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The effects of galactic cosmic radiation on reproductive physiology remain largely unknown. We determined the impact of near-continuous low-dose-rate Californium-252 neutron irradiation (1 mGy/day) as a space-relevant analog on litter size and number of resorptions at embryonic day (E) 12.5 (n = 19 radiated dams, n = 20 controls) and litter size, number of resorptions, fetal growth, and placental signaling and transcriptome (RNA sequencing) at E18.5 (n = 21 radiated dams, n = 20 controls) in pregnant mice. A significantly increased early resorption rate and decreased placental weight were observed in irradiated mice. There were no statistically significant differences in litter size, fetal weight, length, or malformation rate between the groups. Near-continuous radiation had no significant effects on the mechanistic target of rapamycin (mTOR), endoplasmic reticulum stress or inflammatory signaling, rate of double-stranded DNA breaks, and had minimal effects on gene expression in the placenta. These data suggest that near-continuous, low-level galactic cosmic radiation has a limited impact on pregnancy outcomes., Competing Interests: Competing interests: Co-author Dr. Rebecca Blue previously served as an editor for Nature Microgravity in the past but declares no non-financial competing interests. All other authors declare no financial or non-financial competing interests., (© 2024. The Author(s).)

Men and women have different cardiovascular responses to spaceflight; however, few studies have focused on direct comparisons between sexes. We investigated the mechanisms of aortic stiffening in socially and sexually mature 20-week-old male and female Sprague Dawley (SD) rats exposed to hindlimb unloading (HLU) for 14 days. Pulse wave velocity (PWV) was greater in the aortic arch of females after HLU versus control females (n = 6-8). HLU had no effect on aortic PWV in males (n = 5-6). Aortic α smooth muscle actin, myosin, collagen, elastin, and collagen-to-elastin ratio were not different in rats of either sex following HLU. The levels of G protein-coupled estrogen receptor (GPER) were lower in the aorta of SD females exposed to HLU compared with female controls but were not altered in males. HLU females also had lower aortic PPARγ, increased oxidative stress markers, and diastolic dysfunction compared with control females. GPER agonist G1 prevented the increase in PWV and 8-hydroxy-2'-deoxyguanosine without altering PPARγ or p47phox in HLU females (n = 4 in each group) suggesting that lower GPER may contribute to arterial stiffening in the setting of simulated microgravity. This study highlights sex-specific vascular adaptations to the state of simulated microgravity., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Aims: The term ovarian carcinoma (OC) refers to a heterogeneous collection of five distinct diseases known as histotypes. While histotype-specific treatment is still a clinical challenge in OC, well-characterized models are required for testing new therapeutic strategies. We employed OncoTherad® (MRB-CFI-1), an interferon (IFN-γ)-stimulating nano-immunotherapy mediated by Toll-like receptors (TLR) 2/4, in association or not with Erythropoietin (EPO) in a chemically-induced ovarian cancer model. Besides characterization of the therapies effects, we also assessed whether the animal model was representative of human OC by providing histotype classification., Main Methods: Thirty-five Fischer rats were distributed into five groups: Control (Sham surgery); Cancer (7,12-dimethylbenzoanthracene - DMBA injection in the ovarian bursa, 1.25 mg/kg); OncoTherad® (20 mg/kg intraperitoneal); EPO (8.4 µg/kg intraperitoneal); and OncoTherad+EPO (same doses). Ovaries were formalin-fixed into paraffin-embedded blocks. TLR pathway and the inflammatory response profile were evaluated by immunohistochemistry (IHC). After DNA extraction and tissue microarray construction, we assessed typical gene mutations directly (Sanger sequencing) or indirectly (IHC surrogates) and examined biomarkers of different OC histotypes., Key Findings: OC induction decreased TLR2, TLR4, and proinflammatory cytokines. OncoTherad® alone or associated with EPO modulated the OC microenvironment to a cytotoxic immune profile through stimulation of the TLR4-mediated non-canonical pathway. EPO stimulated TLR2-mediated canonical pathway and notably increased Tregs., Significance: The features analyzed favored interpretation of our DMBA-induced tumor model as predominantly low-grade, serous carcinoma-like, in which treatments with OncoTherad® and EPO showed immunomodulatory properties related to the reduction of ovarian lesions., 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 Masson SAS.. All rights reserved.)

Separation of the two mirror images of a chiral molecule, the enantiomers, is a historically complicated problem of major relevance for biological systems. Since chiral molecules are optically active, it has been speculated that strong coupling to circularly polarized fields may be used as a general procedure to unlock enantiospecific reactions. In this work, we focus on how chiral cavities can be used to drive asymmetry in the photochemistry of chiral molecular systems. We first show that strong coupling to circularly polarized fields leads to enantiospecific Rabi splittings, an effect that displays a collective behavior in line with other strong coupling phenomena. Additionally, entanglement with circularly polarized light generates an asymmetry in the enantiomer population of the polaritons, leading to a condensation of the excitation on a preferred molecular configuration. These results confirm that chiral cavities represent a tantalizing opportunity to drive asymmetric photochemistry in enantiomeric mixtures., (Creative Commons Attribution license.)

Large cohort studies have reported that former professional football players have an increased risk of mortality from neurodegenerative disease. Due to emerging concerns regarding the safety of heading the technique is now banned for players under 12. The aim of this systematic review was to evaluate the association between heading exposure and cognitive function in professional football players. A search strategy was devised and entered into seven electronic databases: MEDLINE, Embase, Web of Science, PsycINFO, CENTRAL, SportDiscus and PEDro. The search identified 563 records. After screening records and applying the eligibility criteria, nine cross-sectional studies (n=925) were included in the review, investigating 452 current and 473 former players (859 males, 66 females). Six studies (n=595) reported evidence for an association between heading and impaired cognitive function, while three studies (n=330) reported no association. Diverse cognitive domains were investigated, which might underline the disparity in these results. The association between heading and cognitive function in professional football appears likely but remains inconclusive. Methodological heterogeneity and variability in the presentation of results limits the conclusions drawn. Prospective longitudinal studies using standardised methods, and including females, are required to provide evidence to support or refute an association., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Attentional deficits have tragic consequences on road safety. These deficits are not solely caused by distraction, since they can also arise from other mental impairments such as, most frequently, mental fatigue. Fatigue is among the most prevalent impairing conditions while driving, degrading drivers' cognitive and physical abilities. This issue is particularly relevant for professional drivers, who spend most of their time behind the wheel. While scientific literature already documented the behavioral effects of driving fatigue, most studies have focused on drivers under sleep deprivation or anyhow at severe fatigue degrees, since it is difficult to recognize the onset of fatigue. The present study employed an EEG-driven approach to detect early signs of fatigue in professional drivers during a simulated task, with the aim of studying visual attention as fatigue begins to set in. Short-range and long-range professional drivers were recruited to take part in a 45-min-long simulated driving experiment. Questionnaires were used to validate the experimental protocol. A previously validated EEG index, the MDrow, was adopted as the benchmark measure for identifying the "fatigued" spans. Results of the eye-tracking analysis showed that, when fatigued, professional drivers tended to focus on non-informative portions of the driving environment. This paper presents evidence that an EEG-driven approach can be used to detect the onset of fatigue while driving and to study the related visual attention patterns. It was found that the onset of fatigue did not differentially impact drivers depending on their professional activity (short- vs. long-range delivery).

