bluuebunny/crossref_metadata_2025 huggingface dataset:
HEAD AND SHOULDERS - THE IMPACT OF AN EXTENDED HEAD MODEL ON THE SIMULATION AND OPTIMIZATION OF TRANSCRANIAL ELECTRIC STIMULATION
Authors: Van Hoornweder Sybren , Cappozzo Vittoria , De Herde Laura , Puonti Oula , Siebner Hartwig R. , Meesen Raf L.J. , Thielscher Axel
Published: August 2024

Electric field calculations are increasingly used for dose characterization of transcranial electrical stimulation (tES), but existing open-source head models are inaccurate for extracephalic montages that include electrodes placed on the neck or shoulder. We introduce the “Ernie Extended” model, an MRI- and CT-derived open-source head model extending to the upper shoulder region. Simulations of extracephalic tES targeting the cerebellum and supplementary motor area show significant differences in electric fields when using Ernie Extended compared to the non-extended Ernie model. Additionally, we propose an electrode layout that complements the electroencephalography 10– 20 system with extracephalic electrode positions. We demonstrate the use of this layout for optimizing multi-electrode tES montages for cerebellar stimulation, enhancing focality and reducing off-target stimulation, particularly of the spinal cord. Our results highlight the practical value of the Ernie Extended model for accurately characterizing doses produced by extracephalic tES montages and when targeting more caudal brain regions.
A Systematic Analysis of Read-Across Adaptations in Testing Proposal Evaluations by the European Chemicals Agency
Authors: Roe Hannah M. , Tsai Han-Hsuan D. , Ball Nicholas , Wright Fred A. , Chiu Weihsueh A. , Rusyn Ivan
Published: August 2024

An important element of the European Union’s “Registration, Evaluation, Authorisation and Restriction of Chemicals” (REACH) regulation is the evaluation by the European Chemicals Agency (ECHA) of testing proposals submitted by the registrants to address data gaps in standard REACH information requirements. The registrants may propose adaptations, and ECHA evaluates the reasoning and issues a written decision. Read-across is a common adaptation type, yet it is widely assumed that ECHA often does not agree that the justifications are adequate to waive standard testing requirements. From 2008 to August 2023, a total of 2,630 Testing Proposals were submitted to ECHA; of these, 1,538 had published decisions that were systematically evaluated in this study. Each document was manually reviewed, and information extracted for further analyses. Read-across hypotheses were standardized into 17 assessment elements (AEs); each submission was classified as to the AEs relied upon by the registrants and by ECHA. Data was analyzed for patterns and associations. Testing Proposal Evaluations (TPEs) with adaptations comprised 23% (353) of the total; analogue (168) or group (136) read-across adaptations were most common. Of 304 read-across-containing TPEs, 49% were accepted; the odds of acceptance were significantly greater for group read-across submissions. The data was analyzed by Annex (i.e., tonnage), test guideline study, read-across hypothesis AEs, as well as target and source substance types and their structural similarity. While most ECHA decisions with both positive and negative decisions on whether the proposed read-across was adequate were context-specific, a number of significant associations were identified that influence the odds of acceptance. Overall, this analysis provides an unbiased overview of 15 years of experience with testing proposal-specific read-across adaptations by both registrants and ECHA. These data will inform future submissions as they identify most critical AEs to increase the odds of read-across acceptance.
Extensive transmission and variation in a functional receptor for praziquantel resistance in endemicSchistosoma mansoni
Authors: Berger Duncan J. , Park Sang-Kyu , Crellen Thomas , Vianney Tushabe John , Kabatereine Narcis B. , Cotton James A. , Sanya Richard , Elliot Alison , Tukahebwa Edridah M. , Adriko Moses , Standley Claire J. , Gouvras Anouk , Kinung’hi Safari , Haas Helmut , Rabone Muriel , Emery Aidan , Lamberton Poppy H. L. , Webster Bonnie L. , Allan Fiona , Buddenborg Sarah , Berriman Matthew , Marchant Jonathan S. , Doyle Stephen R. , Webster Joanne P.
Published: August 2024

Mass-drug administration (MDA) of human populations using praziquantel monotherapy has become the primary strategy for controlling and potentially eliminating the major neglected tropical disease schistosomiasis. To understand how long-term MDA impacts schistosome populations, we analysed whole-genome sequence data of 570Schistosoma mansonisamples (and the closely related outgroup species,S. rodhaini)from eight countries incorporating both publicly-available sequence data and new parasite material. This revealed broad-scale genetic structure across countries but with extensive transmission over hundreds of kilometres. We characterised variation across the transient receptor potential melastatin ion channel, TRPMPZQ, a target of praziquantel, which has recently been found to influence praziquantel susceptibility. Functional profiling of TRPMPZQvariants found in endemic populations identified four mutations that reduced channel sensitivity to praziquantel, indicating standing variation for resistance. Analysis of parasite infrapopulations sampled from individuals pre- and post-treatment identified instances of treatment failure, further indicative of potential praziquantel resistance. As schistosomiasis is targeted for elimination as a public health problem by 2030 in all currently endemic countries, and even interruption of transmission in selected African regions, we provide an in-depth genomic characterisation of endemic populations and an approach to identify emerging praziquantel resistance alleles.

