bluuebunny/crossref_metadata_2025 huggingface dataset:
An International Factorial Vignette-Based Survey of Intubation Decisions in Acute Hypoxemic Respiratory Failure
Authors: Yarnell Christopher J. , Paranthaman Arviy , Reardon Peter , Angriman Federico , Bassi Thiago , Bellani Giacomo , Brochard Laurent , De Grooth Harm Jan , Dragoi Laura , Gaus Syafruddin , Glover Paul , Goligher Ewan C. , Lewis Kimberley , Li Baoli , Kareemi Hashim , Tirupakuzhi Vijayaraghavan Bharath Kumar , Mehta Sangeeta , Mellado-Artigas Ricard , Moore Julie , Morris Idunn , Roman-Sarita Georgiana , Pham Tai , Sereeyotin Jariya , Tomlinson George , Wozniak Hannah , Yoshida Takeshi , Fowler Rob ,   for the Canadian Critical Care Trials Group
Published: November 2024

OBJECTIVES:

Intubation is a common procedure in acute hypoxemic respiratory failure (AHRF), with minimal evidence to guide decision-making. We conducted a survey of when to intubate patients with AHRF to measure the influence of clinical variables on intubation decision-making and quantify variability.

DESIGN:

Factorial vignette-based survey asking “Would you recommend intubation?” Respondents selected an ordinal recommendation from a 5-point scale ranging from “Definite no” to “Definite yes” for up to ten randomly allocated vignettes. We used Bayesian proportional odds modeling, with clustering by individual, country, and region, to calculate mean odds ratios (ORs) with 95% credible intervals (CrIs).

SETTING:

Anonymous web-based survey.

SUBJECTS:

Clinicians involved in the decision to intubate.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Between September 2023 and January 2024, 2,294 respondents entered 17,235 vignette responses in 74 countries (most common: Canada [29%], United States [26%], France [9%], Japan [8%], and Thailand [5%]). Respondents were attending physicians (63%), nurses (13%), trainee physicians (9%), respiratory therapists (9%), and other (6%). Lower oxygen saturation, higher Fio
2, noninvasive ventilation compared with high-flow, tachypnea, neck muscle use, abdominal paradox, drowsiness, and inability to obey were associated with increased odds of intubation; diagnosis, vasopressors, and duration of symptoms were not. Nurses were less likely than physicians to recommend intubation. Within a country, the odds of recommending intubation changed between clinicians by an average factor of 2.60; within a region, the same odds changed between countries by 1.56. Respondents from Canada (OR, 0.53; CrI, 0.40–0.70) and the United States (OR, 0.63; CrI, 0.48–0.84) were less likely to recommend intubation than respondents from most other countries.

CONCLUSIONS:

In this international, multiprofessional survey of 2294 clinicians, intubation for patients with AHRF was mostly decided based on oxygenation, breathing pattern, and consciousness, but there was important variation across individuals and countries.
A case report: Can a Titanised polypropylene mesh (TiMesh) obviate a dual mesh for sandwich technique for parastomal hernias??
Authors: Kalikar Vishakha , Patankar Roy
Published: November 2024

The three main surgical techniques for PSH are primary fascial repair, stoma reconstruction, and mesh reconstruction. Both open & laparoscopic repair can be done for PSH and currently mesh reinforcement is widely accepted. Polypropylene mesh permeates the ingrowth of adjacent fascia and potentially adhering onto adjacent organs, including the viscera, leading to mesh erosion and enteric fistula. Polytetrafluoroethylene (PTFE) mesh shrinks significantly in the tissue and thereby increases the chances of PSH recurrence rate. TiMesh (Healthium Medtech, Bengaluru, India) is a titanium-coated polypropylene composite mesh and is included in the guidelines for laparoscopic treatment of ventral & incisional abdominal wall hernias by International Endo hernia Society (IEHS). TiMesh can be used to repair PSH and maybe a useful alternative to dual mesh. We present a case report of a 64-year-old lady who presented with a parastomal hernia after an abdomino-perineal resection and an end sigmoid colostomy. The parastomal hernia was repaired using a laparoscopic meshplasty using TiMesh. With a Dual mesh, the polypropylene side may come in contact with the bowel with a possibility of mesh erosion and fistulation. TiMesh being a coated mesh on both sides reduces these possibilities.
Ambulatory Medication Errors and Adverse Events Involved in Medicine-Related Malpractice Cases From 2011 to 2021
Authors: Boisvert Susan , Nelson Melissa , Ross Jacqueline
Published: November 2024

Objectives:

The aims of the study were to identify the characteristics of medication-related malpractice claims occurring in the ambulatory setting across 2 time periods.

