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Silacycles have exhibited significant potential for application in the fields of medicinal chemistry, agrochemistry, and materials science. Accordingly, the development of effective methods for synthesizing these compounds has attracted increasing attention. Here, we report an efficient Cu-catalyzed enantioselective hydrosilylation of arylmethylenecyclopropanes with hydrosilanes, that allows the rapid assembly of various enantioenriched carbon- and silicon-stereogenic silacyclopentanes in good yields with excellent enantioselectivities and diastereoselectivities under mild conditions. Further stereospecific transformation of the Si-H bond on the chiral silicon center expands the diversity of these C- and Si-stereogenic silacyclopentanes., (© 2024 Wiley-VCH GmbH.)

A highly efficient rhodium-catalyzed asymmetric hydrosilylation of aldehydes, ketones, and α,β-unsaturated ketones with dihydrosilanes is developed, that allows the rapid assembly of a variety of Si-stereogenic alkoxysilanes and silyl enol ethers in good yields and enantioselectivities under mild conditions. The applicability of this methodology was demonstrated by a series of stereospecific transformations to construct diverse Si-stereogenic derivatives.

Despite effective antiretroviral therapy reducing HIV-1 viral loads to undetectable levels, the presence of latently infected CD4 + T cells poses a major barrier to HIV-1 cure. N 6 -methyladenosine (m 6 A) modification of viral and cellular RNA has a functional role in regulating HIV-1 infection. m 6 A modification of HIV-1 RNA can affect its stability, translation, and splicing in cells and suppresses type-I interferon induction in macrophages. However, the function of m 6 A modification in regulating HIV-1 latency reactivation remains unknown. We used the Jurkat T cell line-derived HIV-1 latency model (J-Lat cells) to investigate changes in m 6 A levels of cellular RNA in response to latency reversal. We observed a significant increase in m 6 A levels of total cellular RNA upon reactivation of latent HIV-1 in J-Lat cells. This increase in m 6 A levels was transient and returned to steady-state levels despite continued high levels of viral gene expression in reactivated cells compared to control cells. Upregulation of m 6 A levels occurred without significant changes in the protein expression of m 6 A writers or erasers that add or remove m 6 A, respectively. Knockdown of m 6 A writers in J-Lat cells significantly reduced HIV-1 reactivation. Treatment with an m 6 A writer inhibitor reduced cellular RNA m 6 A levels, along with a reduction in HIV-1 reactivation. Furthermore, using m 6 A-specific sequencing, we identified cellular RNAs that are differentially m 6 A-modified during HIV-1 reactivation in J-Lat cells. Knockdown of identified m 6 A-modified RNA validates these results with an established primary CD4 + T cell model of HIV-1 latency. These results show the importance of m 6 A RNA modification in HIV-1 latency reversal., Importance: RNA m 6 A modification is important for regulating gene expression and innate immune responses to HIV-1 infection. However, the functional significance of m 6 A modification during HIV-1 latency reactivation is unknown. To address this important question, in this study, we used established cellular models of HIV-1 latency, m 6 A-specific sequencing at single-base resolution, and functional assays. We demonstrate that HIV-1 latency reversal leads to increased levels of cellular m 6 A modification, correlates with cellular m 6 A levels, and is dependent on the catalytic activity of the m 6 A methyltransferase enzyme. We also identified cellular genes that are differentially m 6 A-modified during HIV-1 reactivation, as well as the sites of m 6 A within HIV-1 RNA. Our novel findings point toward a significant role for m 6 A modification in HIV-1 latency reversal., Competing Interests: Chuan He is a scientific founder, a member of the scientific advisory board, and an equity holder of Aferna Bio, Inc., and Ellis Bio Inc., a scientific cofounder and equity holder of Accent Therapeutics, Inc., and a member of the scientific advisory board of Rona Therapeutics and Element Biosciences.

Background: The aim of this prospective randomized clinical study was to compare the clinical and second-look arthroscopic outcomes of early weight-bearing and delayed weight-bearing rehabilitation protocols following anterior cruciate ligament (ACL) reconstruction with hamstring tendons., Methods: This prospective study involved 90 patients who underwent ACL reconstruction with hamstring tendons. The patients were randomly assigned to either perform weight-bearing exercises at three weeks postoperatively (group A) or at one week postoperatively (group B). Evaluation of the patients was conducted at 3, 6, and 12 months postoperatively, focusing on knee range of motion, thigh circumference, and knee function assessed using the International Knee Documentation Committee (IKDC) form and Lysholm knee score. Graft evaluation was performed based on tension, tear, and synovial coverage via second-look arthroscopy at least one year after reconstruction., Results: Group B exhibited significantly greater knee extension and flexion angles at 3 and 6 months compared to group A. IKDC and Lysholm scores were significantly higher in group B at 3 and 6 months. Additionally, the difference in thigh circumference between groups A and B was smaller at all evaluation periods, indicating less muscle atrophy in group B. Furthermore, there was no significant difference in synovial coverage, graft tear, or tension between the two groups based on second-look arthroscopy findings., Conclusions: This study demonstrates that an early weight-bearing protocol leads to faster recovery of knee joint function and muscle strength, facilitating a quicker return to sports activities. Additionally, there was no significant difference in graft morphology observed at second-look arthroscopy between the two groups at one year postoperative. Therefore, clinicians are encouraged to develop suitable early weight-bearing rehabilitation protocols for patients who have undergone ACL surgery.

The inherent toxicity and persistence of emerging contaminants such as antibiotics and endocrine disruptors pose substantial threats to the environment. Advanced oxidation processes (AOPs) employed for oxidative degradation could yield toxic oxidation by-products (OBPs), including organic acids and aromatic hydrocarbons. Despite their typically low concentrations, OBPs require scrutiny owing to their potential health risks. Although effective assessment methodologies are available, a comprehensive review focusing on the ecological and environmental effects of these pollutants is lacking. This study offers a succinct overview of existing ecotoxicological exposure assessments for emerging organic pollutants. Further, it encapsulates principal dose-response assessment techniques and provides a comparative analysis of several methods. The straightforward assessment factor method evaluates risk based on exposure and species sensitivity and is suitable for preliminary assessments of single pollutants; Species Sensitivity Distribution (SSD) compares species sensitivities to OBPs, emphasizing the importance of species-specific toxicological responses; microcosm and mesocosm methods simulate and predict the effects of OBPs on aquatic life by considering environmental diversity and biological community structures and are ideal for assessing the toxicity of multiple OBPs; the ecological risk analysis model employs mathematical and probabilistic approaches to comprehensively and accurately assess exposures and effects, accounting for the complexities and uncertainties inherent in ecotoxicological evaluations. Different risk characterization techniques are outlined in this study, including the risk quotient (RQ), which is ideal for quantifying and comparing risks; probabilistic ecological risk assessment (PERA), suitable for managing significant uncertainty; and the Environmental Pollution Index (EPI), the preferred method for quantitative assessment of OBP pollution levels. The merits and limitations of each of these quantitative assessment tools are evaluated, providing a comprehensive view of their applications in risk analysis. In addition, pressing contemporary challenges are identified and trajectories and pivotal issues suggested for future research., 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 B.V. All rights reserved.)