One Sentence Summary

Population genomics and functional genetics of praziquantel resistance inSchistosoma mansoni
Multiyear Improvement In Batting Skills Following Targeted Perceptual Cognitive Training In Softball
Authors: Muraskin Jordan , Sherwin Jason
Published: August 2024

Background

Making quick, accurate decisions is crucial in competitive sports like softball, where perceptual-cognitive skills can significantly impact on-field performance. This study evaluates the long-term effectiveness of a targeted perceptual-cognitive training program, delivered through the uHIT platform, on improving batting performance in collegiate softball players.

Methods

A longitudinal analysis was conducted on data collected from both NCAA and NAIA softball teams over multiple seasons. The study used Bayesian statistical methods to assess the impact of cognitive training on on-base plus slugging percentage (OPS). The analysis incorporated weighted models to account for variability in games played and differences between teams, and the influence of team and year-division effects was considered. Key metrics, including Decision AUC and Response Time, were tracked to evaluate perceptual-cognitive improvements.

Results

The results demonstrated significant improvements in OPS for teams that participated in the cognitive training intervention, with the weighted models indicating a substantial effect of the training on performance. Notably, the intervention was most effective in teams with higher training intensity, as evidenced by the permutation test results. The Bayesian analysis also revealed that the intervention led to statistically significant improvements in decision-making and response times, translating into enhanced on-field performance.

Conclusion

The findings support the effectiveness of perceptual-cognitive training in improving real-world athletic performance in softball. The uHIT platform, as an ecologically valid training tool, has demonstrated its potential to serve as a critical component of athletic development programs. Future research should explore the long-term retention of these cognitive gains and their application across different sports and competitive levels.
Muscle Type-Specific Modulation of Autophagy Signaling in Obesity: Effects of Caloric Restriction and Exercise
Authors: Ji Fujue , Kim Jong-Hee
Published: August 2024

Background

Obesity causes metabolic dysregulation and contributes to various diseases, with autophagy playing a pivotal role in this process. Autophagy, a cellular recycling mechanism, is influenced by factors beyond obesity, like caloric restriction (CR) and CR combined with exercise (CR+Ex), which modulate autophagy in obesity management. However, the regulation of autophagy in skeletal muscle under conditions of obesity, CR, and CR+Ex remains poorly understood.

Method

Mice were divided into six groups: normal diet, normal diet CR, normal diet CR+Ex, high-fat diet, high-fat diet CR, and high-fat diet CR+Ex. All mice were fed ad libitum with either a normal or high-fat diet for the first four months, followed by the respective interventions for the subsequent four months. Body composition, motor function, and skeletal muscle autophagy signaling were assessed.

Results

Obesity resulted in increased total mass, lean mass, fat mass, and fat percentage in tissue; decreased grip strength and endurance capacity. Notably, CR+Ex reduced total mass, lean mass, and fat mass in obese mice. In both normal and obese conditions, the expression of autophagy markers p62, LC3B-I, and LC3B-II is significantly higher in red muscle. Obesity leads to a reduction in cathepsin L expression, while CR further increased LC3B-I expression in red muscle.

Conclusion

CR+Ex proves to be an effective strategy for counteracting the adverse changes in body composition associated with obesity. Unlike red muscle, white muscle exhibits lower baseline autophagic levels and may necessitate elevated expression of autophagy-related proteins, such as cathepsin L, to mitigate the negative effects of obesity.
Role of Divalent Ions in Membrane Models of Polymyxin-Sensitive and Resistant Gram-Negative Bacteria
Authors: Savenko Mariia , Vácha Robert , Ramseyer Christophe , Rivel Timothée
Published: August 2024

Polymyxins, critical last-resort antibiotics, impact the distribution of membrane-bound divalent cations in the outer membrane of Gram-negative bacteria. We employed atomistic molecular dynamics simulations to model the effect of displacing these ions. Two polymyxin-sensitive and two polymyxin-resistant models of the outer membrane of Salmonella enterica were investigated. First, we found that the removal of all calcium ions induces a global stress on the model membranes, leading to substantial membrane restructuring. Next, we used enhanced sampling methods to explore the effects of localized stress by displacing membrane-bound ions. Our findings indicate that creating defects in the membrane-bound ion network facilitates polymyxin permeation. Additionally, our study of polymyxin-resistant mutations revealed that divalent ions in resistant model membranes are less likely to be displaced, potentially contributing to the increased resistance associated with these mutations. Lastly, we compared results from all-atom molecular dynamics simulations with coarse-grained simulations, demonstrating that the choice of force field significantly influences the behavior of membrane-bound ions under stress.
Multi-omics analysis of virus-permissive versus hostile cellular states reveals protein networks controlling virus infection
Authors: Chen Honglin , Charles Philip D , Gu Quan , Liberatori Sabrina , Robertson David L , Palmarini Massimo , Wilson Sam J , Mohammed Shabaz , Castello Alfredo
Published: August 2024