Methods:

A retrospective, descriptive study was used. Ambulatory medication–related closed malpractice events from loss years of 2011–2021 were analyzed. Analysis included gender and age, injury severity, location, major injury, medications, primary and secondary services, roles, contributing factors, primary drivers, indemnity paid, and disposition status. Findings were analyzed using the Candello Explore tool.

Results:

Five hundred four ambulatory medication–related closed malpractice events were included. Family medicine (19.4%) and internal medicine (10.4%) services had the largest number of claims. The top medications were anti-infectants (16.4%), narcotics (15.6%), and anticoagulants (14.4%). Medication-related claims were multifactorial, averaging 4.1 contributing factors per claim. Clinical judgment issues were found in over 55% of the claims, and communication factors were observed in almost 48% of the claims. In the comparison analysis, 433 claims from 2011 to 2015 and 161 claims from 2016 to 2021 were evaluated. A statistical decrease in claims involving anticoagulants and narcotics (P = 0.01) was seen in the second period. There was a statistical increase in claims involving pharmacy dispensing errors during the 2016–2021 period (P = 0.03).

Conclusions:

Adverse drug events in ambulatory care are multifactorial. Errors in the technical process of ordering and managing medications, patient education, patient adherence, and pharmacy dispensing were the primary drivers of ambulatory medication malpractice claims in this study.
Comparative genomics highlights the virulence and evolutionary trajectory of white spot syndrome virus
Authors: Puttirungroj Pattama , Kawato Satoshi , Mwamburi Samuel Mwakisha , Furukawa Miho , Oomine Risako , Koiwai Keiichiro , Kondo Hidehiro , Hirono Ikuo
Published: November 2024

White spot syndrome virus (WSSV) poses a significant threat to shrimp aquaculture, leading to substantial economic losses. This study aims to evaluate the virulence and evolution of recent WSSV outbreaks in Japan. Shrimp infected with WSSV were collected from Okinawa, Miyakojima and Miyazaki prefectures, yielding a total of seven isolates. Through injection and immersion tests, the lethal dose 50% endpoints were determined. Genomic analysis revealed isolates with sizes ranging from 288 to 299 kbp, sharing ~99% nucleotide identity with the reference genome (CN01: NC_003225.3). Variant analysis identified 1197 forms, primarily single-nucleotide polymorphisms, with Miyakojima isolates displaying the highest diversity. Frameshift mutations, notably in ORFs such as wsv006, wsv011, wsv091 and wsv403, were observed across all isolates. Phylogenetic analysis indicated clustering of Miyakojima isolates, suggesting similar outbreak intensities. Furthermore, isolates exhibited smaller genomic sizes compared with the reference genome, indicating ongoing WSSV evolution. Notably, a high frameshift mutation in wsv403, a viral E3 ubiquitin ligase, implies its potential role in the observed outbreaks, particularly in Miyakojima. This study addresses the research question regarding the virulence and evolutionary dynamics of WSSV outbreaks, proposing a hypothesis that genetic variations contribute to the severity and spread of WSSV in shrimp aquaculture.
R-Spondin Mimetic, SZN-043, Induced Proliferation and Wnt Activity, Two Features Deficient in Human Alcohol-Associated Liver Disease
Authors: Fisher Trevor , Patel Mehaben , Deshmukh Shalaka , Shah Darshini , Lu Chenggang , Newman Maureen , Ye Jay , Fletcher Russell , Vanhove Geertrui F. , Tibbitts Jay , Li Yang , Skill Nicholas J , Yang Zhihong , Liangpunsakul Suthat , Baribault Helene
Published: November 2024

Liver regeneration is impaired in patients suffering from alcohol-associated liver (ALD) diseases. Wnt ligands and their FZD receptors are dysregulated in diseased livers. R-spondin and their receptors are known to regulate Wnt activity via the stabilization of FZD receptors. Here, we investigated the components of the Wnt and R-Spondin-signaling pathways and their activity in patients with ALD. We found that while hepatocytes retained high levels of differentiation markers such asASGR1andASGR2, the expression of two R-spondin co-receptors,LGR4andLGR5, and ofCYP1A2and Wnt target genes were strongly reduced.

SZN-043, a hepatocyte-targeted R-Spondin mimetic, is a new investigational drug that stimulates the physiological Wnt repair pathway and proliferation of hepatocytes. Here, we show that SZN-043 induced hepatocyte proliferation in all models tested, including humanized mouse livers, a chronic-binge alcohol-induced liver injury, and a CCl4-induced fibrosis mouse model. Altogether, SZN-043 could be beneficial for the treatment of ALD.
Identification and characterization of a ubiquitin E3 RING ligase of theChlamydia-like bacteriumSimkania negevensis
Authors: Hörner Eva-Maria , Boll Vanessa , Hermanns Thomas , Moldovan Adriana , Hofmann Kay , Kozjak-Pavlovic Vera
Published: November 2024