Radical-based advanced oxidation processes (AOPs) are among the most effective technologies employed to destroy organic pollutants. Compared to common inorganic radicals, such as • OH, O 2 •- , and SO 4 •- , organic radicals are widespread, and more selective, but are easily overlooked. Furthermore, a systematic understanding of the generation and contributions of organic radicals remains lacking. In this review, we systematically summarize the properties, possible generation pathways, detection methods, and contributions of organic radicals in AOPs. Notably, exploring organic radicals in AOPs is challenging due to (1) limited detection methods for generated organic radicals; (2) controversial organic radical-mediated reaction mechanisms; and (3) rapid transformation of organic radicals as reaction intermediates. In addition to their characteristics and reactivity, we examine potential scenarios of organic radical generation in AOPs, including during the peroxide activation process, in water matrices or with coexisting organic pollutants, and due to the addition of quenching agents. Subsequently, we summarize various methods for organic radical detection as reported previously, such as electron paramagnetic resonance spectroscopy (EPR), 31 P nuclear magnetic resonance spectroscopy ( 31 P NMR), liquid/gas chromatography-mass spectroscopy (GC/LC-MS), and fluorescence probes. Finally, we review the contributions of organic radicals to decontamination processes and provide recommendations for future research.

As a crucial endogenous reactive oxygen species, hypochlorous acid (HClO) plays an indispensable role in numerous physiological and pathological processes. Additionally, it serves as a biomarker closely associated with inflammation and liver injury. The utilization of near-infrared fluorescence probes has surged in recent years for live biological imaging, owing to their minimal tissue damage and potent tissue penetration capabilities. In this work, a novel near-infrared fluorescence probe MB-HPD was synthesized to sensitively detect HClO. Probe MB-HPD exhibits remarkable selectivity, high sensitivity (14.3 nM), and rapid response towards HClO (20 s). Probe MB-HPD has demonstrated successful application in the imaging of HClO within cells and zebrafish. Remarkably, it has proven to be effective for detecting HClO within environmental samples, as well as imaging HClO in mice models of arthritis and APAP-induced liver injury. These findings indicate the broad applicability of probe MB-HPD, offering a promising avenue for designing highly selective near-infrared fluorescence probes suitable for real-time HClO monitoring., 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 B.V. All rights reserved.)

Enhancing the effectiveness of utilizing circulating cell-free DNA (cfDNA) for disease screening remains a challenge, necessitating improved sensitivity, specificity, cost-efficiency, and patient adherence. We present here LAMP-MS, an innovative technology that integrates linear amplification with single-base quantitative nucleic acid mass spectrometry on silicon chips. This approach overcomes several limitations in utilizing cfDNA 5-methylcytosine (5 mC) status for colorectal cancer (CRC) screening. LAMP-MS enables unbiased amplification of as little as 1 ng of cfDNA, site-specifically quantify methylation levels of multiple 5 mC sites, thereby facilitating cost-effective, high-resolution quantitative detection of cfDNA methylation markers. We have validated the accuracy of DNA methylation determination using DNA probes and cfDNA from patient plasma samples, confirmed by mass spectrometric peak areas. Additionally, we have further shown this Mass Array technology could be expanded to also quantify RNA m 6 A modification sites. Combining the ability to work with ultra-low input materials and a visually interpretable output, LAMP-MS stands out as a promising method for real-world applications in clinics and laboratories for nucleic acid methylation detection and quantification., (© 2024 Wiley-VCH GmbH.)

N 6 -methyladenosine (m 6 A) is the most abundant chemical modification in mRNA and plays important roles in human and mouse embryonic stem cell pluripotency, maintenance, and differentiation. We have recently reported that m 6 A is involved in the postnatal control of β-cell function in physiological states and in type 1 and 2 diabetes. However, the precise mechanisms by which m 6 A acts to regulate the development of human and mouse pancreas are unexplored. Here, we show that the m 6 A landscape is dynamic during human pancreas development, and that METTL14, one of the m 6 A writer complex proteins, is essential for the early differentiation of both human and mouse pancreatic cells., Competing Interests: Disclosure and competing interests statement SK is an employee of Boehringer Ingelheim Pharmaceuticals, Inc. RNK is on the Scientific Advisory Board of Novo Nordisk, Biomea and Inversago Therapeutics. CH is a scientific founder, a member of the scientific advisory board and equity holder of Aferna Bio, Inc. and AccuaDX Inc., a scientific co-founder and equity holder of Accent Therapeutics, Inc., and a member of the scientific advisory board of Rona Therapeutics. RIG is a co-founder, scientific advisory board member, and equity holder of Redona Therapeutics. The Gregory lab receives or has received research funding from Sanofi, Astellas, and Ono. The authors declare no competing interests., (© 2024. The Author(s).)

Biothiols, characterized by their unique sulfhydryl (-SH) groups, possess excellent antioxidant properties, effectively neutralizing the damage to cellular structures caused by reactive oxygen species (ROS) in living organisms. Additionally, lysosomes play a crucial role in decomposing damaged biomolecules through the action of their internal enzymes, regulating the cellular redox state, and mitigating oxidative stress. To facilitate rapid monitoring of intracellular biothiols, particularly within lysosomes, we constructed a lysosome-targeted biothiol fluorescent probe, PHL-DNP, in this study. PHL-DNP exhibited excellent photophysical properties in an aqueous test system, including strong fluorescence enhancement response, excellent selectivity, and low detection limits (Cys 16.5 nM, Hcy 16.8 nM, GSH 21.3 nM, Cap 26.6 nM). These attributes enabled easy and efficient qualification of Cys on test strips and accurate determination of the effective content of captopril tablets. Notably, PHL-DNP demonstrated low cytotoxicity and precise lysosomal targeting. Through bioimaging, PHL-DNP not only monitored changes in biothiol levels under oxidative stress but also assessed biothiols in complex biological systems such as live HeLa cells, zebrafish, tumor tissue sections, and radish roots. This provides a promising tool for quantitative analysis of biothiols, disease marker detection, and drug testing., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

How the anion ligands of manganese precursors affect the catalytic activity of amorphous manganese oxides (MnOx) in Fenton-like process is poorly understood. Here, five amorphous MnOx synthesized by Mn(II) precursors with different ligands were characterized and adopted to activate peracetic acid (PAA) for bisphenol A (BPA) degradation. Although > 90 % BPA removal was achieved in the five MnOx/PAA processes via both adsorption and oxidation, the oxidation k obs greatly differentiates by the ligands types with the order of MnOx-N > MnOx-S > MnOx-Cl > MnOx-AA > MnOx-OA. Ligands types would affect the specific surface area of MnOx and their ability to adsorb BPA, however which is not the decisive factor in determining the contaminant oxidation efficiency. Multiple experimental results indicate that the generation of oxygen vacancies induced by the ligands alters the Mn(III)/Mn(IV) ratio, ultimately contributing to the different efficiency of BPA oxidation driven by the direct electron transfer mechanism. Moreover, amorphous MnOx holds the promise of practical applications in catalytic PAA of various micropollutants with good stability. This study advances the fundamental understanding of ligand-regulated amorphous MnOx-catalyzed PAA process., 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 B.V. All rights reserved.)