The capacity of host cells to sustain or restrict virus infection is influenced by their proteome. Understanding the compendium of proteins defining cellular permissiveness is key to many questions in fundamental virology. Here, we apply a multiomic approach to determine the proteins that are associated with highly permissive, intermediate, and hostile cellular states. We observed two groups of differentially regulated genes: i) with robust changes in mRNA and protein levels, and ii) with protein/RNA discordances. Many of the latter are classified as interferon stimulated genes (ISGs) but have no reported antiviral activity. This suggests that IFN-dependent changes in mRNA levels do not imply antiviral function. Phosphoproteomics revealed an additional regulatory layer involving non-signalling proteins with altered phosphorylation. Indeed, we confirmed that several permissiveness-associated proteins with changes in abundance or phosphorylation regulate infection fitness. Altogether, our study provides a comprehensive and systematic map of the cellular alterations driving virus susceptibility.
The Impact of Brain-Derived Neurotrophic Factor rs6265 (Val66Met) Polymorphism on Therapeutic Electrical Stimulation for Peripheral Nerve Regeneration: A Preclinical Study of Therapy-Genotype Interactions
Authors: Walters Jordan , Quezada Maria J. , He Suning , Steece-Collier Kathy , Collier Timothy J. , Sortwell Caryl E. , Franz Colin K.
Published: August 2024

The Impact of Brain-Derived Neurotrophic Factor rs6265 (Val66Met) Polymorphism on Therapeutic Electrical Stimulation for Peripheral Nerve Regeneration: A Preclinical Study of Therapy-Genotype Interactions

Introduction

Peripheral nerve injuries (PNIs) significantly impact patient quality of life. Therapeutic electrical stimulation (TES) shows promise in enhancing nerve regeneration, but outcomes vary widely. This study investigates the impact of the rs6265 single nucleotide polymorphism (SNP) on TES efficacy in a preclinical rat model and human stem cell-derived motor neurons.

Methods

Wild-type (WT) and rs6265 variant rats underwent sciatic nerve transection and received either TES or sham treatment. Muscle reinnervation was assessed through compound muscle action potentials and muscle fiber cross-sectional area. Isogenic human iPSC-derived motor neurons were used to study activity-dependent BDNF secretion.

Results

TES improved muscle reinnervation and fiber size in WT but not rs6265 allele carriers. rs6265 allele carriers exhibited impaired activity-dependent BDNF secretion in vitro.

Discussion

The rs6265 polymorphism influences TES efficacy, highlighting the need for personalized approaches in PNI treatment. These findings suggest that genetic screening could optimize therapeutic outcomes.

Clinical Relevance

Understanding genetic factors affecting TES response can enhance treatment strategies for PNI, potentially improving patient recovery and reducing outcome variability.
qBiCo: A method to assess global DNA conversion performance in epigenetics via single-copy genes and repetitive elements
Authors: Karkala Faidra , Simons Roy B. , Claessens Floor , Kalamara Vivian , Kayser Manfred , Vidaki Athina
Published: August 2024

Human DNA methylation profiling offers great promises in various biomedical applications, including ageing, cancer and even forensics. So far, most DNA methylation techniques are based on a chemical process called sodium bisulfite conversion, which specifically converts non-methylated cytosines into uracils. However, despite the popularity of this approach, it is known to cause DNA fragmentation and loss affecting standardization, while incomplete conversion may result in potential misinterpretation of methylation-based outcomes. To offer the community a solution, we developed qBiCo - a novel quality-control method to address the quantity and quality of bisulfite-converted DNA. qBiCo is a 5-plex, TaqMan®probe-based, quantitative (q)PCR assay that amplifies single- and multi-copy DNA fragments of converted and non-converted nature. It estimates four parameters: converted DNA concentration, fragmentation, global conversion efficiency, and potential PCR inhibition. We optimized qBiCo using synthetic DNA standards and assessed it using standard developmental validation criteria, showcasing that qBiCo is reliable, robust and sensitive down to picogram level. We also evaluated its performance by testing decreasing DNA amounts using several commercial bisulfite conversion kits. Depending on the starting DNA quantity, bisulfite-converted DNA recoveries ranged from 8.5 – 100 %, conversion efficiencies from 78 - 99.9 %, while certain kits highly fragment DNA, demonstrating large variability in their performance. Towards building a prototype tool, we further optimized key functionalities, for example, by replacing the poorest performing single-plex assay and creating a more representative DNA standard. Aiming to scale-up and move towards implementation, we successfully transferred and validated our novel method in six different qPCR platforms from different major manufacturers. Overall, with the present study, we offer researchers in the epigenetic field a novel long-awaited QC tool that for the first time allows them to measure key quality and quantity parameters of the most popular DNA conversion process. The tool also enables standardization to prevent inconsistent data and false outcomes in the future, regardless of the downstream experimental analysis of DNA methylation-based research and applications across different fields of biology and biomedicine.
EstablishedPseudomonas syringaepv.tomatoinfection disrupts immigration of leaf surface bacteria to the apoplast
Authors: Cowles Kimberly N. , Iyer Arjun S. , McConnell Iain , Guillemette Ellie G. , Nellore Dharshita , Zaacks Sonia C. , Barak Jeri D.
Published: August 2024