Curcumin (Cur) and resveratrol (Rsv) have already been proposed for both anti-tumor and wound healing applications and contrasting results have been published regarding their anti- or pro-angiogenic activity; depending on the final application, an anti- or a pro-angiogenic activity is required. In the present study, a comparison of Cur and Rsv loaded electrospun fibers based on collagen and polycaprolactone (PCL) mixture was performed in order to make a contribution to understanding whether the two polyphenols have anti or pro-angiogenic activity. Despite their hydrophobic character, the two polyphenols affected morphology and wettability of the fibers, and Rsv-loaded fibers resulted larger and more quickly wettable. After hydration, collagen/PCL fibers loaded with both Cur and Rsv exhibited higher elongation and better deformation with respect to the unloaded fibers. Fourier transformed infrared spectroscopy and thermal analysis showed interactions between the polyphenols and collagen. Both fiber formulations resulted biocompatible with an increase of fibroblast number during 7 days of culture; confocal microscopy analyses demonstrated that Cur released by the fibers was internalized by the cells which remained vital and adherent. Chick embryo chorioallantoic membrane assay showed that both fibers had anti-angiogenic behavior, suggesting that an anti-cancer application more than a wound healing one could be envisaged., 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 article., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In targeted cancer therapy, antibody-drug-conjugates using mertansine (DM1)-based cytotoxic compounds rely on covalent bonds for drug conjugation. Consequently, the cytotoxic DM1 derivative released upon their proteolytic digestion is up to 1000-fold less potent than DM1 and lacks a bystander effect. To overcome these limitations, we developed a DM1 derivative (keto-DM1) suitable for bioconjugation through an acid-reversible hydrazone bond. Its acid-reversible hydrazone conjugate with biotin (B-Hz-DM1) was generated and tested for efficacy using the cetuximab-targeted Avidin-Nucleic-Acid-NanoASsembly (ANANAS) nanoparticle (NP) platform. NP-tethered B-Hz-DM1 is stable at neutral pH and releases its active moiety only in endosome/lysosome mimicking acidic pH. In vitro, the NP/Cetux/B-Hz-DM1 assembly showed high potency on MDA-MB231 breast cancer cells. In vivo both B-Hz-DM1 and NP/Cetux/B-Hz-DM1 reduced tumor growth. A significantly major effect was exerted by the nanoformulation, associated with an increased in situ tumor cell death. Keto-DM1 is a promising acid-reversible mertansine derivative for targeted delivery in cancer therapy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: In autoimmune hepatitis, achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response., Approach and Results: The relation between metabolites and treatment response was assessed in 337 individuals from 4 European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanine nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N = 146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 mL) compared to those failing to maintain CBR (181 pmol/0.2 mL; p = 0.0014) or never achieving CBR (153 pmol/0.2 mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223 pmol/0.2 mL (sensitivity: 76% and specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 mL following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%; p < 0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321 pmol/0.2 mL; p < 0.0001) and lowered 6MMP (2125→184 pmol/0.2 mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%., Conclusions: Maintaining CBR in autoimmune hepatitis was associated with 6TGN ≥223 pmol/0.2 mL. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, comedication of allopurinol alongside low-dose thiopurines represents an efficient alternative., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction: Artificial intelligence-based chatbots offer a potential avenue for delivering personalized counseling to patients with autoimmune hepatitis. We assessed accuracy, completeness, comprehensiveness, and safety of Chat Generative Pretrained Transformer-4 responses to 12 inquiries out of a pool of 40 questions posed by 4 patients with autoimmune hepatitis., Methods: Questions were categorized into 3 areas: diagnosis (1-3), quality of life (4-8), and medical treatment (9-12). 11 key opinion leaders evaluated responses using a Likert scale with 6 points for accuracy, 5 points for safety, and 3 points for completeness and comprehensiveness., Results: Median scores for accuracy, completeness, comprehensiveness, and safety were 5 (4-6), 2 (2-2), and 3 (2-3), respectively; no domain exhibited superior evaluation. Postdiagnosis follow-up question was the trickiest with low accuracy and completeness, but safe and comprehensive features. Agreement among key opinion leaders (Fleiss Kappa statistics) was slight for the accuracy (0.05) but poor for the remaining features (-0.05, -0.06, and -0.02, respectively)., Discussion: Chatbots show good comprehensibility, but lack reliability. Further studies are needed to integrate Chat Generative Pretrained Transformer within clinical practice., (Copyright © 2024 by The American College of Gastroenterology.)

The benzoxaborinine scaffold, a homologue of benzoxaborole with an additional carbon atom in the boracycle, shows significant potential in developing new therapeutic agents. This study reports the synthesis, inhibition assays against four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, and anti-melanoma evaluation of 7-aryl(thio)ureido-substituted benzoxaborinines. Some derivatives, particularly compound 11 , exhibited potent inhibitory activity (below 65 nM) against hCA IX and XII and stronger antiproliferative effects than SLC-0111 on human melanoma cells under hypoxia. Crystallographic studies of benzoxaborinine 3 adducts with hCA I and II demonstrated the binding mode of this chemotype, revealing that although both benzoxaborinine 3 and benzoxaborole 10 share a similar zinc-binding mode, the expanded ring in benzoxaborinine led to a different orientation within the active site. These findings suggest that benzoxaborinines hold promise for designing novel carbonic anhydrase inhibitors.