Background: Rapid on-site evaluation (ROSE) plays an important role during transbronchial sampling, providing an intraoperative cytopathologic evaluation. However, the shortage of cytopathologists limits its wide application. This study aims to develop a deep learning model to automatically analyze ROSE cytological images., Methods: The hierarchical multi-label lung cancer subtyping (HMLCS) model that combines whole slide images of ROSE slides and serum biological markers was proposed to discriminate between benign and malignant lesions and recognize different subtypes of lung cancer. A dataset of 811 ROSE slides and paired serum biological markers was retrospectively collected between July 2019 and November 2020, and randomly divided to train, validate, and test the HMLCS model. The area under the curve (AUC) and accuracy were calculated to assess the performance of the model, and Cohen's kappa (κ) was calculated to measure the agreement between the model and the annotation. The HMLCS model was also compared with professional staff., Results: The HMLCS model achieved AUC values of 0.9540 (95% confidence interval [CI]: 0.9257-0.9823) in malignant/benign classification, 0.9126 (95% CI: 0.8756-0.9365) in malignancy subtyping (non-small cell lung cancer [NSCLC], small cell lung cancer [SCLC], or other malignancies), and 0.9297 (95% CI: 0.9026-0.9603) in NSCLC subtyping (lung adenocarcinoma [LUAD], lung squamous cell carcinoma [LUSC], or NSCLC not otherwise specified [NSCLC-NOS]), respectively. In total, the model achieved an AUC of 0.8721 (95% CI: 0.7714-0.9258) and an accuracy of 0.7184 in the six-class classification task (benign, LUAD, LUSC, NSCLC-NOS, SCLC, or other malignancies). In addition, the model demonstrated a κ value of 0.6183 with the annotation, which was comparable to cytopathologists and superior to trained bronchoscopists and technicians., Conclusion: The HMLCS model showed promising performance in the multiclassification of lung lesions or intrathoracic lymphadenopathy, with potential application to provide real-time feedback regarding preliminary diagnoses of specimens during transbronchial sampling procedures., Clinical Trial Number: Not applicable., (© 2024. The Author(s).)

Background: In patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; Hi-CHOP) versus rituximab plus CHOP (R-CHOP) treatment regimens., Methods: In a 2:1 ratio, eligible patients were assigned randomly to receive treatment of six cycles of either 375 mg/m 2 zuberitamab or rituximab together with conventional CHOP chemotherapy. The objective response rate (ORR) at C6D50 served as the primary endpoint, and a non-inferiority margin of 10% was established. The secondary endpoints included the complete response (CR) rate at C6D50, duration of response (DOR), progression-free survival (PFS) and event-free survival (EFS) judged by blinded-independent review committee (BIRC), overall survival (OS) and safety outcomes., Results: Of the 487 randomized patients, 423 patients including 287 in the Hi-CHOP and 136 in the R-CHOP groups completed the C6D50 assessment. For the full analysis set (FAS) and per-protocol set (PPS), BIRC-assessed ORR at C6D50 for the Hi-CHOP and R-CHOP groups were 83.5% versus 81.4% and 95.3% versus 93.7%, respectively. The non-inferiority was confirmed as the lower limit of the two-sided 95% CI for the intergroup differences of -5.2% and -3.3%; both were >-10% in the FAS and PPS. The BIRC-assessed CR rate of Hi-CHOP was significantly higher in PPS (85.7% vs 77.3%, p=0.038), but comparable in FAS (75.2% vs 67.9%, p=0.092). After a median follow-up of 29.6 months, patients in the Hi-CHOP group had a slight advantage with regard to the DOR (HR 0.74, p=0.173), PFS (HR 0.67, p=0.057), EFS (HR 0.90, p=0.517) and OS (HR 0.60, p=0.059). Patients with the germinal-center B cell-like subtype who received Hi-CHOP exhibited statistically significant improvements in ORR (p=0.034) and CR rate (p=0.038) at C6D50, EFS (p=0.046) and OS (p=0.014). Treatment-emergent adverse event occurrence rates were comparable across groups (all p>0.05). Infusion-related responses occurred more often in the Hi-CHOP group (32.1% vs 19.9%, p=0.006), all of grade 1-3 severity., Conclusions: Zuberitamab (375 mg/m 2 ) plus CHOP was non-inferior to R-CHOP regarding ORR but exhibited a higher CR rate and was well tolerated in CD20-positive, previously untreated Chinese patients with DLBCL., Trial Registration Number: Chinese Clinical Trial Registry, ChiCTR2000040602, retrospectively registered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Quiescence acquisition of proliferating neural stem cells (NSCs) is required to establish the adult NSC pool. The underlying molecular mechanisms are not well understood. Here, we showed that conditional deletion of the m 6 A reader Ythdf2, which promotes mRNA decay, in proliferating NSCs in the early postnatal mouse hippocampus elevated quiescence acquisition in a cell-autonomous fashion with decreased neurogenesis. Multimodal profiling of m 6 A modification, YTHDF2 binding, and mRNA decay in hippocampal NSCs identified shared targets in multiple transforming growth factor β (TGF-β)-signaling-pathway components, including TGF-β ligands, maturation factors, receptors, transcription regulators, and signaling regulators. Functionally, Ythdf2 deletion led to TGF-β-signaling activation in NSCs, suppression of which rescued elevated quiescence acquisition of proliferating hippocampal NSCs. Our study reveals the dynamic nature and critical roles of mRNA decay in establishing the quiescent adult hippocampal NSC pool and uncovers a distinct mode of epitranscriptomic control via co-regulation of multiple components of the same signaling pathway., Competing Interests: Declaration of interests G.-l.M. is a member of the editorial board of Cell Stem Cell., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nuclear speckles are nuclear membraneless organelles in higher eukaryotic cells playing a vital role in gene expression. Using an in situ reverse transcription-based sequencing method, we study nuclear speckle-associated human transcripts. Our data indicate the existence of three gene groups whose transcripts demonstrate different speckle localization properties: stably enriched in nuclear speckles, transiently enriched in speckles at the pre-messenger RNA stage, and not enriched. We find that stably enriched transcripts contain inefficiently excised introns and that disruption of nuclear speckles specifically affects splicing of speckle-enriched transcripts. We further reveal RNA sequence features contributing to transcript speckle localization, indicating a tight interplay between transcript speckle enrichment, genome organization, and splicing efficiency. Collectively, our data highlight a role of nuclear speckles in both co- and posttranscriptional splicing regulation. Last, we show that genes with stably enriched transcripts are over-represented among genes with heat shock-up-regulated intron retention, hinting at a connection between speckle localization and cellular stress response.

Utilizing infrared spectroscopy coupled with batch equilibrium methods, the adsorption and desorption characteristics of the novel Insecticide fluchlordiniliprole were assessed in four different soil types. It was found that fluchlordiniliprole's adsorption and desorption in these soils were consistent with the Freundlich isotherm, exhibiting adsorption capacities (K F-ads ) ranging from 8.436 to 36.269. Temperature fluctuations, encompassing both high and low extremes, impaired the ability of soil to adsorb fluchlordiniliprole. In addition, adsorption dynamics were modulated by several other factors, including soil pH, ionic strength, amendments (e.g., biochar and humic substances), and the presence of various surfactants and microplastics. Although capable of leaching, fluchlordiniliprole exhibited weak mobility in most soils. Therefore, it appears that fluchlordiniliprole seems to pose a threat to surface soil and aquatic biota, but a minimal threat to groundwater. SYNOPSIS STATEMENT: This research examines the dynamics of fluchlordiniliprole in soil, an will aid in maintaining ecological safety and managing agricultural pesticides. The study's comprehensive analysis of adsorption, desorption, and soil migration patterns significantly contributes to our understanding of pesticide interactions with diverse soil types. The results of this study will enable the development of environmentally responsible agricultural practices., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Redox-inactive metal-ion-driven modulation of the oxidation behavior of high-valent metal-oxo complex has garnered significant interest in biological and chemical synthesis; however, their role in permanganate (Mn(VII)) oxidation for the removal of organic pollutants has been largely neglected. Here, we uncover the impact of six metal ions (i.e., Ca 2+ , Mg 2+ , Ni 2+ , Zn 2+ , Al 3+ , and Sc 3+ ) presenting in water environments on Mn(VII) activity. These ions uniformly boost the electron and oxygen transfer capabilities of Mn(VII) while impeding proton transfer, as evidenced by electrochemical tests, thioanisole probe analysis, and the kinetic isotope effect. The observed effects are intricately linked to the Lewis acidity of the metal ions. Further mechanistic insights reveal that Mn(VII) can interact with metal ions without direct reduction. Such interactions modify the electronic configuration of Mn(VII) and create an acidic microenvironment, thus increasing its electrophilicity and the energy barrier for the abstraction of proton from organic substrates. More importantly, the efficacy of Mn(VII) in removing phenolic pollutants is regulated by these ions through changing the driving force for proton and electron transfer, i.e., facilitated at pH > 4.5 and inhibited at lower pH. The contribution of active Mn intermediates is also discussed to reveal the oxidative mechanism of the metal ion/Mn(VII) system. These findings not only facilitate the rational design of Mn(VII) oxidation conditions in the presence of metal ions for water decontamination but also offer an alternative paradigm for enhancing electrophilic oxidation.