Bacterial disease alters the infection court creating new niches. The apoplast is an oasis from the hardships of the leaf surface and is generally inaccessible to nonpathogenic members of the phyllosphere bacterial community. Previously, we demonstrated thatSalmonella entericaimmigrants to the leaf surface can both enter the apoplast and replicate due to conditions created by an establishedXanthomonas hortorumpv.gardneri(Xhg) infection. Here, we have expanded our investigation of how infection changes the host by examining the effects of another water-soaking pathogen,Pseudomonas syringaepvtomato(Pst), on immigrating bacteria. We discovered that, despite causing macroscopically similar symptoms as Xhg, Pst infection disruptsS. entericacolonization of the apoplast. To determine if these effects were broadly applicable to phyllosphere bacteria, we examined the fates of immigrant Xhg and Pst arriving on an infected leaf. We found that this effect is not specific toS. enterica, but that immigrating Xhg or Pst also struggled to fully join the infecting Pst population established in the apoplast. To identify the mechanisms underlying these results, we quantified macroscopic infection symptoms, examined stomata as a pinch point of bacterial entry, and characterized aspects of interbacterial competition. While it may be considered common knowledge that hosts are fundamentally altered following infection, the mechanisms that drive these changes remain poorly understood. Here, we investigated these pathogens to reach a deeper understanding of how infection alters a host from a rarely accessible, inhabitable environment to an obtainable, habitable niche.

IMPORTANCE

Pathogens dramatically alter the host during infection. Changes in host physical and biochemical characteristics benefit the pathogen and can reshape the composition of the bacterial community. In fact, rare members of the plant microbiota, namely bacterial human pathogens, such asSalmonella enterica,thrive in some plant infection courts. The increased success of human pathogens results from the conversion of the rarely accessible, inhabitable apoplast to an obtainable, habitable niche following infection. Here, we compared two phytopathogens,Pseudomonas syringaepv.tomatoandXanthomonas hortorumpv.gardneriwithin a tomato host and uncovered relevant niche changes potentially overlooked by the similarity in macroscopic symptoms. We investigated mechanisms used to reshape the host environment to the pathogen’s benefit and either success or failure of newly arriving immigrant bacteria. This study reveals information about bacterial disease of leaves and key changes that remodel inhospitable niches to new, conducive environments in the diseased host.
Genetically-encoded phase separation sensors for intracellular probing of biomolecular condensates
Authors: Avecilla Alexa Regina Chua , Thomas Jeremy , Quiroz Felipe Garcia
Published: August 2024

Biomolecular condensates are dynamic membraneless compartments with enigmatic roles across intracellular phenomena. Intrinsically-disordered proteins (IDPs) often function as condensate scaffolds, fueled by their liquid-liquid phase separation (LLPS) dynamics. Intracellular probing of these condensates relies on live-cell imaging of IDP-scaffolds tagged with fluorescent proteins. Conformational heterogeneity in IDPs, however, renders them uniquely sensitive to molecular-level fusions, risking distortion of the native biophysical properties of IDP-scaffolds and their assemblies. Probing epidermal condensates in mouse skin, we recently introduced genetically encoded LLPS-sensors that circumvent the need for molecular-level tagging of skin IDPs. The concept of LLPS-sensors involves a shift in focus from subcellular tracking of IDP-scaffolds to higher-level observations that report on the assembly and liquid-dynamics of their condensates. Towards advancing the repertoire of intracellular LLPS-sensors, here we demonstrate biomolecular approaches for the evolution and tunability of epidermal LLPS-sensors and assess their impact in early and late stages of intracellular LLPS dynamics. Benchmarking against scaffold-bound fluorescent reporters, we found that tunable ultraweak scaffold-sensor interactions are key to the sensitive and innocuous probing of nascent and established biomolecular condensates. Our LLPS-sensitive tools pave the way for the high-fidelity intracellular probing of IDP-governed biomolecular condensates across biological systems.
CoordinatedTbx3/Tbx5transcriptional control of the adult ventricular conduction system
Authors: Burnicka-Turek Ozanna , Trampel Katy A. , Laforest Brigitte , Broman Michael T. , Yang Xinan H. , Khan Zoheb , Rytkin Eric , Li Binjie , Schaffer Ella , Gadek Margaret , Shen Kaitlyn M. , Efimov Igor R. , Moskowitz Ivan P.
Published: August 2024

The cardiac conduction system (CCS) orchestrates the electrical impulses that enable coordinated contraction of the cardiac chambers. The T-box transcription factorsTBX3andTBX5are required for cardiac conduction system development and associated with overlapping and distinct human cardiac conduction system diseases. We evaluated the coordinated role ofTbx3andTbx5in the murine ventricular conduction system (VCS). We engineered a compoundTbx3:Tbx5conditional knockout allele for both genes located incison mouse chromosome 5. Conditional deletion of both T-box transcriptional factors in the ventricular conduction system, using the VCS-specificMinK:Cre,caused loss of VCS function and molecular identity. CombinedTbx3andTbx5deficiency in the adult VCS led to conduction defects, including prolonged PR and QRS intervals and elevated susceptibility to ventricular tachycardia. These electrophysiological defects occurred prior to detectable alterations in cardiac contractility or histologic morphology, indicative of a primary conduction system defect.Tbx3:Tbx5double knockout VCS cardiomyocytes revealed a transcriptional shift towards non-CCS-specialized working myocardium, indicating a change to their cellular identity. Furthermore, optical mapping revealed a loss of VCS-specific conduction system propagation. Collectively, these findings indicate thatTbx3andTbx5coordinate to control VCS molecular fate and function, with implications for understanding cardiac conduction disorders in humans.
Analogues of the anti-malaria drug mefloquine have broad spectrum antifungal activity and are efficacious in a model of disseminatedCandida aurisinfection
Authors: Guin Soumitra , Montoya Marhiah C. , Wang Xiaoyu , Zarnowski Robert , Andes David R. , Meyers Marvin J. , Williams Noelle S. , Krysan Damian J.
Published: August 2024