Fragment crystallizable gamma receptors (FcγRs) mediate various cellular responses with significant cardiovascular implications. They contribute to the anticancer activity of trastuzumab (TRZ), a recombinant humanized monoclonal antibody that interferes with human epidermal growth factor receptor 2 (HER2), thereby blocking its physiological function in cardiac cells. This is responsible for cardiac complications that hamper TRZ clinical application. In this study we investigated the involvement of FcγRs in the TRZ cardiotoxicity. We used a recombinant antigen-binding fragment (Fab) of TRZ (rFab-HER2) to examine whether the absence of the Fc region resulted in fewer cardiomyocyte toxicity while preserving TRZ's ability to inhibit HER2. When exposed to rFab-HER2, AC16 human adult ventricular cardiomyocytes were less vulnerable to damage and death, than to TRZ. Specifically, TRZ exhibited cytotoxicity at a lower concentration (150 µg/mL, corresponding to ~1 µM) compared to rFab-HER2 (250 µg/mL, corresponding to ~5 µM). Like TRZ, rFab-HER2 negatively modulated HER2 levels in cardiomyocyte (without inducing cytotoxic activity in BJ human fibroblast cells that either did not express or express very low levels of HER2) and inhibited the downstream ERK/AKT cascades. But rFab-HER2 did not alter cardiomyocyte mitochondrial dynamic balance, and affect apoptosis and inflammation, while it limited cytosolic and mitochondrial ROS indicators. On contrary, the Fc region (50-250 μg/mL) exerted direct cytotoxic action on cardiomyocytes (but not on human fibroblasts that lacked Fc receptors). TRZ (150 μg/mL) markedly upregulated the expression level of FcγRIIA (a FcγRs strongly involved in TRZ-induced antibody-dependent cellular toxicity) in cardiomyocytes, whereas the Fab fragment (150 μg/mL) had no effect. Our results demonstrate that Fc region plays an important pathogenic role in TRZ-induced cardiomyocyte toxicity. In addition, targeting FcγRIIA might contribute to the off-target effects of TRZ therapy., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Ocular artifacts, including blinks and saccades, pose significant challenges in the analysis of electroencephalographic (EEG) data, often obscuring crucial neural signals. This tutorial provides a comprehensive guide to the most effective methods for correcting these artifacts, with a focus on algorithms designed for both laboratory and real-world settings. We review traditional approaches, such as regression-based techniques and Independent Component Analysis (ICA), alongside more advanced methods like Artifact Subspace Reconstruction (ASR) and deep learning-based algorithms. Through detailed step-by-step instructions and comparative analysis, this tutorial equips researchers with the tools necessary to maintain the integrity of EEG data, ensuring accurate and reliable results in neurophysiological studies. The strategies discussed are particularly relevant for wearable EEG systems and real-time applications, reflecting the growing demand for robust and adaptable solutions in applied neuroscience.

Objective:  This study aimed to compare rehospitalization rates, diagnoses, and well-baby nursery (WBN) length of stay (LOS) among rehospitalized infants born during the COVID-19 pandemic to those born prior., Study Design:  A retrospective comparison of 215 infants rehospitalized from March 1, 2019, to March 1, 2021, was performed in an urban academic center. Rates of readmission were determined for all infants using an unadjusted odds ratio. Among infants rehospitalized at ≤30 and ≤7 days, key cohort characteristics were analyzed using chi-square analysis, Fisher's exact test, independent t -test, and nonparametric testing as applicable. Differences in readmission diagnoses determined by International Classification of Diseases (ICD) code and chart review were evaluated with multivariable logistic regression comparing infants born during the pandemic to the year prior., Results:  Pandemic infants had a 51% increased odds of rehospitalization ≤7 days of discharge from WBN compared with prepandemic infants (95% confidence interval [CI]: 1.09-2.09). Rehospitalized infants born during the pandemic had shorter WBN LOS; infants rehospitalized ≤30 days had LOS of 54.3 ± 18.6 versus 59.6 ± 16.2 hours ( p  = 0.02) and infants rehospitalized ≤7 days had LOS of 53.8 ± 17.8 versus 60.8 ±17.0 hours ( p  = 0.02). The pandemic group of infants had a 3.5 increased odds of being readmitted for hyperbilirubinemia compared with other diagnoses after adjusting for biological sex, ethnicity, percent weight lost at time of discharge, gestational age, and mode of delivery (CI 1.9, 6.4)., Conclusion:  Rehospitalization ≤7 days post-WBN discharge was more common in infants born during the pandemic. Infants rehospitalized during the pandemic were more likely to have shorter WBN LOS and to be rehospitalized for hyperbilirubinemia. Retrospective analyses limit conclusions about causation but suggest that being born during the pandemic increased risk of rehospitalization for hyperbilirubinemia among infants in urban, under resourced setting warranting further investigation., Key Points: · Newborns rehospitalized during the pandemic had a shorter newborn nursery stay.. · Newborns in the pandemic had a higher rate of rehospitalization within 7 days of birth compared to year prior.. · More infants who required readmission during the pandemic were hospitalized for hyperbilirubinemia.., Competing Interests: None declared., (Thieme. All rights reserved.)

Current research suggests that menstruating female athletes might be at greater risk of musculoskeletal injury in relation to hormonal changes throughout the menstrual cycle. A separate body of work suggests that spatial cognition might also fluctuate in a similar manner. Changes in spatial cognition could, in theory, be a contributing risk factor for injury, especially in fast-paced sports that require precise, millisecond accuracy in interactions with moving objects in the environment. However, existing theories surrounding causes for increased injury risk in menstruating females largely focus on biomechanical mechanisms, with little consideration of possible cognitive determinants of injury risk. Therefore, the aim of this proof-of-principle study was to explore whether menstruating females exhibit fluctuations in cognitive processes throughout their cycle on a novel sport-oriented cognitive test battery, designed to measure some of the mental processes putatively involved in these sporting situations. A total of 394 participants completed an online cognitive battery, a mood scale and a symptom questionnaire twice, 14 days apart. After exclusions, 248 eligible participants were included in the analyses (mean: 28 ± 6 years) (male = 96, female(menstruating) = 105, female(contraception) = 47). Cycle phase for menstruating females was based on self-reported information. The cognitive battery was designed to measure reaction times, attention, visuospatial functions (including 3D mental rotation) and timing anticipation. Three composite scores were generated using factor analysis with varimax rotation (Errors, Reaction Time, Intra-Individual Variability). Mixed model ANOVAs and repeated measures ANOVAs were performed to test for between and within-subject effects. There was no group difference in reaction times and accuracy between males and females (using contraception and not). However, within subject analyses revealed that regularly menstruating females performed better during menstruation compared to being in any other phase, with faster reaction times (10ms c.ca, p < 0.01), fewer errors (p < 0.05) and lower dispersion intra-individual variability (p < 0.05). In contrast they exhibited slower reaction times (10ms c.ca, p < 0.01) and poorer timing anticipation (p < 0.01) in the luteal phase, and more errors in the predicted ovulatory phase (p < 0.01). Self-reported mood, cognitive and physical symptoms were all worst during menstruation (p < 0.01), and a significant proportion of females felt that their symptoms were negatively affecting their cognitive performance during menstruation on testing day, which was incongruent with their actual performance. These findings suggest that visuospatial and anticipatory processes may fluctuate throughout the menstrual cycle in the general population, with better performance during the menstrual phase and poorer performance during the luteal phase. If these extend to associations between phase-specific cognitive performance and injury incidence, they would support a cognitive theory of determinants of injury risk in cycling female athletes, opening an opportunity to develop mitigation strategies where appropriate., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). The Prevent Acute Chest Syndrome checklist (PACScheck) was created to drive appropriate ordering of opioids, incentive spirometry (IS), intravenous fluids (IVF), evaluation of oxygen desaturation, and bronchodilator use., Objectives: Decrease the development of ACS by 5% in a hospitalized pediatric SCD population., Methods: A multidisciplinary team conducted a quality improvement (QI) project between April 2020 and August 2021 on an inpatient pediatric hematology unit. At-risk hospitalizations were patients with SCD who did not have ACS upon hospital admission. PACScheck was implemented and weekly run charts assessed documentation. Process control (p) charts, geometric control (g) charts, and chi-square tests assessed checklist process measures pre- and post-PACScheck. G chart assessed the number of encounters between ACS events., Results: A total of 483 at-risk hospitalizations were identified in the 12 months prior and 363 during the study period. A g chart demonstrated that fewer encounters developed ACS during PACScheck. A p chart demonstrated that IS documentation increased during PACScheck. A run chart of PACScheck documentation demonstrated a median of 100% documentation at least once per hospitalization during the last six months of the intervention., Conclusion: Development of ACS can be reduced by implementing a best-practices checklist (PACScheck) on an inpatient pediatric hematology unit with a multidisciplinary team., (© 2024 Wiley Periodicals LLC.)