Subjective cognitive decline (SCD) marks the initial stage in Alzheimer's disease continuum. Nonetheless, current research findings regarding brain structural changes in the SCD are inconsistent. In this study, 37 SCD patients, 28 mild cognitive impairment (MCI) patients, and 42 healthy controls (HC) were recruited to investigate structural alterations. Morphological and microstructural differences among the three groups were analyzed based on T1- and diffusion-weighted images, correlating them with neuropsychological assessments. Additionally, classification analysis was performed by using support vector machines (SVM) categorize participants into three groups based on MRI features. Both SCD and MCI showed decreased volume in left inferior parietal lobe (IPL) compared to HC, while SCD showed altered morphologies in the right inferior temporal gyrus (ITG), right insula and right amygdala, and microstructures in fiber tracts of the right ITG, lateral occipital cortex (LOC) and insula relative to MCI. Moreover, the volume in the left IPL, right LOC, right amygdala and diffusivity value in fiber tracts of right LOC were significantly correlated with cognitive functions across all subjects. The classification models achieved an accuracy of > 0.7 (AUC = 0.8) in distinguishing the three groups. Our findings suggest that SCD and MCI share similar atrophy in the IPL but show more differences in morphological and microstructural features of cortical-subcortical areas., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sigmoid Ventricular Septum (SVS) is a type of hypertrophic cardiomyopathy characterized by a reduced angle between the basal interventricular septum and the ascending aorta, and SVS can lead to dynamic Left Ventricular Outflow Tract obstruction (LVOTO) during hypercontractile states. Patients experiencing LVOTO may manifest symptoms such as angina, syncope, etc. Radiofrequency ablation (RFA) has been utilized to treat patients with hypertrophic obstructive cardiomyopathy, but there is no reports on its use in treating LVOTO resulting from SVS. Our report describes two cases of SVS treated with endocardial ablation to improve LVOTO., Case Report: Case 1: A 74-year-old female patient with angina and syncope was admitted to the hospital and diagnosed with SVS by transthoracic echocardiogram. The patient exhibited LVOTO and Systolic Anterior Motion (SAM) phenomena during the administration of the dobutamine stress test. After RFA was performed, the patient's symptoms significantly improved. Additionally, septum decreased from 16 to 13 mm after ten months, and the morphological changes associated with SVS also disappeared. Case 2: A 57-year-old female was admitted to the hospital due to recurrent chest pain after physical activity for more than four years. The transthoracic echocardiogram indicated that the patient met the diagnostic criteria for SVS, and LVOTO and SAM phenomenaoccurred following dobutamine stress test. The patient had significant improvement in symptoms after undergoing RFA treatment., Conclusions: These two cases represent the first documented instances where dynamic LVOTO caused by SVS could be effectively managed through endocardial RFA., 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., (© 2024 Huang, Wang, Li, Xiong, He, Feng, Jing and Ma.)

Purpose: Using the prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial samples, we identified cell-free DNA (cfDNA) candidate biomarkers bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that detected occult colorectal cancer (CRC) up to 36 months before clinical diagnosis., Materials and Methods: We performed the 5hmC-seal assay and sequencing on ≤8 ng cfDNA extracted from PLCO study participant plasma samples, including n = 201 cases (diagnosed with CRC within 36 months of blood collection) and n = 401 controls (no cancer diagnosis on follow-up). We conducted association studies and machine learning modeling to analyze the genome-wide 5hmC profiles within training and validation groups that were randomly selected at a 2:1 ratio., Results: We successfully obtained 5hmC profiles from these decades-old samples. A weighted Cox model of 32 5hmC-modified gene bodies showed a predictive detection value for CRC as early as 36 months before overt tumor diagnosis (training set AUC, 77.1% [95% CI, 72.2 to 81.9] and validation set AUC, 72.8% [95% CI, 65.8 to 79.7]). Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and race/ethnicity, and significantly outperformed risk factors such as age and obesity (assessed as BMI). Finally, when splitting cases at median weighted prediction scores, Kaplan-Meier analyses showed significant risk stratification for CRC occurrence in both the training set (hazard ratio, [HR], 3.3 [95% CI, 2.6 to 5.8]) and validation set (HR, 3.1 [95% CI, 1.8 to 5.8])., Conclusion: Candidate 5hmC biomarkers and a scoring algorithm have the potential to predict CRC occurrence despite the absence of clinical symptoms and effective predictors. Developing a minimally invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient outcomes.

Mutation of tet methylcytosine dioxygenase 2 (encoded by TET2) drives myeloid malignancy initiation and progression 1-3 . TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant haematopoietic stem cell self-renewal 4,5 . However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukaemic cells and haematopoietic stem and progenitor cells 5 is inconsistent with the designated role of DNA 5-methylcytosine oxidation of TET2. Here we show that chromatin-associated retrotransposon RNA 5-methylcytosine (m 5 C) can be recognized by the methyl-CpG-binding-domain protein MBD6, which guides deubiquitination of nearby monoubiquitinated Lys119 of histone H2A (H2AK119ub) to promote an open chromatin state. TET2 oxidizes m 5 C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. TET2 depletion thereby leads to globally decreased H2AK119ub, more open chromatin and increased transcription in stem cells. TET2-mutant human leukaemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocking proliferation of TET2-mutant leukaemic cells and largely reversing the haematopoiesis defects caused by Tet2 loss in mouse models. Together, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m 5 C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies., (© 2024. The Author(s).)

Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N 6 -methyladenosine (m 6 A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. Here, we demonstrate that the absence of m 6 A methyltransferase-like 14 (METTL14) modifies the BAT secretome to improve systemic insulin sensitivity independent of UCP1. Using lipidomics, we identify prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as BAT-secreted insulin sensitizers. PGE2 and PGF2a inversely correlate with insulin sensitivity in humans and protect mice from high-fat-diet-induced insulin resistance by suppressing specific AKT phosphatases. Mechanistically, METTL14-mediated m 6 A promotes the decay of PTGES2 and CBR1, the genes encoding PGE2 and PGF2a biosynthesis enzymes, in brown adipocytes via YTHDF2/3. Consistently, BAT-specific knockdown of Ptges2 or Cbr1 reverses the insulin-sensitizing effects in M14 KO mice. Overall, these findings reveal a novel biological mechanism through which m 6 A-dependent regulation of the BAT secretome regulates systemic insulin sensitivity., Competing Interests: Declaration of interests R.N.K. is on the scientific advisory boards of Novo Nordisk, Biomea, Inversago, and REDD. C.H. is a scientific founder and a member of the scientific advisory board of Accent Therapeutics. M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Novo Nordisk, Novartis, Pfizer, and Sanofi., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study investigates the molecular mechanisms behind ischaemia/reperfusion (I/R) injury in the brain, focusing on neuronal apoptosis. It scrutinizes the role of the Jun proto-oncogene in apoptosis, involvement of SOCS1 in neural precursor cell accumulation in ischaemic regions, and the upregulation of C-EBPβ in the hippocampus following I/R. Key to the study is understanding how Jun controls C-EBPβ degradation via SOCS1, potentially offering new clinical treatment avenues for I/R. Techniques such as mRNA sequencing, KEGG enrichment analysis and protein-protein interaction (PPI) in mouse models have indicated involvement of Jun (AP-1) in I/R-induced cerebral damage. The study employs middle cerebral artery occlusion in different mouse models and oxygen-glucose deprivation/reoxygenation in cortical neurons to examine the impacts of Jun and SOCS1 manipulation on cerebral I/R injury and neuronal damage. The findings reveal that I/R reduces Jun expression in the brain, but its restoration lessens cerebral I/R injury and neuron death. Jun activates SOCS1 transcriptionally, leading to C-EBPβ degradation, thereby diminishing cerebral I/R injury through the SOCS1/C-EBPβ pathway. These insights provide a deeper understanding of post-I/R cerebral injury mechanisms and suggest new therapeutic targets for cerebral I/R injury. KEY POINTS: Jun and SOCS1 are poorly expressed, and C-EBPβ is highly expressed in ischaemia/reperfusion mouse brain tissues. Jun transcriptionally activates SOCS1. SOCS1 promotes the ubiquitination-dependent C-EBPβ protein degradation. Jun blunts oxygen-glucose deprivation/reoxygenation-induced neuron apoptosis and alleviates neuronal injury. This study provides a theoretical basis for the management of post-I/R brain injury., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Purpose: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that conventional dendritic cells (cDC) maintain Treg, we sought to identify and target cDC signaling to block Treg infiltration after radiation., Experimental Design: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT but also associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT., Results: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration., Conclusions: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy. See related commentary by Kalinski et al., p. 4260., (©2024 American Association for Cancer Research.)