Only three classes of antifungal drugs are currently in clinical use. Here, we report that derivatives of the malarial drug mefloquine have broad spectrum antifungal activity including difficult to treat molds and endemic fungi. Pharmacokinetic and efficacy studies of NSC-4377 indicate it penetrates the central nervous system and is active againstCandida aurisin vivo. These data strongly support the further development of mefloquine analogs as a potentially new class of antifungal molecules.
Functional characterisation of neuropeptides that act as ligands for both calcitonin-type and pigment-dispersing factor-type receptors in a deuterostome
Authors: Cong Xiao , Liu Huachen , Liu Lihua , Elphick Maurice R. , Chen Muyan
Published: August 2024

The calcitonin (CT) family of related peptides exert their diverse physiological effects in mammals via two G-protein coupled receptors, CTR and the CTR-like receptor CLR. Analysis of the phylogenetic distribution of CT-type signaling has revealed the occurrence of CT-type peptides and CTR/CLR-type proteins in deuterostome and protostome invertebrates. Furthermore, experimental studies have revealed that in the protostomeDrosophila melanogasterthe CT-like peptide DH31can act as a ligand for a CTR/CLR-type receptor and a pigment-dispersing factor (PDF) receptor. Here we investigated the signaling mechanisms and functions of CT-type neuropeptides in a deuterostome invertebrate, the sea cucumberApostichopus japonicus(phylum Echinodermata). InA. japonicus,a single gene encodes two CT-type peptides (AjCT1 and AjCT2), both of which act as ligands for a CTR/CLR-type receptor (AjCTR) and two PDF-type receptors (AjPDFR1, AjPDFR2), but with differential activation of downstream cAMP/PKA, Gαq/Ca2+/PKC and ERK1/2 signaling pathways. Analysis of the expression of the gene encoding AjCT1 and AjCT2 revealed transcripts in a variety of organ systems, but with highest expression in the circumoral nervous system.In vitropharmacological experiments revealed that AjCT1 and/or AjCT2 cause dose-dependent relaxation of longitudinal body wall muscle and intestine preparations. Furthermore,in vivopharmacological experiments and loss-of-function tests revealed a potential physiological role for AjCT2 signaling in promoting feeding and growth inA. japonicus. This is the first study to obtain evidence that CT-type peptides can act as ligands for both CTR/CLR-type and PDF-type receptors in a deuterostome. Furthermore, because of the economic importance ofA. japonicusas a foodstuff, discovery of the potential role for CT-type peptides as regulators of feeding and growth in this species may provide a basis for practical applications in aquaculture.

Graphical abstract

A schematic showing proposed molecular mechanisms by which CT-type neuropeptides regulate feeding and growth inA. japonicus. AjCT1 and AjCT2 are represented by purple and yellow circles, respectively. For cell signaling, black arrows indicate that this process is activated, whilst the pink arrow indicates that the ERK1/2 is activated in the AjCT1/AjPDFR1, AjCT2/AjPDFR1 and AjCT2/AjPDFR2 signaling pathways.
Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers
Authors: Owens Katherine , Rahman Aminur , Bozic Ivana
Published: August 2024

The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.
Effect of high-intensity anaerobic exercise on electrocortical activity in athletes and non-athletes
Authors: Costa Élida , Gongora Mariana , Bittencourt Juliana , Marinho Victor , Cagy Mauricio , Teixeira Silmar , Nicoliche Eduardo , Fernandes Isabelle , Fagundes Danilo , Machado Caroline , Dias Juliana , Vicente Renan , Ribeiro Pedro , Gupta Daya S. , Velasques Bruna , Budde Henning
Published: August 2024

Aim

The present study aims to verify the information processing in athletes through electroencephalography, analyze cortical areas responsible for cognitive functions related to attentional processing of visual stimuli, and investigate motor activity’s influence on cognitive aspects.

Material and Methods

The sample consisted of 29 subjects, divided into an experimental group (n = 13 modern pentathlon athletes) and a control group (n = 16 non-athletes). We collected the electrocortical activity before and after the Wingate Anaerobic Test. During the electrophysiological measures, the volunteers performed a saccadic eye movement paradigm. They also performed cognitive tasks, resting heart rate, and anthropometric measurements.