In the context of electroencephalographic (EEG) signal processing, artifacts generated by ocular movements, such as blinks, are significant confounding factors. These artifacts overwhelm informative EEG features and may occur too frequently to simply remove affected epochs without losing valuable data. Correcting these artifacts remains a challenge, particularly in out-of-lab and online applications using wearable EEG systems (i.e. with low number of EEG channels, without any additional channels to track EOG). Objective. The main objective of the present work consisted in validating a novel ocular blinks artefacts correction method, named multi-stage OCuLar artEfActs deNoising algorithm (o-CLEAN), suitable for online processing with minimal EEG channels. Approach. The research was conducted considering one EEG dataset collected in highly controlled environment, and a second one collected in real environment. The analysis was performed by comparing the o-CLEAN method with previously validated state-of-art techniques, and by evaluating its performance along two dimensions: (a) the ocular artefacts correction performance (IN-Blink), and (b) the EEG signal preservation when the method was applied without any ocular artefacts occurrence (OUT-Blink). Main results. Results highlighted that (i) o-CLEAN algorithm resulted to be, at least, significantly reliable as the most validated approaches identified in scientific literature in terms of ocular blink artifacts correction, (ii) o-CLEAN showed the best performances in terms of EEG signal preservation especially with a low number of EEG channels. Significance. The testing and validation of the o-CLEAN addresses a relevant open issue in bioengineering EEG processing, especially within out-of-the-lab application. In fact, the method offers an effective solution for correcting ocular artifacts in EEG signals with a low number of available channels, for online processing, and without any specific template of the EOG. It was demonstrated to be particularly effective for EEG data gathered in real environments using wearable systems, a rapidly expanding area within applied neuroscience., (Creative Commons Attribution license.)

The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last session will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver disease, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.

Introduction: In operational environments, human interaction and cooperation between individuals are critical to efficiency and safety. These states are influenced by individuals' cognitive and emotional states. Human factor research aims to objectively quantify these states to prevent human error and maintain constant performances, particularly in high-risk settings such as aviation, where human error and performance account for a significant portion of accidents., Methods: Thus, this study aimed to evaluate and validate two novel methods for assessing the degree of cooperation among professional pilots engaged in real-flight simulation tasks. In addition, the study aimed to assess the ability of the proposed metrics to differentiate between the expertise levels of operating crews based on their levels of cooperation. Eight crews were involved in the experiments, consisting of four crews of Unexperienced pilots and four crews of Experienced pilots. An expert trainer, simulating air traffic management communication on one side and acting as a subject matter expert on the other, provided external evaluations of the pilots' mental states during the simulation. The two novel approaches introduced in this study were formulated based on circular correlation and mutual information techniques., Results and Discussion: The findings demonstrated the possibility of quantifying cooperation levels among pilots during realistic flight simulations. In addition, cooperation time is found to be significantly higher ( p < 0.05) among Experienced pilots compared to Unexperienced ones. Furthermore, these preliminary results exhibited significant correlations ( p < 0.05) with subjective and behavioral measures collected every 30 s during the task, confirming their reliability., Competing Interests: VR, NS, GB, GD, AV, AG, FB, and PA were employed by BrainSigns srl. The remaining 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Capotorto, Ronca, Sciaraffa, Borghini, Di Flumeri, Mezzadri, Vozzi, Giorgi, Germano, Babiloni and Aricò.)

In this work, we present ab initio cavity quantum electrodynamics (QED) methods which include interactions with a static magnetic field and nuclear spin degrees of freedom using different treatments of the quantum electromagnetic field. We derive explicit expressions for QED-HF magnetizability, nuclear shielding, and spin-spin coupling tensors. We apply this theory to explore the influence of the cavity field on the magnetizability of saturated, unsaturated, and aromatic hydrocarbons, showing the effects of different polarization orientations and coupling strengths. We also examine how the cavity affects aromaticity descriptors, such as the nucleus-independent chemical shift and magnetizability exaltation. We employ these descriptors to study the trimerization reaction of acetylene to benzene. We show how the optical cavity induces modifications in the aromatic character of the transition state leading to variations in the activation energy of the reaction. Our findings shed light on the effects induced by the cavity on magnetic properties, especially in the context of aromatic molecules, providing valuable insights into understanding the interplay between the quantum electromagnetic field and molecules.

The study aimed at investigating the impact of an innovative Wake Vortex Alert (WVA) avionics on pilots' operation and mental states, intending to improve aviation safety by mitigating the risks associated with wake vortex encounters (WVEs). Wake vortices, generated by jet aircraft, pose a significant hazard to trailing or crossing aircrafts. Despite existing separation rules, incidents involving WVEs continue to occur, especially affecting smaller aircrafts like business jets, resulting in aircraft upsets and occasional cabin injuries. To address these challenges, the study focused on developing and validating an alert system that can be presented to air traffic controllers, enabling them to warn flight crews. This empowers the flight crews to either avoid the wake vortex or secure the cabin to prevent injuries. The research employed a multidimensional approach including an analysis of human performance and human factors (HF) issues to determine the potential impact of the alert on pilots' roles, tasks, and mental states. It also utilizes Human Assurance Levels (HALs) to evaluate the necessary human factors support based on the safety criticality of the new system. Realistic flight simulations were conducted to collect data of pilots' behavioural, subjective and neurophysiological responses during WVEs. The data allowed for an objective evaluation of the WVA impact on pilots' operation, behaviour and mental states (mental workload, stress levels and arousal). In particular, the results highlighted the effectiveness of the alert system in facilitating pilots' preparation, awareness and crew resource management (CRM). The results also highlighted the importance of avionics able to enhance aviation safety and reducing risks associated with wake vortex encounters. In particular, we demonstrated how providing timely information and improving situational awareness, the WVA will minimize the occurrence of WVEs and contribute to safer aviation operations., Competing Interests: Declaration of Competing Interest Declarations of interest: none, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context/objective: Perceived job quality is a key indicator of sustainable work among persons with spinal cord injuries (PwSCI). This study aimed at (a) describing three indicators of perceived job quality ( i.e. job satisfaction, job performance, and work stress) among working PwSCI, and (b) identifying whether and how different person-job match dimensions ( i.e. interest congruence, demands-abilities fit, needs-supplies fit, and effort-reward imbalance) as well as sociodemographic and health-related factors ( e.g. age, sex, SCI-related characteristics, pain problems, and depressive symptoms) are associated with perceived job quality., Design: Cross-sectional, self-report survey., Setting: Community., Participants: 549 working-age PwSCI who participated in the 2017 community survey of the Swiss Spinal Cord Injury Cohort study and reported being engaged in paid work., Outcome Measures: Job satisfaction, job performance, and work stress., Results: Higher interest congruence, better needs-supplies fit and lower effort-reward imbalance, as well as female sex, were associated with higher job satisfaction, while higher effort-reward imbalance, poorer demands-abilities fit (underqualification), and - surprisingly - better needs-supplies fit were associated with higher work stress. Moreover, underqualification, worse needs-supplies fit as well as pain, depressive symptoms, and language region were associated with lower job performance., Conclusion: Integrating individuals in jobs that match their abilities, interests and needs, and which adequately reward their efforts may contribute to better job quality among PwSCI. Beyond that, common secondary health conditions and comorbidities such as pain and depressive symptoms should receive particular attention in interventions that aim to promote job quality and ultimately sustainable work in the SCI population.