Bisulfite sequencing (BS-seq) to detect 5-methylcytosine (5mC) is limited by lengthy reaction times, severe DNA damage, overestimation of 5mC level and incomplete C-to-U conversion of certain DNA sequences. We present ultrafast BS-seq (UBS-seq), which uses highly concentrated bisulfite reagents and high reaction temperatures to accelerate the bisulfite reaction by ~13-fold, resulting in reduced DNA damage and lower background noise. UBS-seq allows library construction from small amounts of purified genomic DNA, such as from cell-free DNA or directly from 1 to 100 mouse embryonic stem cells, with less overestimation of 5mC level and higher genome coverage than conventional BS-seq. Additionally, UBS-seq quantitatively maps RNA 5-methylcytosine (m 5 C) from low inputs of mRNA and allows the detection of m 5 C stoichiometry in highly structured RNA sequences. Our UBS-seq results identify NSUN2 as the major 'writer' protein responsible for the deposition of ~90% of m 5 C sites in HeLa mRNA and reveal enriched m 5 C sites in 5'-regions of mammalian mRNA, which may have functional roles in mRNA translation regulation., (© 2024. The Author(s).)

Background: Digital subtraction angiography (DSA) is most commonly used in vessel disease examinations and treatments. We aimed to develop a novel deep learning-based method to deblur the large focal spot DSA images, so as to obtain a clearer and sharper cerebrovascular DSA image., Methods: The proposed network cascaded several residual dense blocks (RDBs), which contain dense connected layers and local residual learning. Several loss functions for image restoration were investigated. Our training set consisted of 52 paired images of angiography with more than 350,000 cropped patches. The testing set included 10 body phantoms and 80 clinical images of different types of diseases for subjective evaluation. All test images were acquired using a large focal spot, and phantom images were simultaneously acquired using a micro focal spot as ground-truth. Peak-to-noise ratio (PSNR) and structural similarity (SSIM) were determined for quantitative analysis. The deblurring results were compared with the original data, and the image quality was subjectively evaluated and graded by two clinicians., Results: For quantitative analysis of phantom images, the average PSNR/SSIM based on the deep-learning approach (35.34/0.9566) was better than that of large focal spot images (30.64/0.9163). For subjective evaluation of 80 clinical patient images, image quality in all types of cerebrovascular diseases was also improved based on a deep-learning approach ( p  < 0.001)., Conclusions: Deep learning-based focal spot deblur algorithm can efficiently improve DSA image quality for better visualization of blood vessels and lesions in the image., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from cancer patients, but not in other immune cells tested. Elevated YTHDF1 expression of DCs was associated with poor outcomes in patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) via increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through STING-IFN-I signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine, significantly improving the therapeutic effect of RT and radio-immunotherapy in a murine melanoma model. Our findings reveal a new layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.

Abstract: Exosomes have emerged as promising vehicles for delivering therapeutic cargoes to specific cells or tissues, owing to their superior biocompatibility, reduced immunogenicity, and enhanced targeting capabilities compared with conventional drug delivery systems. In this study, we developed a delivery platform using exosomes derived from monocytes, specifically designed for targeted delivery of bortezomib (Btz) to multiple myeloma (MM) cells. Our approach involved the genetic modification of monocytes to express antibodies targeting B-cell maturation antigen (anti-BCMA), because BCMA selectively expresses on myeloma cells. This modified anti-BCMA was then efficiently incorporated into the monocyte-derived exosomes. These adapted exosomes effectively encapsulated Btz, leading to enhanced drug accessibility within MM cells and sustained intracellular accumulation over an extended period. Remarkably, our results demonstrated that anti-BCMA-modified exosome-loaded Btz (anti-BCMA-Exo-Btz) outperformed free Btz in vitro, exhibiting a more potent myeloma-suppressive effect. In orthotopic MM xenograft models, anti-BCMA-Exo-Btz exhibited a significant antitumor effect compared with free Btz. Furthermore, it demonstrated remarkable specificity in targeting Btz to myeloma cells in vivo. Importantly, we observed no significant histological damage in mice treated with anti-BCMA-Exo-Btz and a slight effect on peripheral blood mononuclear cells. In addition, our study highlighted the multifunctional potential of monocyte exosomes, which induced cell apoptosis, mediated immune responses, and enhanced the osteogenic potential of mesenchymal stromal cells. In conclusion, our study suggests that exosomes modified with targeting ligands hold therapeutic promise for delivering Btz to myelomas, offering substantial potential for clinical applications., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The oil sludge produced while extracting large oil and gas fields in the middle and high latitude regions has caused serious pollution to the surrounding soil. The key to solving this problem in the future is to unify the remediation of soil and the treatment of oil sludge. This study uses supercritical carbon dioxide(scCO 2 ) technology to construct a low-carbon method, providing a new approach to achieve this goal. The study determines the optimal extraction conditions for black calcareous soil with 15% oil content to be 55 °C, 25 MPa, and 90 min through single factor and response surface experiments. Experiments on the scCO 2 extraction coupled with freeze-thaw cycles show that oil sludge with a water content of 10% can improve the extraction efficiency of scCO 2 by about 2.69% after less than five freeze-thaw cycles. The study also compares the extraction efficiency of the four soils, with a difference of 6.03% observed under the same conditions. Additionally, we analyze the impact of the extraction process on changes in the properties of the oil and soil in the oil sludge. Comprehensive tests, including scanning electron microscope (SEM), nutrient detection, X-ray powder diffractometer (XRD), fourier transform infrared spectroscopy (FTIR), and Gas Chromatography (GC), have been conducted. Results show that standalone scCO 2 extraction can remove up to 98.2% of petroleum hydrocarbons from the oil sludge, while simultaneously causing small changes to the soil microstructure and the crystal structure of the oil sludge. Furthermore, this process does not lead to a significant depletion of key nutrients or the generation of new pollutants., 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 Inc. All rights reserved.)

