests: Declaration of interests DJP has received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, and Falk Foundation; travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, Eisai, Roche, DaVolterra, and Astra Zeneca; and research funding (to their institution) from MSD and BMS. MLa has acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen, and Gilead; and has received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen, Libbs, Knight, and Sandoz. FM has received consulting fees from Eli Lilly, MSD, Takeda, and Roche; and travel support from Sanofi. SP reported that their spouse is employed by AstraZeneca. ASa has received consulting fees from Arqule, Sanofi, and Incyte; speaker's fees from Takeda, BMS, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Eli Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD; and participation on data monitoring committees for BMS, Servier, Gilead, Pfizer, Eisai, Bayer, and MSD. FG has received consulting fees from Novocure, BMS, PharmaMar, and Novartis; speaker's fees from Novocure; travel support from MSD, Novocure, BMS, Boehringer Ingelheim, PharmaMar, Novartis, and Pierre Fabre; and participation on a data safety monitoring board for MSD, BMS, PharmaMar and Novartis. JH has a leadership role with Blood Cancer UK. NS-G has received speakers' fees from Amgen. GG has received consulting fees or had an advisory role for Janssen, AbbVie, AstraZeneca, Roche, Incyte, and BeiGene, and reported speaker fees from Janssen and AbbVie. LRi has received consulting fees from Taiho Oncology, Servier, Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, and Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, and Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks. JT reports consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; speaker's fees from Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and institutional research support from Amgen, Array Biopharma, AstraZeneca Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA, Spanish Association Against Cancer Scientific Foundation, and Cancer Research UK. MB has received speakers' fee from Eisai pharma, Gilead Sciences, Merck, and ViiV; and has had leadership roles in the European AIDS Clinical Society, UNAIDS, WHO, and The European Hematology Association/ European Society of Medical Oncology. AC has received consulting fees from MSD, BMS, AstraZeneca, and Roche; and speakers' fee from AstraZeneca, MSD, Novartis, and Eisai. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: A significant proportion of patients with cancer who recover from Coronavirus Disease 2019 (COVID-19) may experience COVID-19 sequelae in the early post-infection phase, which negatively affect their continuity of care and oncological outcome. The long-term prevalence and clinical impact of the post-COVID-19 syndrome in patients with cancer are largely unknown., Methods: In this study, we describe the time course of COVID-19 sequelae in patients with non-advanced cancers enrolled in the OnCovid registry., Results: Overall, 186 patients were included, with a median observation period of 9.9 months (95%CI:8,8-11.3) post-COVID-19 resolution. After a median interval of 2.3 months post-COVID-19 (interquartile range: 1.4-3.7), 31 patients (16.6%) reported ≥1 sequelae, including respiratory complications (14, 7.6%), fatigue (13, 7.1%), neuro-cognitive sequelae (7, 3.8%). The vast majority of the patients were not vaccinated prior to COVID-19. COVID-19-related sequelae persisted in 9.8% and 8% of patients 6 and 12 months after COVID-19 resolution. Persistence of sequelae at first oncological follow-up was associated with history of complicated COVID-19 (45.2% vs 24.8%, p = 0.0223), irrespective of oncological features at COVID-19 diagnosis., Conclusion: This study confirms for the first time that, in a largely unvaccinated population, post-COVID-19 syndrome can affect a significant proportion of patients with non-advanced cancer who recovered from the acute illness. COVID-19 sequelae may persist up to 12 months in some patients, highlighting the need for dedicated prevention and supportive strategies., Competing Interests: Conflict of interest statement Alessio Cortellini received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers’ fee from AstraZeneca, MSD, Novartis and Eisai. David J Pinato received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS. Aleix Prat has declared personal honoraria from Pfizer, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb. Matteo Lambertini acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work. Thomas Newsom-Davis has declared consulting/advisory role for Amgen, Bayer, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Roche, and Takeda; speakers fees from AstraZeneca, MSD, Roche, Takeda and travel, accommodations and expenses paid by AstraZenca, BMS, Boehringer Ingelheim, Lilly, MSD, Otsuka, Roche, and Takeda. Joan Brunet has declared consulting/advisory role for MSD and Astra Zeneca. Alessandra Gennari has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis and Roche. Gianluca Gaidano has declared consulting/advisory role for Janssen, Abbvie, Astra-Zeneca and BeiGene, and speaker fees from Janssen and Abbvie. Lorenza Rimassa received consulting fees from Servier, Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

C2-ketonyl-2-deoxysugars, sugars with the C2-hydroxyl group replaced by a ketone side chain, are important carbohydrate mimetics in glycobiology and drug discovery studies; however, their preparation remains a vital challenge in organic synthesis. Here we report the first direct strategy to synthesize this class of glycomimetics from readily available 1-bromosugars and silyl enol ethers via an excited-state palladium-catalyzed 1,2-spin-center shift (SCS) process. This step-economic reaction features broad substrate scope, has a high functional group tolerance, and can be used in late-stage functionalization of natural product- and drug-glycoconjugates. Preliminary experimental and computational mechanistic studies suggested a non-chain radical mechanism involving photoexcited palladium species, a 1,2-SCS process, and a radical Mizoroki-Heck reaction., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Based on in-depth interviews with 24 middle-class Indian child participants, this is the first exploratory qualitative study, in India, to demonstrate the ways in which children as reflexive social actors re-negotiated everyday schedules, drew on classed resources at their disposal and made sense of the impact of the pandemic on their educational pathways and future aspirations. These narratives offer a unique lens on the politics of middle-classness and its constitutive relation to constructions of normative childhoods in contemporary India. Study findings contribute to the sociology of Indian childhood and more generally help enrich our understanding of southern childhoods and the reproduction of inequalities in contemporary India., (© 2022 The Authors. Children & Society published by National Children's Bureau and John Wiley & Sons Ltd.)