The development of new methodologies for the selective synthesis of individual enantiomers is still one of the major challenges in synthetic chemistry. Many biomolecules, and also many pharmaceutical compounds, are indeed chiral. While the use of chiral reactants or catalysts has led to substantial progress in the field of asymmetric synthesis, a systematic approach applicable to general reactions has still not been proposed. In this work, we demonstrate that strong coupling to circularly polarized fields can induce asymmetry in otherwise nonselective reactions. Specifically, we show that the field induces stereoselectivity in the early stages of chemical reactions by selecting an energetically preferred direction of approach for the reagents. Although the effects observed thus far are too small to significantly drive asymmetric synthesis, our results provide a proof of principle for field-induced stereoselective mechanisms. These findings lay the groundwork for future research.

Introduction: In the process of bone regeneration, a prominent role is played by macrophages involved in both the initial inflammation and the regeneration/vascularization phases, due to their M2 anti-inflammatory phenotype. Together with osteoclasts, they participate in the degradation of the bone matrix if the inflammatory process does not end. In this complex scenario, recently, much attention has been paid to extracellular communication mediated by nanometer-sized vesicles, with high information content, called exosomes (EVs). Considering these considerations, the purpose of the present work is to demonstrate how the presence of a pulsed electromagnetic field (PEMF) can positively affect communication through EVs., Methods: To this aim, macrophages and osteoclasts were treated in vitro with PEMF and analyzed through molecular biology analysis and by electron microscopy. Moreover, EVs produced by macrophages were characterized and used to verify their activity onto osteoclasts., Results: The results confirmed that PEMF not only reduces the inflammatory activity of macrophages and the degradative activity of osteoclasts but that the EVS produced by macrophages, obtained from PEMF treatment, positively affect osteoclasts by reducing their activity., Discussion: The co-treatment of PEMF with M2 macrophage-derived EVs (M2-EVs) decreased osteoclastogenesis to a greater degree than separate treatments., Competing Interests: Professor Shlomo Barak is the chairman of the board of Magdent Ltd. Dr Oleg Dolkart is a consultant for Magdent Ltd. The authors report no other conflicts of interest in this work., (© 2024 Trentini et al.)

The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space and preparations for exploration-class (lasting longer than one year) missions. Such rapid advancement into space from many new companies, countries and space-related entities has enabled a 'second space age'. This era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, and encompass multi-omic, single-cell and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics, as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this Perspective, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration, Japan Aerospace Exploration Agency, European Space Agency and other space agencies, and detail the entrance of the commercial spaceflight sector (including SpaceX, Blue Origin, Axiom and Sierra Space) into aerospace medicine and space biology, the first aerospace medicine biobank, and various upcoming missions that will utilize these tools to ensure a permanent human presence beyond low Earth orbit, venturing out to other planets and moons., (© 2024. Springer Nature Limited.)

Fibroblast growth factors (FGFs) act as proangiogenic and mitogenic cytokines in several cancers, including multiple myeloma (MM). Indeed, corrupted FGF autocrine and paracrine secretion induces an aberrant activation of the FGF receptor (FGFR) signaling sustaining cancer cell spreading and resistance to pharmacological treatments. Thus, FGF traps may represent a promising anti-cancer strategy to hamper the ligand-dependent activation of the FGF/FGFR system. We previously identified NSC12 as the first orally available small molecule FGF trap able to inhibit the growth and progression of several FGF-dependent tumor models. NSC12 is a pregnenolone derivative carrying a 1,1-bis-trifluoromethyl-1,3-propanediol chain in position 17 of the steroid nucleus. Investigation of structure-activity relationships (SARs) provided more potent and specific NSC12 steroid derivatives and highlighted that the C17-side chain is pivotal for the FGF trap activity. Here, a scaffold hopping approach allowed to obtain two FGF trap compounds (22 and 57) devoid of the steroid nucleus and able to efficiently bind FGF2 and to inhibit FGFR activation in MM cells. Accordingly, these compounds exert a potent anti-tumor activity on MM cell lines both in vitro and in vivo and on MM patient-derived primary cells, strongly affecting the survival of both proteasome-inhibitor sensitive and resistant MM cells. These results propose a new therapeutic option for relapsed/refractory MM patients and set the bases for the development of novel FGF traps prone to chemical diversification to be used in the clinic for the treatment of those tumors in which the FGF/FGFR system plays a pivotal role, including MM., 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 Ltd.. All rights reserved.)

Mixed-gender studies predominate in the current literature exploring the interaction between physical activity and dementia risk. Considering that menopause appears to contribute to females' increased risk of cognitive decline when compared to males, further clarity is required on the impact of physical activity in reducing late-life dementia risk, specifically in perimenopausal females. A literature search of MEDLINE, EMBASE, Web of Science, SCOPUS and CINAHL databases yielded fourteen studies for review. A significant inverse relationship between perimenopausal leisure time physical activity, or physical fitness, and future all-cause dementia risk was found in most studies exploring this interaction. Higher levels of perimenopausal household physical activity and combined non-leisure time physical activity also displayed a favorable impact in lowering dementia risk. A dose-response effect was demonstrated, with approximately 10 MET-hour/week of leisure time physical activity required for significant dementia risk reduction. Three of four papers exploring causality provided analyses proposed to counter the reverse causation argument, suggesting that physical activity may indeed have a protective role in reducing dementia risk post-menopause. The current systematic review provides promising results regarding the impact of pre- and perimenopausal physical activity on reducing late-life dementia risk, suggesting that promoting perimenopausal physical activity may serve as a crucial tool in mitigating the risk of post-menopausal cognitive decline., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Cochlear implants (CI) allow deaf patients to improve language perception and improving their emotional valence assessment. Electroencephalographic (EEG) measures were employed so far to improve CI programming reliability and to evaluate listening effort in auditory tasks, which are particularly useful in conditions when subjective evaluations are scarcely appliable or reliable. Unfortunately, the presence of CI on the scalp introduces an electrical artifact coupled to EEG signals that masks physiological features recorded by electrodes close to the site of implant. Currently, methods for CI artifact removal have been developed for very specific EEG montages or protocols, while others require many scalp electrodes. In this study, we propose a method based on the Multi-channel Wiener filter (MWF) to overcome those shortcomings. Nine children with unilateral CI and nine age-matched normal hearing children (control) participated in the study. EEG data were acquired on a relatively low number of electrodes ( n = 16) during resting condition and during an auditory task. The obtained results obtained allowed to characterize CI artifact on the affected electrode and to significantly reduce, if not remove it through MWF filtering. Moreover, the results indicate, by comparing the two sample populations, that the EEG data loss is minimal in CI users after filtering, and that data maintain EEG physiological characteristics.