Boron dipyrromethenes (BODIPYs) are some of the most popular and indispensable tetracoordinate boron compounds and have found widespread applications owing to their excellent spectroscopic and photophysical properties. BODIPYs possessing boron-stereogenic centres are scarce, and strategies for the synthesis of enantioenriched boron-stereogenic BODIPYs with structural diversity remain underdeveloped. In theory, the BODIPY core skeleton has several sites that could be decorated with different substituents. However, due to the lack of general and efficient asymmetric synthetic methods, this potential diversity of chiral BODIPYs has not been exploited. Here we demonstrate a modular enantioselective assembly of multi-substituted boron-stereogenic BODIPYs in high efficiency with excellent enantioselectivities. Key to the success is the Pd-catalysed desymmetric Suzuki cross-coupling, enabling the precise discrimination of the two α C-Cl bonds of the designed prochiral BODIPY scaffold, giving access to a wide range of highly functionalized boron-stereogenic BODIPYs. Derivatizations, photophysical properties and applications in chiral recognition of the obtained optical BODIPYs are further explored., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Co-infection with diverse bacteria is commonly seen in patients infected with the novel coronavirus, SARS-CoV-2. This type of co-infection significantly impacts the occurrence and development of novel coronavirus infection. Bacterial co-pathogens are typically identified in the respiratory system and blood culture, which complicates the diagnosis, treatment, and prognosis of COVID-19, and even exacerbates the severity of disease symptoms and increases mortality rates. However, the status and impact of bacterial co-infections during the COVID-19 pandemic have not been properly studied. Recently, the amount of literature on the co-infection of SARS-CoV-2 and bacteria has gradually increased, enabling a comprehensive discussion on this type of co-infection. In this study, we focus on bacterial infections in the respiratory system and blood of patients with COVID-19 because these infection types significantly affect the severity and mortality of COVID-19. Furthermore, the progression of COVID-19 has markedly elevated the antimicrobial resistance among specific bacteria, such as Klebsiella pneumoniae , in clinical settings including intensive care units (ICUs). Grasping these resistance patterns is pivotal for the optimal utilization and stewardship of antibiotics, including fluoroquinolones. Our study offers insights into these aspects and serves as a fundamental basis for devising effective therapeutic strategies. We primarily sourced our articles from PubMed, ScienceDirect, Scopus, and Google Scholar. We queried these databases using specific search terms related to COVID-19 and its co-infections with bacteria or fungi, and selectively chose relevant articles for inclusion in our review., Competing Interests: The authors declare that they have no competing interests., (© 2024 Liu et al.)

H 2 O 2 as a green oxidant plays a crucial role in numerous green chemical reactions. However, how to improve its activation and utilization efficiency as well as regulate the distribution of ROS remains a pressing challenge. In this work, a sulfur quantum dots (SQDs) modified zero-valent iron (SQDs@ZVI) was delicately designed and prepared, whose iron sites can coordinate with strongly electronegative sulfur atoms to construct highly reactive Fe-S dual active sites, for high-efficient selective H 2 O 2 activation and utilization with potent • OH production. Experimental tests, in situ FTIR/Raman spectra and theoretical calculations demonstrated that SQDs modulates the local coordination structure and electronic density of iron centers, thus effectively enhancing its Fenton reactivity and promoting the rate-limiting H 2 O 2 adsorption and subsequent barrierless dissociation of peroxyl bonds into • OH via the formation of bridged S-O-O-Fe complexes. Consequently, substantial generated surface-bound • OH induced by the highly reactive Fe-S dual sites enabled excellent degradation of miscellaneous organic pollutants over a broad pH range (3.0-9.0). The developed device-scale Fenton filter realized durable performance (up to 200 h), verifying the vast potential of SQDs@ZVI with diatomic sites for practical application. This work presents a promising strategy to construct metal-nonmetal diatomic active sites toward boosting selective activation and effective utilization of H 2 O 2 , which may inspire the design of efficient heterogeneous Fenton reaction for water decontamination., 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.)

Background and Aims: Electrical stimulation (ES) has been shown to substantially enhance the quality of life by alleviating pain in patients with chronic wounds. This study aimed to observe the effects of low-frequency pulsed wearable ES at the common peroneal nerve on chronic refractory wounds of the lower limb., Methods: Forty-eight participants were randomly divided into control group ( n  = 24) and treatment group ( n  = 24) in this study. The control group received standard wound care (SWC) exclusively, whereas the treatment group was administered both SWC and the wearable low-frequency ES targeting the common peroneal nerve. Measurements of wound area, pain intensity, wound status, and quality of life scores were systematically recorded both before and after 4 weeks treatment., Results: After 4 weeks of intervention, the percentage area reduction was significantly higher in the treatment group compared to the control group ( Z  = -3.9, p  < 0.001), and the healing rate of the treatment group was significantly higher than that of the control group (33% vs. 4%). Moreover, the visual Analog Scale for Pain score ( β  = -0.65, p  = 0.019), the Bates-Jensen Wound Assessment Tool score ( p  < 0.05), and the questionnaire on quality of life with chronic wounds (Wound-Qol) score ( β  = -4.23, p  = 0.003) were significantly decreased in the patients in the treatment group compared to the control group., Conclusion: The wearable low-frequency pulsed ES at the common peroneal nerve for the treatment of chronic refractory wounds showed significant improvement and were far superior compared to SWC. Future research should broaden its scope to include a diverse range of wound types and benefit from collaboration across multiple research centers., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.)

Topoisomerase I (TOP1) is an essential enzyme that relaxes DNA to prevent and dissipate torsional stress during transcription. However, the mechanisms underlying the regulation of TOP1 activity remain elusive. Using enhanced cross-linking and immunoprecipitation (eCLIP) and ultraviolet-cross-linked RNA immunoprecipitation followed by total RNA sequencing (UV-RIP-seq) in human colon cancer cells along with RNA electrophoretic mobility shift assays (EMSAs), biolayer interferometry (BLI), and in vitro RNA-binding assays, we identify TOP1 as an RNA-binding protein (RBP). We show that TOP1 directly binds RNA in vitro and in cells and that most RNAs bound by TOP1 are mRNAs. Using a TOP1 RNA-binding mutant and topoisomerase cleavage complex sequencing (TOP1cc-seq) to map TOP1 catalytic activity, we reveal that RNA opposes TOP1 activity as RNA polymerase II (RNAPII) commences transcription of active genes. We further demonstrate the inhibitory role of RNA in regulating TOP1 activity by employing DNA supercoiling assays and magnetic tweezers. These findings provide insight into the coordinated actions of RNA and TOP1 in regulating DNA topological stress intrinsic to RNAPII-dependent transcription., Competing Interests: Declaration of interests E.L.V.N. is co-founder, member of the Board of Directors, on the SAB, equity holder, and paid consultant for Eclipse BioInnovations. E.L.V.N.’s interests have been reviewed and approved by the Baylor College of Medicine in accordance with its conflict-of-interest policies. C.H. is a scientific founder, a member of the scientific advisory board and equity holder of Aferna Bio, Inc. and Ellis Bio Inc., a scientific co-founder and equity holder of Accent Therapeutics, Inc., and a member of the scientific advisory board of Rona Therapeutics and Element Biosciences., (Published by Elsevier Inc.)