The mechanisms underlying memory loss associated with Alzheimer's disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of genes encoding chaperones that localize to the endoplasmic reticulum (ER). These chaperones fold and traffic plasticity-related proteins to the cell surface during long-lasting forms of synaptic plasticity and memory. Dysregulation of Nr4a transcription factors and ER chaperones is linked to ADRD, and overexpressing Nr4a1 or the chaperone Hspa5 ameliorates long-term memory deficits in a tau-based mouse model of ADRD, pointing toward innovative therapeutic approaches for treating memory loss. Our findings establish a unique molecular concept underlying long-term memory and provide insights into the mechanistic basis of cognitive deficits in dementia.

Excited-state palladium catalysis has emerged as a promising strategy for developing novel and valuable reactions. Herein, we report the first excited-state Pd-catalyzed 1,2-radical migratory Mizoroki-Heck reaction that enables C2-alkenylation of carbohydrates using readily available 1-bromosugars and alkenes. The reaction tolerates a wide variety of functional groups and complex molecular architectures, including derivatives of natural products and marketed drugs. Preliminary mechanistic studies and DFT calculations suggest the involvement of visible-light-induced photoexcitation of Pd species, 1,2-spin-centered-shift (SCS) process, and Heck-type cross-coupling reaction. The reaction expands the reactivity profile of excited-state Pd catalysis and provides a streamlined protocol for the preparation of a wide variety of C2-alkenylated carbohydrate mimetics to aid the discovery and development of new therapeutics, agrochemicals, and materials.

Objective: To describe thiamine-prescribing patterns and to study the association of thiamine supplementation with clinical outcomes in hospitalized patients with altered mental status (AMS)., Methods: We conducted a retrospective cohort study of all adult hospitalized patients with AMS with index admission in calendar year 2017. We studied the association of a) supplemental thiamine and b) timing of thiamine relative to glucose, with hospital outcomes - length of stay (LOS), 90-day readmission rates, and mortality rates - using linear, logistic, and extended Cox models, respectively. We also modeled association of supplemental thiamine on time to resolution of AMS using extended Cox models in patients admitted with AMS., Results: Of 985 patients, 178 (18%) received thiamine, including 123 (12.5%) who received thiamine before, with, or without glucose (thiamine first). We identified 365 (37%) patients who received intravenous glucose before or without thiamine (glucose first). We found that patients who received glucose first had longer LOS and higher rate of in-hospital deaths compared to those who did not. Patients who received thiamine supplementation had longer LOS compared to those who did not. There were no significant differences in other hospital outcomes or AMS resolution by discharge compared to their respective reference groups., Conclusion: Although thiamine supplementation was not associated with better hospital or cognitive outcomes, we do not have enough evidence to suggest a change in current practice. Thiamine must be administered prior to glucose in hospitalized patients with AMS.

Nonylphenol (NP), an environmentally persistent and toxic endocrine-disrupting chemical with estrogenic properties, has severe implications on humans and wildlife. Accumulating evidence demonstrates the toxic response of NP on the developmental process, nervous system, and reproductive parameters. Although NP exposure has been implicated in chronic liver injury, the underlying events associated with hepatic pathophysiology remain less investigated. Using male zebrafish (Danio rerio) as the model, the present study investigates the impact of environmentally relevant concentrations of NP (50 and 100 μg/L, 21 days) on hepatic redox homeostasis vis-à-vis cellular energy sensors, inflammatory response, and cell death involving a mechanistic insight into estrogen receptor (ER) modulation. Our results demonstrate that congruent with significant alteration in transcript abundance of antioxidant enzymes (SOD1, SOD2, Catalase, GPx1a, GSTα1), chronic exposure to NP promotes ROS synthesis, more specifically superoxide anions and H 2 O 2 levels, and lipid peroxidation potentially through elevated NOX4 expression. Importantly, NP perturbation of markers associated with fatty acid biosynthesis (srebf1/fasn) and cellular energy-sensing network (sirt1/ampkα/pgc1α) indicates dysregulated energy homeostasis, metabolic disruption, and macrovesicular steatosis, albeit with differential sensitivity at the dose level tested. Besides, elevated p38-MAPK phosphorylation (activation) together with loss of ER homeostasis at both mRNA (esr1, esr2a, esr2b) and protein (ERα, ERβ) levels suggest that NP modulation of ER abundance may have a significant influence on hepatic events. Elevated expression of inflammatory markers (TLR4, p-NF-κB, TNF-α, IL-6, IL-1β, and NOS2) and pro-apoptotic and necrotic regulators, e.g., Bax, caspase- 8, -9 and cleaved PARP1 (50 kDa), indicate chronic inflammation and hepatotoxicity in NP-exposed males. Collectively, elevated oxidative stress, metabolic dysregulation and immune modulation may lead to chronic liver injury in organisms exposed to metabolic disrupting chemicals., (Copyright © 2021 Elsevier B.V. All rights reserved.)