The development of broad-spectrum coronavirus vaccines is essential to prepare for future respiratory virus pandemics. We demonstrated broad neutralization by a trivalent subunit vaccine, formulating the receptor-binding domains of SARS-CoV, MERS-CoV, and SARS-CoV-2 XBB.1.5 with Alum and CpG55.2. Vaccinated mice produced cross-neutralizing antibodies against all three human Betacoronaviruses and others currently exclusive to bats, indicating the epitope preservation of the individual antigens during co-formulation and the potential for epitope broadening., (© 2024. The Author(s).)

Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX is a tumor-associated CA isoform induced by hypoxia and involved in the adaptation of tumor cells to acidosis. Indeed, several tumor-driving pathways can induce CA IX expression, and this in turn has been associated to cancer cells invasion and metastatic features as well as to induction of stem-like features, drug resistance and recurrence. After its functional and structural characterization CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues, and to date this field has seen an incredible acceleration in terms of therapeutic options and biological readouts. Small molecules inhibitors, hybrid/dual targeting drugs, targeting antibodies and adoptive (CAR-T based) cell therapy have been developed at preclinical level, whereas a sulfonamide CA IX inhibitor and an antibody entered Phase Ib/II clinical trials for the treatment and imaging of different solid tumors. Here recent advances on CA IX biology and pharmacology in cancer, and its therapeutic targeting will be discussed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roberto Ronca reports financial support was provided by Italian Association for Cancer Research. If there are other authors, they 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 B.V. All rights reserved.)

A hybrid cellulose-based programmable nanoplatform for applications in precision radiation oncology is described. Here, sugar heads work as tumor targeting moieties and steer the precise delivery of radiosensitizers, i.e. gold nanoparticles (AuNPs) into triple negative breast cancer (TNBC) cells. This "Trojan horse" approach promotes a specific and massive accumulation of radiosensitizers in TNBC cells, thus avoiding the fast turnover of small-sized AuNPs and the need for high doses of AuNPs for treatment. Application of X-rays resulted in a significant increase of the therapeutic effect while delivering the same dose, showing the possibility to use roughly half dose of X-rays to obtain the same radiotoxicity effect. These data suggest that this hybrid nanoplatform acts as a promising tool for applications in enhancing cancer radiotherapy effects with lower doses of X-rays.

Autoimmune liver diseases (AILDs) constitute the fourth most common indication for liver transplantation (LT) across the world. In general, the outcomes after LT are acceptable; however, disease recurrence after LT is common for all AILD, which can negatively affect graft and overall survival. Several questions persist, including the risk factors associated with recurrent disease, optimal antirejection medications, strategies to reduce the risk of recurrence, and how to best incorporate these strategies into clinical practice. For that reason, we assembled an international group of experts to review evidence to address these outstanding questions regarding LT for AILD. Survival rates after LT are ~90% and 70% at 1 and 5 years, and recurrent disease occurs in 10%-50% of patients with AILD. In patients with disease recurrence, graft survival decreased by 18% and 28% and overall survival by 8% and 12% at 5 and 10 years after LT, respectively. Recurrent autoimmune hepatitis is associated with high aminotransferases and immunoglobulin G (IgG) before LT, lymphoplasmacytic infiltrates in the explants, and may be associated with the absence of steroids after LT. However, the efficiency and safety of triple immunosuppressive maintenance therapy is still debatable. Younger age at diagnosis with primary biliary cholangitis or LT is associated with primary biliary cholangitis recurrence. Preventive use of ursodeoxycholic acid reduces the risk of recurrence and has a benefit in graft and patient survival. Episodes of systemic inflammation, including T-cell-mediated rejection, active ulcerative colitis, and episodes of cholangitis, are associated with recurrent PSC. Recurrent disease for AILD is associated with worse graft and patient survival. Patients with autoimmune hepatitis could be considered for long-term low-dose predniso(lo)ne, whereas patients with primary biliary cholangitis should be placed on preventive ursodeoxycholic acid after LT. There are no specific treatments for PSC recurrence; however, adequate control of inflammatory bowel disease and optimal immunosuppression to avoid T-cell-mediated rejection should be encouraged., (Copyright © 2024 American Association for the Study of Liver Diseases.)

COVID-19, caused by the SARS-CoV-2 virus, is a highly pathogenic emerging infectious disease. Healthcare personnel (HCP) are presumably at higher risk of acquiring emerging infections because of occupational exposure. The prevalence of COVID-19 in HCP is unknown, particularly in low- to middle-income countries like El Salvador. The goal of this study was to determine the seroprevalence of anti-SARS-CoV-2 antibodies among HCP in El Salvador just prior to vaccine rollout in March 2021. We evaluated 2176 participants from a nationally representative sample of national healthcare institutions. We found 40.4% ( n = 880) of the study participants were seropositive for anti-spike protein antibodies. Significant factors associated with infection included younger age; living within the central, more populated zone of the country; living in a larger household (≥7 members); household members with COVID-19 or compatible symptoms; and those who worked in auxiliary services (i.e., housekeeping and food services). These findings provide insight into opportunities to mitigate SARS-CoV-2 risk and other emerging respiratory pathogens in HCP in El Salvador.

In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested in vitro for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative 11 , which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An in silico study was conducted to assess the binding mode of 11 within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

RNA viruses, like SARS-CoV-2, depend on their RNA-dependent RNA polymerases (RdRp) for replication, which is error prone. Monitoring replication errors is crucial for understanding the virus's evolution. Current methods lack the precision to detect rare de novo RNA mutations, particularly in low-input samples such as those from patients. Here we introduce a targeted accurate RNA consensus sequencing method (tARC-seq) to accurately determine the mutation frequency and types in SARS-CoV-2, both in cell culture and clinical samples. Our findings show an average of 2.68 × 10 -5 de novo errors per cycle with a C > T bias that cannot be solely attributed to APOBEC editing. We identified hotspots and cold spots throughout the genome, correlating with high or low GC content, and pinpointed transcription regulatory sites as regions more susceptible to errors. tARC-seq captured template switching events including insertions, deletions and complex mutations. These insights shed light on the genetic diversity generation and evolutionary dynamics of SARS-CoV-2., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Dengue virus (DENV) is one of the most significant vector-borne pathogens worldwide. In this report, we describe clinical features and laboratory detection of dengue in a 45-year-old traveler to Nicaragua on return home to the United States in 2019. Clinical presentation was mild, with rash, headache, and fatigue, with only low-grade transient fever. Infection dynamics were documented by serology and PCR of serially collected body fluids. DENV serotype 2 was detected in whole blood 1 day after symptoms emerged, with viral RNA isolated to the red cell fraction, and remained detectable through day 89. DENV-2 RNA was detected in serum only on day 4, and IgM was undetectable on day 4 but evident by day 13. Viral RNA was also detected in urine. This report of DENV-2 RNA persistence in blood cells but only transient appearance in serum, supports the potential diagnostic value of whole blood over serum for PCR and opportunity of an expanded testing window. Informed testing approaches can improve diagnostic accuracy and inform strategies that preserve individual and public health., 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. Published by Elsevier Ltd.)