Cancer is generally defined as a disease of aging. With aging, the composition, diversity and functional characteristics of the gut microbiota occur changes, with a decline of beneficial commensal microbes triggered by intrinsic and extrinsic factors (e.g., diet, drugs and chronic health conditions). Nowadays, dysbiosis of the gut microbiota is recognized as a hallmark of cancer. At the same time, aging is accompanied by changes in innate and adaptive immunity, known as immunosenescence, as well as chronic low-grade inflammation, known as inflammaging. The elevated cancer incidence and mortality in the elderly are linked with aging-associated alterations in the gut microbiota that elicit systemic metabolic alterations, leading to immune dysregulation with potentially tumorigenic effects. The gut microbiota and immunosenescence might both affect the response to treatment in cancer patients. In-depth understanding of age-associated alterations in the gut microbiota and immunity will shed light on the risk of cancer development and progression in the elderly. Here, we describe the aging-associated changes of the gut microbiota in cancer, and review the evolving understanding of the gut microbiota-targeted intervention strategies. Furthermore, we summarize the knowledge on the cellular and molecular mechanisms of immunosenescence and its impact on cancer. Finally, we discuss the latest knowledge about the relationships between gut microbiota and immunosenescence, with implications for cancer therapy. Intervention strategies targeting the gut microbiota may attenuate inflammaging and rejuvenate immune function to provide antitumor benefits in elderly patients., 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.)

Background and Objectives: Craniocervical junction (CCJ) arteriovenous fistulas (AVFs) are rare. Variability in clinical manifestations and treatment strategies for CCJ AVFs stems from differences in their angioarchitecture. Our study aims to categorize CCJ AVFs based on their angioarchitecture and explore the associated clinical features and treatment modalities for distinct CCJ AVF types., Methods: The authors conducted a retrospective analysis of patients with CCJ AVFs treated at a single neurosurgical facility over the past decade. These patients were classified based on the angioarchitecture of their CCJ AVFs. The analysis included an evaluation of angioarchitecture, clinical characteristics, treatment strategies, and outcomes., Results: The study included 155 patients, with a median age of 56 years, collectively manifesting 165 CCJ AVFs. Our classification identified 4 distinct CCJ AVF types: epidural AVFs (19 [11.5%]), dural AVFs (98 [59.4%]), radicular AVFs (33 [20.0%]), and perimedullary AVFs (15 [9.1%]). Further differentiation was applied based on the presence of pial feeders. The predominant fistula location was at cervical-1 (77.0%). Ascending intradural drainage (52.7%) and descending intradural drainage (52.1%) were frequently observed drainage patterns. Patients with dural AVF predominantly presented with venous hypertensive myelopathy, whereas patients with other types of CCJ AVFs showed a higher incidence of subarachnoid hemorrhage (P = .012). Microsurgery was the predominant treatment, applied in the management of 126 (76.4%) AVFs, whereas 8 (4.8%) AVFs exclusively underwent interventional embolization and 25 (15.2%) received a combination of interventional embolization and microsurgical treatment., Conclusion: CCJ AVFs can be distinguished based on the fistula location and the arterial feeders. Currently, microsurgery stands as the preferred treatment strategy for CCJ AVFs, whereas interventional embolization plays a distinctive role in cases with specific angioarchitecture or as a pretreatment measure before microsurgery., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Thiols function as antioxidants in food, prolonging shelf life and enhancing flavor. Moreover, thiols are vital biomolecules involved in enzyme activity, cellular signal transduction, and protein folding among critical biological processes. In this paper, the fluorescent probe PYL-NBD was designed and synthesized, which utilized the fluorescent molecule pyrazoline, the lysosome-targeted morpholine moiety, and the sensing moiety NBD. Probe PYL-NBD was tailored for the recognition of biothiols through single-wavelength excitation, yielding distinct fluorescence emission signals: blue for Cys, Hcy, and GSH; green for Cys, Hcy. Probe PYL-NBD exhibited rapid reaction kinetics (<10 min), distinct fluorescence response signals, and low detection limits (15.7 nM for Cys, 14.4 nM for Hcy, and 12.6 nM for GSH). Probe PYL-NBD enabled quantitative determination of Cys content in food samples and L-cysteine capsules. Furthermore, probe PYL-NBD had been successfully applied for confocal imaging with dual-channel detection of biothiols in various biological specimens, including HeLa cells, zebrafish, tumor sections, and Arabidopsis thaliana., 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 B.V. All rights reserved.)

As a type of reactive oxygen species, hypochlorous acid (ClO - ) plays an important role in sterilization, disinfection and protection in organisms. However, excessive production of ClO - is closely related to various diseases. In this work, we have designed a robust ratiometric fluorescent probe, RDB-ClO, using the excited-state intramolecular proton transfer (ESIPT) strategy. RDB-ClO was achieved by modifying 2-(2-(benzo[d]thiazol-2-yl)-6-(diethylamino)-3-oxo-3H-xanthen-9-yl) benzoic acid (RDB-OH) with a 1-naphthoyl chloride group, specifically for the sensitive detection of ClO - . In the presence of ClO - , RDB-ClO demonstrated relatively good performance, showing swift response time (35 s), low detection limit of 5.1 nM and high selectivity towards ClO - . Notably, the convenience and accessibility detection of ClO - has been implemented using test strip and agarose probe. RDB-ClO effectively tracked both endogenous and exogenous ClO - in HeLa cells, HepG2 cells and zebrafish. Additionally, it is successfully applied to detect changes of exogenous ClO - content in E. coli. and acetaminophen (APAP)-induced liver injury in mice. The development of RDB-ClO represents a promising molecular tool for studying the pathogenesis of DILI and biotransformation of ClO - in bacteria., 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 B.V. All rights reserved.)

In this study, we prepared a low-cost novel Cu/Cu 2 O/BC nanocomposite visible-light photocatalyst by the impregnation method using CuSO 4 ·5H 2 O and rice husk biochar (BC) as raw materials and Na 2 S 2 O 4 as a single reductant to improve the stability and dispersion of the Cu/Cu 2 O nanoparticles, in order to solve their aggregation tendency during photocatalysis. The morphology and structure of the Cu/Cu 2 O/BC were characterized using various analytical and spectroscopic techniques. The photocatalytic effect and cyclic stability of the synthesized photocatalyst on methyl orange (MO) removal were investigated under visible light radiation and various parameter conditions, including the mass ratio of BC to Cu/Cu 2 O, initial MO concentration, pH, temperature, and catalyst dosage. The results show that the synthesized Cu/Cu 2 O/BC nanocomposite composed of Cu/Cu 2 O spherical particles was loaded on the BC carrier, which has better stability and dispersion. The best adsorption-photocatalytic effect of the Cu/Cu 2 O/BC is exhibited when the mass ratio of BC to Cu/Cu 2 O is 0.2. A total of 100 mg of Cu/Cu 2 O/BC can remove 95% of the MO and 88.26% of the COD in the aqueous solution at pH = 6, T = 25 °C, and an initial MO concentration of 100 mg/L. After five cycles of degradation, the MO degradation rate in the sample can still remain at 78.41%. Both the quasi-secondary kinetic model and the Langmuir isothermal adsorption model describe the adsorption process. Additionally, the thermodynamic analysis demonstrates that the photocatalytic process follows the quasi-primary kinetic model and that the removal process is of spontaneous heat absorption. The photocatalyst described in this paper offers a cost-effective, easily prepared, and visible-light-responsive solution for water pollution treatment.

Recent studies have suggested that mRNA internal m 7 G and its writer protein METTL1 are closely related to cell metabolism and cancer regulation. Here, we identify that IGF2BP family proteins IGF2BP1-3 can preferentially bind internal mRNA m 7 G. Such interactions, especially IGF2BP3 with m 7 G, could promote the degradation of m 7 G target transcripts in cancer cells. IGF2BP3 is more responsive to changes of m 7 G modification, while IGF2BP1 prefers m 6 A to stabilize the bound transcripts. We also demonstrate that p53 transcript, TP53, is m 7 G-modified at its 3'UTR in cancer cells. In glioblastoma, the methylation level and the half lifetime of the modified transcript could be modulated by tuning IGF2BP3, or by site-specific targeting of m 7 G through a dCas13b-guided system, resulting in modulation of cancer progression and chemosensitivity., (© 2024. The Author(s).)