In the arms race between a pathogen and the host, many bacteria have acquired a sizable armory to counteract or change the defense mechanisms of the host cell, including the eukaryotic ubiquitin system.Simkania negevensis, an obligate intracellularChlamydia-like bacterium, is one such example.S. negevensishas a biphasic developmental cycle, similar to other members of theChlamydialesorder. The bacterium develops inside a tubular membranous compartment calledSimkania-containing vacuole, which is in close contact with the host endoplasmic reticulum (ER) and mitochondria. It can infect a wide range of hosts, with a long infection cycle lasting up to 15 days, and is associated with respiratory tract diseases. Recently,S. negevensishas been discovered to possess an unusually large number of deubiquitinating enzymes, but not much is known about the variety of other ubiquitin-modifying enzymes in this bacterium. Our study provides an initial description of the activity of a so far uncharacterizedS. negevensisubiquitin E3 RING-ligase (SNE_A12920 or SneRING). We report that SneRING primarily generates K63- and K-11 linked ubiquitin chains and preferentially interacts with UbcH5b and UBE2T E2 ubiquitin ligases among the ones we tested. Bacteria express SneRING upon infection of various human cell lines, as well as amoeba. In addition, we demonstrate that a portion of the expressed SneRING co-localizes with mitochondria and ER. Mass spectrometry studies of the SneRING interactome show enrichment in mitochondrial and ER proteins containing a prohibitin domain and involved in organelle morphology, respiration, and stress response. Our work offers the first insights into the function of anS. negevensisRING ligase, an enzyme potentially involved in organelle remodeling to accommodate the unique lifestyle of this intracellular bacterium.
The effects of chronic neuropathic pain states on the discriminative stimulus effect of fentanyl and other MOR agonists
Authors: Burgess Gwendolyn E. , Traynor John R. , Jutkiewicz Emily M.
Published: November 2024

Pleasant subjective effects of drugs (e.g., euphoria) have been demonstrated to contribute to their abuse potential. In humans, there is some evidence that acute pain states may decrease the positive subjective effects of opioids; however, no studies have directly tested the impact of a long-lasting pain state. Therefore, the goal of this study was to directly evaluate the discriminative stimulus of mu opioid receptor (MOR) agonist, fentanyl, or the non-opioid drug of abuse, cocaine, in the presence or absence of spared nerve injury (SNI) induced chronic neuropathic pain. Prior to surgery, MOR agonists (fentanyl, morphine, nalbuphine) dose-dependently increased % fentanyl-like responding, as expected; surprisingly, after surgery, we saw small, significant rightward shifts in the fentanyl and morphine dose response curves inbothsham and SNI groups suggesting that the observed shifts were not due to chronic pain. In both sham and SNI groups, there was an increase in the generalization of nalbuphine to the fentanyl-discriminative stimulus. There was no change in the discriminative stimulus of cocaine (or amphetamine substitutions) over 4 months of SNI-induced chronic neuropathic pain or sham states, suggesting that the SNI model failed to alter the discriminative stimuli of fentanyl and cocaine. Following induction of chronic neuropathic pain, there was an observed increase in quinpirole-induced generalization to the cocaine discriminative stimulus. In the future, studies should directly examine the abuse potential of low efficacy MOR agonists and dopaminergic agonists in the presence and absence of chronic pain states.

Significance Statement

Subjective or interoceptive effects of drugs of abuse are known to contribute to the abuse potential. This study demonstrated that long-lasting neuropathic pain failed to alter the discriminative stimulus of mu opioid receptor agonists or cocaine; however, we observed an increase in quinpirole-induced generalization to the cocaine discriminative stimulus, suggesting the abuse potential of direct dopaminergic agonists should be further evaluated in the presence or absence of pain states.
Occurrence of Aneuploidy Across the Range of Coast Redwood (Sequoia sempervirens)
Authors: Nikolaeva Alexandra Sasha , Santangelo James , Smith Lydia , Dodd Richard , Nielsen Rasmus
Published: November 2024

1

Aneuploidy, a condition characterized by an abnormal number of chromosomes, can have significant consequences for fitness of an organism, often manifesting in reduced fertility and other developmental challenges. In plants, aneuploidy is particularly complex to study, especially in polyploid species such as coast redwood (Sequoia sempervirens), which is a hexaploid conifer (2n=6x=66). This study leverages a novel Markov Chain Monte Carlo (MCMC) method based on sequence depth to investigate the occurrence of aneuploidy across the range of coast redwood.