Results

A mixed ANOVA was applied to analyze the statistical differences between groups (athletes and control) and moments (before and after exercise) for F3, F4, P3, and P4 electrodes during rest one and task (pre-stimulus GO). There was an interaction for the group vs. moment factors in F3 [F = 17,129; p = 0,000; η² = 0.512], F4 [F = 22,774; p = 0,000; η² = 0.510], P3 [F = 11,429; p = 0,001; η² = 0.405], and P4 electrodes [F = 18,651; p = 0,000; η² = 0.379]. We found the main effect for group factors in the frontal and parietal electrodes of the right hemisphere (F4 and P4) and a main effect of the moment factor on the frontal (F3 and F4) and parietal (P3 and P4) electrodes. There was an interaction between the group vs. moment factors for the reaction time. The groups were different in Peak Power (Watts/kg), Average Power (Watts/kg), Fatigue Index (%), and Maximum Power (ms).

Conclusions

We identified chronic effects of exercise training on the cortical activity of modern pentathlon athletes, read-through differences in absolute alpha power, and acute effects of a high-intensity exercise session for athletes and non-athletes for electrocortical and behavioral responses.
Computational design of serine hydrolases
Authors: Lauko Anna , Pellock Samuel J. , Anischanka Ivan , Sumida Kiera H. , Juergens David , Ahern Woody , Shida Alex , Hunt Andrew , Kalvet Indrek , Norn Christoffer , Humphreys Ian R. , Jamieson Cooper , Kang Alex , Brackenbrough Evans , Bera Asim K. , Sankaran Banumathi , Houk K. N. , Baker David
Published: August 2024

Enzymes that proceed through multistep reaction mechanisms often utilize complex, polar active sites positioned with sub-angstrom precision to mediate distinct chemical steps, which makes their de novo construction extremely challenging. We sought to overcome this challenge using the classic catalytic triad and oxyanion hole of serine hydrolases as a model system. We used RFdiffusion1to generate proteins housing catalytic sites of increasing complexity and varying geometry, and a newly developed ensemble generation method called ChemNet to assess active site geometry and preorganization at each step of the reaction. Experimental characterization revealed novel serine hydrolases that catalyze ester hydrolysis with catalytic efficiencies (kcat/Km) up to 3.8 × 103M-1s-1, closely match the design models (Cα RMSDs < 1 Å), and have folds distinct from natural serine hydrolases. In silico selection of designs based on active site preorganization across the reaction coordinate considerably increased success rates, enabling identification of new catalysts in screens of as few as 20 designs. Our de novo buildup approach provides insight into the geometric determinants of catalysis that complements what can be obtained from structural and mutational studies of native enzymes (in which catalytic group geometry and active site makeup cannot be so systematically varied), and provides a roadmap for the design of industrially relevant serine hydrolases and, more generally, for designing complex enzymes that catalyze multi-step transformations.
Comprehensive profiling of migratory primordial germ cells reveals niche-specific differences in non-canonical Wnt and Nodal-Lefty signaling in anterior vs posterior migrants
Authors: Jaszczak Rebecca G. , Zussman Jay W. , Wagner Daniel E. , Laird Diana J.
Published: August 2024

Mammalian primordial germ cells (PGCs) migrate asynchronously through the embryonic hindgut and dorsal mesentery to reach the gonads. We previously found that interaction with different somatic niches regulates PGC proliferation along the migration route. To characterize transcriptional heterogeneity of migrating PGCs and their niches, we performed single-cell RNA sequencing of 13,262 mouse PGCs and 7,868 surrounding somatic cells during migration (E9.5, E10.5, E11.5) and in anterior versus posterior locations to enrich for leading and lagging migrants. Analysis of PGCs by position revealed dynamic gene expression changes between faster or earlier migrants in the anterior and slower or later migrants in the posterior at E9.5; these differences include migration-associated actin polymerization machinery and epigenetic reprogramming-associated genes. We furthermore identified changes in signaling with various somatic niches, notably strengthened interactions with hindgut epithelium via non-canonical WNT (ncWNT) in posterior PGCs compared to anterior. Reanalysis of a previously published dataset suggests that ncWNT signaling from the hindgut epithelium to early migratory PGCs is conserved in humans. Trajectory inference methods identified putative differentiation trajectories linking cell states across timepoints and from posterior to anterior in our mouse dataset. At E9.5, we mainly observed differences in cell adhesion and actin cytoskeletal dynamics between E9.5 posterior and anterior migrants. At E10.5, we observed divergent gene expression patterns between putative differentiation trajectories from posterior to anterior including Nodal signaling response genesLefty1, Lefty2,andPycr2and reprogramming factorsDnmt1, Prc1,andTet1.At E10.5, we experimentally validated anterior migrant-specificLefty1/2upregulation via whole-mount immunofluorescence staining for LEFTY1/2 proteins, suggesting that elevated autocrine Nodal signaling accompanies the late stages of PGC migration. Together, this positional and temporal atlas of mouse PGCs supports the idea that niche interactions along the migratory route elicit changes in proliferation, actin dynamics, pluripotency, and epigenetic reprogramming.
Consensus guideline for the management of patients with appendiceal tumors: Part 2: Appendiceal tumors with peritoneal involvement
Authors:   PSM Appendiceal Tumor Writing Group,   PSM Consortium Group, Turaga Kiran K.
Published: August 2024

Background

Appendiceal tumors comprise a heterogeneous group of tumors which frequently disseminate to the peritoneum. Management of appendiceal tumors is lacking high quality data, given its rarity and heterogeneity. In general, appendiceal tumor treatment is extrapolated in part from colorectal cancer or pooled studies, without definitive evidence of disease-specific benefit. Many practices are controversial and vary widely between institutions. A national consensus update of best management practices for appendiceal malignancies was performed to better standardize care. Herein we present recommendations for management of appendiceal tumors with peritoneal involvement.