Background: Surgical resection of the lesions remains the main treatment method for most symptomatic spinal cord cavernous malformations (SCCMs) to eliminate the occupation and associated subsequent lifelong haemorrhagic risk. However, the timing of surgical intervention remains controversial, especially for patients in the acute stage after severe haemorrhage., Methods: Patients diagnosed with SCCMs who were surgically treated between January 2002 and December 2021 were selected and retrospectively reviewed. The Modified McCormick Scale (MMS) was used to evaluate neurological and disability status. All medical information was reviewed, and all patients were followed up for at least 6 months., Results: A total of 279 patients were ultimately included. With regard to long-term outcomes, 110 (39.4%) patients improved, 159 (57.0%) remained unchanged and 10 (3.6%) worsened. For patients with an MMS score of 2-5 on admission, in univariate and multivariate analyses, a ≤6 weeks period between onset and surgery (adjusted OR 3.211, 95% CI 1.504 to 6.856, p=0.003) was a significant predictor of improved MMS. Among 69 patients who first presented with severe haemorrhage, undergoing surgery within 6 weeks of the onset of severe haemorrhage (adjusted OR 4.901, 95% CI 1.126 to 21.325, p=0.034) was significantly associated with improvement of MMS score., Conclusion: Surgical timing can influence the long-term outcome of SCCMs. For patients with symptomatic SCCMs, especially those with severe haemorrhage, early surgical intervention within 6 weeks can provide more benefit., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The purpose of this systematic review and meta-analysis was to evaluate the perioperative and short-term results of the Robot of Stereotactic Assistance (ROSA) compared to traditional approaches in individuals with intracerebral hemorrhage (ICH). We will perform a comprehensive computerized search of PubMed, CNKI, Embase, and Google Scholar to identify relevant literature on ROSA vs. conventional therapy for intracerebral hemorrhage, covering publications from the inception of each database until July 2024. This study will include both English and Chinese language studies. Literature screening will adhere strictly to inclusion and exclusion criteria, focusing on randomized controlled trials (RCTs) and cohort studies. The ROBINS-I tool is utilized for evaluating bias risk in non-RCTs. Analysis of the data from the studies included will be conducted with Review Manager 5.4.1. The final analysis included 7 retrospective cohort studies and 1 randomized controlled study, involving a total of 844 patients. Among these, 433 patients underwent ROSA, while 411 received conventional treatment (conservative treatment, conventional craniotomy, or stereotactic frame-assisted surgery). Compared to conventional therapy, patients treated with ROSA showed improvements in operative time, postoperative rebleeding, postoperative extubation time, and intracranial infection. Nonetheless, there was no notable contrast in mortality or central hyperthermia outcomes between the two treatments. ROSA is a safe and viable option for treating patients with cerebral hemorrhage, showing significant advantages in terms of surgery duration, postoperative rebleeding, time to remove the breathing tube, and intracranial infection compared to conservative treatment, traditional craniotomy, or stereotactic surgery., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

The pollutants such as heavy metals, organic matter, and nitrates in soil and water pose challenges to environmental remediation technology. Nano zero valent iron has shown enormous potential in the field of environmental remediation due to its excellent adsorption performance. By using carbon based materials, rock minerals, biomolecules, etc. , as supporting materials for nZVI, and through structural and performance modifications, its performance has been successfully optimized, reducing defects such as aggregation and easy oxidation of the material. This article compares and summarizes the modification effects of different loadings on nZVI, and comprehensively reviews the latest progress, preparation methods, and application of nZVI particles in soil and water remediation. Specifically, this article explores in detail the impact and mechanism of nZVI particles in commonly used antibiotics contaminated environments. Firstly, the combination methods of different types of materials with zero valent iron, as well as the synthesis methods and application scenarios of nZVI, were integrated. Secondly, the interaction mechanism between pollutants and nZVI was introduced in detail, including adsorption, redox reactions, and co-precipitation. Subsequently, environmental factors that affect repair efficiency were emphasized, such as pH value, coexisting components, oxygen, contact time, and temperature. Finally, the challenges faced by the application of nZVI in actual polluted soil and water bodies, as well as the prospects for its long-term efficacy and safety evaluation, are proposed to promote further development in the future., Competing Interests: 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., (This journal is © The Royal Society of Chemistry.)

The equilibrium state of hydrogen sulfide (H 2 S), a gaseous signaling molecule produced by lysosomal metabolites, in vivo is crucial for cellular function. Abnormal fluctuations in H 2 S concentration can interfere with the normal function of lysosomes, which has been closely linked to the pathogenesis of a variety of diseases. In view of this, a novel fluorescent probe Lyso-DPP based on 1,3,5-triarylpyrazolines was developed for the precise detection of H 2 S in lysosomes by using the hydrophilic morpholine moiety as a lysosomal targeting unit, and 2,4-dinitroanisole as a fluorescence-quenching and H 2 S-responsive unit. The probe cleverly combines the advantages of simple synthesis, sensitive blue fluorescence turn-on with a limit of detection, LOD, of 97.3 nM, good stability, and fast response time (10 min), which makes Lyso-DPP successful in portable monitoring of meat freshness in the form of test strips. Moreover, the excellent biocompatibility and precise targeting capability of the probe Lyso-DPP make it perform well in the monitoring of H 2 S in lysosomes, living cells, and zebrafish. This work not only provides new technical tools for food quality control but also paves up new ideas for early diagnosis and treatment of H 2 S-related diseases.

Direct copper-to-copper (Cu-Cu) bonding is a promising technology for advanced electronic packaging. Nanocrystalline (NC) Cu receives increasing attention due to its unique ability to promote grain growth across the bonding interface. However, achieving sufficient grain growth still requires a high thermal budget. This study explores how reducing grain size and controlling impurity concentration in NC Cu leads to substantial grain growth at low temperatures. The fabricated NC Cu has a uniform nanograin size of around 50 nm and a low impurity level of 300 ppm. To prevent ungrown NC and void formation caused by impurity aggregation, we propose a double-layer (DL) structure comprising a normal coarse-grained (CG) layer underneath the NC layer. The CG layer, with a grain size of 1 μm and an impurity level of 3 ppm, acts as a sink, facilitating impurity diffusion from the NC layer to the CG layer. Thanks to sufficient grain growth throughout the entire NC layer, cross-interface Cu-Cu bonding becomes possible under a low thermal budget, either at 100 °C for 60 min or at 200 °C for only 5 min., (© 2024. The Author(s).)

Pseudouridine (Ψ) is a widespread RNA modification found in various RNA species, including rRNA, tRNA, snRNA, mRNA, and long noncoding RNA (lncRNA). Understanding the function of Ψ in these RNA types requires a robust method for the detection and quantification of the Ψ level at single-nucleotide resolution. A previously used method utilizes Ψ labeling by N-cyclohexyl- N '-β-(4-methylmorpholinium)ethylcarbodiimide (CMC). The quantification of Ψ is based on the stop ratio after reverse transcription. However, the use of CMC followed by strong alkaline treatment causes severe RNA degradation, often requiring a large amount of RNA. The removal of CMC and recovery of RNA by ethanol precipitation are also time-consuming. Here, we introduce a B isulfite I ncorporation Hind ered ligation-based method (BIHIND), which can detect and quantify Ψ sites on rRNA, mRNA, and noncoding RNA. BIHIND can be coupled with quantitative PCR (BIHIND-qPCR) for quantitative detection of Ψ fraction at individual modification sites, as well as with next-generation sequencing (BIHIND-seq) for high-throughput sequencing of Ψ without requiring reverse transcription. We validated the robustness of BIHIND with the elucidation of Ψ dynamics following pseudouridine synthase depletion.