A new experimental setup combining X-ray photon correlation spectroscopy (XPCS) in the hard X-ray regime and a high-pressure sample environment has been developed to monitor the pressure dependence of the internal motion of complex systems down to the atomic scale in the multi-gigapascal range, from room temperature to 600 K. The high flux of coherent high-energy X-rays at fourth-generation synchrotron sources solves the problems caused by the absorption of diamond anvil cells used to generate high pressure, enabling the measurement of the intermediate scattering function over six orders of magnitude in time, from 10 -3  s to 10 3  s. The constraints posed by the high-pressure generation such as the preservation of X-ray coherence, as well as the sample, pressure and temperature stability, are discussed, and the feasibility of high-pressure XPCS is demonstrated through results obtained on metallic glasses., (open access.)

Uveal melanoma (UM) is the most common primary ocular tumor in the adult population. Even though these primary tumors are successfully treated in 90% of cases, almost 50% of patients ultimately develop metastasis, mainly in the liver, via hematological dissemination, with a median survival spanning from 6 to 12 months after diagnosis. In this context, chemotherapy regimens and molecular targeted therapies have demonstrated poor response rates and failed to improve survival. Among the multiple reasons for therapy failure, the presence of cancer stem-like cells (CSCs) represents the main cause of resistance to anticancer therapies. In the last few years, the existence of CSCs in UM has been demonstrated both in preclinical and clinical studies, and new molecular pathways and mechanisms have been described for this subpopulation of UM cells. Here, we will discuss the state of the art of CSC biology and their potential exploitation as therapeutic target in UM., 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. Published by Elsevier B.V.)

Competing Interests: Declaration of competing interest The authors declare no competing financial interests.

The biological and biomechanical functions of cartilage, bone and osteochondral tissue are naturally orchestrated by a complex crosstalk between zonally dependent cells and extracellular matrix components. In fact, this crosstalk involves biomechanical signals and the release of biochemical cues that direct cell fate and regulate tissue morphogenesis and remodelling in vivo. Three-dimensional bioprinting introduced a paradigm shift in tissue engineering and regenerative medicine, since it allows to mimic native tissue anisotropy introducing compositional and architectural gradients. Moreover, the growing synergy between bioprinting and drug delivery may enable to replicate cell/extracellular matrix reciprocity and dynamics by the careful control of the spatial and temporal patterning of bioactive cues. Although significant advances have been made in this direction, unmet challenges and open research questions persist. These include, among others, the optimization of scaffold zonality and architectural features; the preservation of the bioactivity of loaded active molecules, as well as their spatio-temporal release; the in vitro scaffold maturation prior to implantation; the pros and cons of each animal model and the graft-defect mismatch; and the in vivo non-invasive monitoring of new tissue formation. This work critically reviews these aspects and reveals the state of the art of using three-dimensional bioprinting, and its synergy with drug delivery technologies, to pattern the distribution of cells and/or active molecules in cartilage, bone and osteochondral engineered tissues. Most notably, this work focuses on approaches, technologies and biomaterials that are currently under in vivo investigations, as these give important insights on scaffold performance at the implantation site and its interaction/integration with surrounding tissues., (© 2023. The Author(s).)

Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound. This study assessed the biological effects of disulfiram on leukemia cells and evaluated its potential as a treatment strategy. We found that disulfiram inhibits the viability of a diverse panel of acute lymphoblastic and myeloid leukemia cell lines (n = 16) and patient-derived xenograft cells from patients with poor outcome and treatment-resistant disease (n = 15). The drug induced oxidative stress and apoptosis in leukemia cells within hours of treatment and was able to potentiate the effects of daunorubicin, etoposide, topotecan, cytarabine, and mitoxantrone chemotherapy. Upon combining disulfiram with auranofin, a drug approved for the treatment of rheumatoid arthritis that was previously shown to exert antileukemic effects, strong and consistent synergy was observed across a diverse panel of acute leukemia cell lines, the mechanism of which was based on enhanced ROS induction. Acute leukemia cells were more sensitive to the cytotoxic activity of disulfiram than solid cancer cell lines and non-malignant cells. While disulfiram is currently under investigation in clinical trials for solid cancers, this study provides evidence for the potential of disulfiram for acute leukemia treatment. KEY MESSAGES: Disulfiram induces rapid apoptosis in leukemia cells by boosting oxidative stress. Disulfiram inhibits leukemia cell growth more potently than solid cancer cell growth. Disulfiram can enhance the antileukemic efficacy of chemotherapies. Disulfiram strongly synergises with auranofin in killing acute leukemia cells by ROS induction. We propose testing of disulfiram in clinical trial for patients with acute leukemia., (© 2024. The Author(s).)

The N-terminal region of troponin T (TnT) does not bind any protein of the contractile machinery and the role of its hypervariability remains uncertain. In this review we report the evidence of the interaction between TnT and AMP deaminase (AMPD), a regulated zinc enzyme localized on the myofibril. In periods of intense muscular activity, a decrease in the ATP/ADP ratio, together with a decrease in the tissue pH, is the stimulus for the activation of the enzyme that deaminating AMP to IMP and NH 3 displaces the myokinase reaction towards the formation of ATP. In skeletal muscle subjected to strong tetanic contractions, a calpain-like proteolytic activity produces the removal in vivo of a 97-residue N-terminal fragment from the enzyme that becomes desensitized towards the inhibition by ATP, leading to an unrestrained production of NH 3 . When a 95-residue N-terminal fragment is removed from AMPD by trypsin, simulating in vitro the calpain action, rabbit fast TnT or its phosphorylated 50-residue N-terminal peptide binds AMPD restoring the inhibition by ATP. Taking in consideration that the N-terminus of TnT expressed in human as well as rabbit white muscle contains a zinc-binding motif, we suggest that TnT might mimic the regulatory action of the inhibitory N-terminal domain of AMPD due to the presence of a zinc ion connecting the N-terminal and C-terminal regions of the enzyme, indicating that the two proteins might physiologically associate to modulate muscle contraction and ammonia production in fast-twitching muscle under strenuous conditions., (© 2023. The Author(s).)