Methods

As previously described, modified Delphi consensus was performed to update the previous 2018 Chicago consensus guideline. Recommendations were supported using rapid systematic reviews of key issues in surgical and systemic therapy. Key pathology concepts and recommendations were synthesized in collaboration with content experts.

Results

A consensus-based pathway was generated for any type of non-neuroendocrine appendiceal tumor with peritoneal involvement. The first round of Delphi consensus included 138 participants and 133 (96%) participated in the second round, with over 90% consensus achieved for all pathway blocks. Key items include recommending evaluation for cytoreduction to most patients with low-grade peritoneal disease who are surgical candidates, and to many patients with high-grade disease, as well as timing of systemic chemotherapy and surveillance protocols. Common pitfalls in pathologic classification and their clinical implications are also presented.

Conclusion

These consensus recommendations provide guidance regarding the management of appendiceal tumors with peritoneal involvement, including a review of current evidence in management of recurrent and unresectable disease.
Thoracic Aortic Shape: A Data-Driven Scale Space Approach
Authors: Pugar Joseph A. , Kim Junsung , Khabaz Kameel , Yuan Karen , Pocivavsek Luka
Published: August 2024

The scale and resolution of anatomical features extracted from medical CT images are crucial for advancing clinical decision-making tools. While traditional metrics, such as maximum aortic diameter, have long been the standard for classifying aortic diseases, these one-dimensional measures often fall short in capturing the rich geometrical nuances available in progressively advancing imaging modalities. Recent advancements in computational methods and imaging have introduced more sophisticated geometric signatures, in particular scale-invariant measures of aortic shape. Among these, the normalized fluctuation in total integrated Gaussian curvatureover a surface mesh model of the aorta has emerged as a particularly promising metric. However, there exists a critical tradeoff between noise reduction and shape signal preservation within the scale space parameters – namely, smoothing intensity, meshing density, and partitioning size. Through a comprehensive analysis of over 1200 unique scale space constructions derived from a cohort of 185 aortic dissection patients, this work pinpoints optimal resolution scales at which shape variations are most strongly correlated with surgical outcomes. Importantly, these findings emphasize the pivotal role of a secondary discretization step, which consistently yield the most robust signal when scaled to approximately 1 cm. This approach enables the development of models that are not only clinically effective but also inherently resilient to biases introduced by patient population heterogeneity. By focusing on the appropriate intermediate scales for analysis, this study paves the way for more precise and reliable tools in medical imaging, ultimately contributing to improved patient outcomes in cardiovascular surgery.
Systemic inflammation during fasting and postprandial states: a comprehensive study of key determinants in a deeply characterized cohort of young adults
Authors: Ebrahimi Parvaneh , Horner David , Burgner David , Brustad Nicklas , Wang Tingting , Ali Mina , Chen Liang , Schoos Ann-Marie M , Bønnelykke Klaus , Stokholm Jakob , Acar Evrim , Vahman Nilo , Chawes Bo , Rasmussen Morten A.
Published: August 2024

Systemic inflammation contributes to the pathogenesis of many noncommunicable diseases. Additionally, postprandial inflammation can exacerbate systemic inflammation. These emphasize the need to examine inflammation in both fasting and postprandial states, to identify modifiable factors to alleviate inflammation. This study investigated a comprehensive list of factors spanning from foetal stage to young-adulthood against inflammation levels at fasting (chronic inflammation) and postprandial states (meal-induced transient inflammation). A meal challenge was undertaken in 18-year-olds(n= 298), and inflammation was assessed using the robust GlycA biomarker. Associations between inflammation and various factors were observed, some of which were sex-specific; e.g. the associations of alcohol consumption and smoking with inflammation were significantly stronger in females. Moreover, novel associations from gestation and early life (e.g. pregnancy smoking) were identified. Our findings highlight factors that should inform dietary and lifestyle interventions for reducing systemic inflammation and highlight the importance of considering inflammation in precision nutrition practices.
Estimating optimal therapeutic drug levels of anti-tuberculosis medications based on treatment safety and effectiveness
Authors: Amorim Gustavo , Haas David W. , Cordeiro-Santos Marcelo , Kritski Afrânio L. , Figueiredo Marina C. , Staats Cody , Hachey Brian , Turner Megan , Andrade Bruno B. , Rolla Valeria C. , Sterling Timothy R. ,   the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil network
Published: August 2024

Background

Therapeutic drug ranges (TDR) for standard anti-tuberculosis (TB) treatment have been determined based on expected drug levels at least 2 hours after taking the dose. In this study we constructed TDR for TB drug levels based on minimizing drug toxicity and maximizing treatment effectiveness.

Methods

Participants were followed prospectively in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil observational cohort study. We focused on participants with culture-confirmed drug-susceptible pulmonary TB who underwent standard TB therapy. TDR were estimated for each TB drug separately: isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA). TDR were defined as drug concentrations that were both safe and effective: safety was defined as the probability of having an ADR of at most 5%, while effectiveness was defined as a probability of at least 95% of not having either TB treatment failure or recurrence.

Results

There were 765 plasma samples from 448 patients; 110 (24.6%) were people with HIV, 9 (2.0%) had a grade 3 or higher ADR, and 15 (3.3%) had treatment failure/recurrence. Higher drug concentrations of INH, RIF and EMB were associated with increased odds of having ADR. High concentrations of INH suggested protection against treatment failure/recurrence. Estimated therapeutic drug range for INH (2.3-8.2 µg/ml) and for RIF (0.5-7.5 µg/ml) differed from the currently recommended drug ranges (3-5 µg/ml and 8-24 µg/ml, respectively). Estimates for PZA and EMB were similar to the currently recommended values.

Conclusions

Our estimated upper end TDR were higher for INH and lower for RIF compared to currently recommended ranges.
Open Access Data Repository and Common Data Model for Pulse Oximeter Performance Data
Authors: Fong Nicholas , Lipnick Michael S. , Behnke Ella , Chou Yu , Elmankabadi Seif , Ortiz Lily , Almond Christopher S. , Auchus Isabella , Burnett Garrett W. , Bisegerwa Ronald , Conrad Desireé R , Hendrickson Carolyn M. , Hooli Shubhada , Kopotic Robert , Leeb Gregory , Martin Daniel , McCollum Eric D. , Monk Ellis P. , Moore Kelvin L. , Shmuylovich Leonid , Scott J. Brady , Wong An-Kwok Ian , Zhou Tianyue , Pirracchio Romain , Bickler Philip E. , Feiner John , Law Tyler
Published: August 2024

The OpenOximetry Repository is a structured database storing clinical and lab pulse oximetry data, serving as a centralized repository and data model for pulse oximetry initiatives. It supports measurements of arterial oxygen saturation (SaO2) by arterial blood gas co-oximetry and pulse oximetry (SpO2), alongside processed and unprocessed photoplethysmography (PPG) data and other metadata. This includes skin color measurements, finger diameter, vital signs (e.g., arterial blood pressure, end-tidal carbon dioxide), and arterial blood gas parameters (e.g., acid-base balance, hemoglobin concentration).

Data contributions are encouraged. All data, from desaturation studies to clinical trials, are collected prospectively to ensure accuracy. A common data model and standardized protocols for consistent archival and interpretation ensure consistent data archival and interpretation. The dataset aims to facilitate research on pulse oximeter performance across diverse human characteristics, addressing performance issues and promoting accurate pulse oximeters.

The initial release includes controlled lab desaturation studies (CLDS), with ongoing updates planned as further data from clinical trials and CLDS become available.
Routine Testing for Chlamydia and Gonorrhea in an HIV Pre-Exposure Prophylaxis Program in Hanoi, Vietnam: Implications for Low- and Middle-Income Countries
Authors: Adamson Paul C. , Bui Hao T.M. , Pham Loc Q. , Truong Phuong T. , Le Ngan T. , Le Giang M. , Klausner Jeffrey D.
Published: August 2024

Objectives

To assess the prevalence, anatomical distribution, and correlates ofNeisseria gonorrhoeae(NG) andChlamydia trachomatis(CT) infections within an HIV pre-exposure prophylaxis (PrEP) program in Hanoi, Vietnam.

Design

Cross-sectional, observational study

Methods

Between January-December 2022, HIV PrEP program clients who were male at birth, ≥16 years old, reported ≥1 male sex partner in the prior 12 months, were enrolled. A questionnaire collected sociodemographics, sexual behaviors, and clinical data. CT/NG testing was performed on self-collected urine, rectal, and pharyngeal specimens. Multivariate logistic regression was used to identify factors associated with infections.

Results

Among 529 participants, the prevalence of CT or NG was 28.9% (153/529). The prevalence of NG was 14.4% (76/529) and highest for pharyngeal infections (11.7%; 62/528), while for CT, the prevalence was 20.4% (108/529) and highest for rectal infections (15.0%; 74/493). Symptoms in the prior week were reported by 45.8% (70/153) of those with CT or NG infections. Among asymptomatic participants, there was a low prevalence of urethral CT (3.1%; 14/457) and NG (0.9%; 4/457). Condomless anal sex (aOR= 1.98; 95% CI: 1.27, 3.09) and sexualized drug use in the prior 6 months (aOR= 1.71; 95% CI: 1.09, 2.69) were associated with CT/NG infections.

Conclusions

The study found a high prevalence of CT/NG infections, particularly pharyngeal and rectal infections, within an HIV PrEP program in Hanoi, Vietnam. The findings suggest testing for urethral infections among asymptomatic individuals is of limited value. Further research is needed for STI prevention strategies and updated guidelines for CT/NG screening in HIV PrEP programs in low- and middle-income countries.