Lyophilized plant-origin extracts are rich in highly potent antioxidant polyphenols. In order to incorporate them into food products, it is necessary to protect these phytochemicals from atmospheric factors such as heat, light, moisture, or pH, and to enhance their bioavailability due to their low solubility. To address these challenges, recent studies have focused on the development of encapsulation techniques for antioxidant compounds within polymeric structures. In this study, lyophilized olive leaf extracts were microencapsulated with the aim of overcoming the aforementioned challenges. The method used for the preparation of the studied microparticles involves external ionic gelation carried out within a water-oil (W/O) emulsion at room temperature. HPLC analysis demonstrates a high content of polyphenols, with 90% of the bioactive compounds encapsulated. Meanwhile, quantification by inductively coupled plasma optical emission spectroscopy (ICP-OES) reveals that the dried leaves, lyophilized extract, and microencapsulated form contain satisfactory levels of macro- and micro-minerals (calcium, potassium, sodium). The microencapsulation technique could be a novel strategy to harness the polyphenols and minerals of olive leaves, thus enriching food products and leveraging the antioxidant properties of the polyphenolic compounds found in the lyophilized extract.

In the last decades, carbonic anhydrases (CAs) have become the top investigated innovative pharmacological targets and, in particular, isoforms IX and XII have been widely studied due to the evidence of their overexpression in hypoxic tumors. The frantic race to find new anticancer agents places the quick preparation of large libraries of putative bioactive compounds as the basis of a successful drug discovery and development programme. In this context, multi-component and, in general, one-step reactions are becoming very popular and, among them, Biginelli's reaction gave clean and easy-to-isolate products. Thus, we synthesized a series of Biginelli's products (10-17a-b) and similar derivatives (20-21) bearing the benzenesulfonamide moiety, which is known to inhibit CA enzymes. Through the stopped-flow technique, we were able to assess their ability to inhibit the targeted CAs IX and XII in the nanomolar range with promising selectivity over the physiologically relevant isoforms I and II. Crystallography studies and docking simulations helped us to gain insight into the interaction patterns established in the enzyme-inhibitor complex. From a chemical similarity-based screening of in-house libraries of compounds, a diphenylpyrimidine (23) emerged. The surprisingly potent inhibitory activity of 23 for CAs IX and XII along with its strong antiproliferative effect on two (triple-negative breast cancer MDA-MB-231 and glioblastoma U87MG) cell lines laid the foundation for further investigation, again confirming the key role of CAs in cancer., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Two-dimensional moiré materials have emerged as the most versatile platform for realizing quantum phases of electrons. Here, we explore the stability origins of correlated states in WSe&#95;{2}/WS&#95;{2} moiré superlattices. We find that ultrafast electronic excitation leads to partial melting of the Mott states on timescales 5 times longer than predictions from the charge hopping integrals and that the melting rates are thermally activated, with activation energies of 18±3 and 13±2  meV for the one- and two-hole Mott states, respectively, suggesting significant electron-phonon coupling. A density functional theory calculation of the one-hole Mott state confirms polaron formation and yields a hole-polaron binding energy of 16 meV. These findings reveal a close interplay of electron-electron and electron-phonon interactions in stabilizing the polaronic Mott insulators at transition metal dichalcogenide moiré interfaces.

Objectives. Musculoskeletal (MSK) complaints are prevalent in law enforcement officers (LEOs), but research that examines their risk factors is limited. This study aimed to identify the self-reported MSK complaint prevalence and perceived causes in LEOs. Methods. The Nordic musculoskeletal questionnaire was used to identify the 12-month and 7-day prevalence of MSK 'trouble' (ache, pain, discomfort) for nine body sites. The perceived cause, participant characteristics and occupational role were reported. Body fat percentage was measured using bioelectrical impedance. Results. Complete submissions of 186 questionnaires were received (80% male, median age 40.6 years, interquartile range 10.1). Eighty-six per cent of officers reported having an MSK complaint in the last 12 months, where lower back, shoulder and neck complaint prevalence was 59.1, 48.4 and 42.5%, respectively. The occupational role was associated with the site and presence of complaints ( p  < 0.05), where armed officers presented with more shoulder, lower back and hip/thigh complaints. Age, sex and body fat did not impact complaint prevalence. Participants mainly attributed their complaints to occupation equipment or to sport and exercise. Conclusion. MSK complaints were highly prevalent in this cohort, particularly armed officers. Further research is required to establish the impact of these complaints and how they can be mitigated.

Exposure to cosmic ionizing radiation is an innate risk of the spaceflight environment that can cause DNA damage and altered cellular function. In astronauts, longitudinal monitoring of physiological systems and interactions between these systems are important to consider for mitigation strategies. In addition, assessments of sex-specific biological responses in the unique environment of spaceflight are vital to support future exploration missions that include both females and males. Here we assessed sex-specific, multi-system immune and endocrine responses to simulated cosmic radiation. For this, 24-week-old, male and female C57Bl/6J mice were exposed to simplified five-ion, space-relevant galactic cosmic ray (GCRsim) radiation at 15 and 50 cGy, to simulate predicted radiation exposures that would be experienced during lunar and Martian missions, respectively. Blood and adrenal tissues were collected at 3- and 14-days post-irradiation for analysis of immune and endocrine biosignatures and pathways. Sexually dimorphic adrenal gland weights and morphology, differential total RNA expression with corresponding gene ontology, and unique immune phenotypes were altered by GCRsim. In brief, this study offers new insights into sexually dimorphic immune and endocrine kinetics following simulated cosmic radiation exposure and highlights the necessity for personalized translational approaches for astronauts during exploration missions., (© 2024. The Author(s).)

The drivers' distraction plays a crucial role in road safety as it is one of the main impacting causes of road accidents. The phenomenon of distraction encompasses both psychological and environmental factors and, therefore, addressing the complex interplay contributing to human distraction in automotive is crucial for developing technologies and interventions for improving road safety. In scientific literature, different works were proposed for the distraction characterization in automotive, but there is still the lack of a univocal measure to assess the degree of distraction, nor a gold-standard tool that allows to "detect" eventual events, road traffic, and additional driving tasks that might contribute to the drivers' distraction. Therefore, the present study aimed at developing an EEG-based "Distraction index" obtained by the combination of the driver's mental workload and attention neurometrics and investigating and validating its reliability by analyzing together subjective and behavioral measures. A total of 25 licensed drivers were involved in this study, where they had to drive in two different scenarios, i.e., City and Highway, while different secondary tasks were alternatively proposed in addition to the main one to modulate the driver's attentional demand. The statistical analysis demonstrated the reliability of the proposed EEG-based distraction index in identifying the drivers' distraction when driving along different roads and traffic conditions (all p < 0.001). More importantly, the proposed index was demonstrated to be reliable in identifying which are the most impacting additional driving tasks on the drivers' distraction (all p < 0.01).

AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60-68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain., (© 2024. The Author(s).)