We show that aneuploidy is prevalent in second-growth redwoods, predominantly as additional chromosomes, while tissue culture plants frequently experience chromosome loss. Although our study does not directly assess the fitness of aneuploids, the frequency of chromosomal instability observed in tissue culture plants compared to second-growth and old-growth trees raises questions about their long-term developmental viability and potential to become established trees. These findings have significant implications for redwood conservation and restoration strategies, especially as tissue culture becomes the primary mode of producing nursery stock plants used in reforestation.
Quantitative contributions of hepatic and renal organic cation transporters to the clinical pharmacokinetic cimetidine-metformin interaction
Authors: Ailabouni Anoud Sameer , Singh Dilip Kumar , Thakur Aarzoo , Paine Mary F. , Boone Erin C. , Gaedigk Andrea , Prasad Bhagwat
Published: November 2024

The widely prescribed oral anti-diabetic drug metformin is eliminated unchanged in the urine primarily through active tubular secretion. This process is mediated by organic cation transporter 2 (OCT2), an uptake transporter expressed on the basolateral membrane of renal proximal tubule cells. Metformin uptake into the liver, the site of action, is mediated by OCT1, which is expressed on the sinusoidal membrane of hepatocytes. Sixteen healthy adults participated in a clinical pharmacokinetic drug-drug interaction study in which they were orally administered metformin (50 mg) as a dual OCT1/2 substrate alone (baseline) and with cimetidine (400 mg) as an OCT inhibitor. Relative to baseline, metformin systemic plasma exposure increased by 24% (p<0.05) in the presence of cimetidine, which was accompanied by a disproportional decrease (8%) in metformin renal clearance (p=0.005). Genetic variants ofOCT1andOCT2moderately impacted the significance and magnitude of the interaction. Collectively, we hypothesized that the cimetidine-metformin interaction involves inhibition of hepatic OCT1 as well as renal OCT2. We tested this hypothesis by developing a physiologically based pharmacokinetic (PBPK) model and assessing potential OCT biomarkers in plasma and urine to gain mechanistic insight into the transporters involved in this interaction. The PBPK model predicted that cimetidine primarily inhibits hepatic OCT1 and, to a lesser extent, renal OCT2. The unchanged renal clearance of potential OCT2 biomarkers following cimetidine exposure supports a minimal role for renal OCT2 in this interaction.
Pleiotropy increases with gene age in six model multicellular eukaryotes
Authors: Martin Reese , Tate Ann T.
Published: November 2024

Fundamental traits of genes, including function, length and GC content, all vary with gene age. Pleiotropy, where a single gene affects multiple traits, arises through selection for novel traits and is expected to be removed from the genome through subfunctionalization following duplication events. It is unclear, however, how these opposing forces shape the prevalence of pleiotropy through time. We hypothesized that the prevalence of pleiotropy would be lowest in young genes, peak in middle aged genes, and then either decrease to a middling level in ancient genes or stay near the middle-aged peak, depending on the balance between exaptation and subfunctionalization. To address this question, we have calculated gene age and pleiotropic status for several model multicellular eukaryotes, includingHomo sapiens,Mus musculus,Danio rerio,Drosophila melanogaster,Caenorhabditis elegans, andArabidopsis thaliana. Gene age was determined by finding the most distantly related species that shared an ortholog using the Open Tree of Life and the Orthologous Matrix Database (OMAdb). Pleiotropic status was determined using both protein-protein interactions (STRINGdb) and associated biological processes (Gene Ontology). We found that middle-aged and ancient genes tend to be more pleiotropic than young genes, and that this relationship holds across all species evaluated and across both modalities of measuring pleiotropy. We also found absolute differences in the degree of pleiotropy based on gene functional class, but only when looking at biological process count. From these results we propose that there is a fundamental relationship between pleiotropy and gene age and further study of this relationship may shed light on the mechanism behind the functional changes genes undergo as they age.

Impact statement

Pleiotropy, the phenomenon where a single gene acts on multiple traits, is fundamental to genomic organization and has profound consequences for fitness. This work identifies a previously unknown relationship between pleiotropy and gene age, highlighting the dynamism of pleiotropy across time. This relationship holds across six distantly related model organisms, suggesting that it could be a highly generalizable finding, at least among multicellular eukaryotes. Following from this work, future investigation into mechanisms dictating the prevalence of pleiotropy at the gene or cellular level could provide fundamental insight into the maintenance of pleiotropy despite the potential for constraining rapid adaptation.
Utility of TaqMan Array Cards for detection of Acute febrile illness etiologies in patients suspected of Viral Hemorrhagic Fever Infections in Uganda
Authors: Akurut GG , Nyakarahuka L , Whitmer S , Namanya D , Kilama K , Mulei S , Baluku J , Tumusime A , Kyondo J , Lutwama Julius J , Shoemaker Trevor , Patel K , Montgomery Joel , Klena JD , Balinandi S
Published: November 2024

Introduction

Attributing a causative agent to acute febrile illnesses (AFI) remains a challenging diagnostic task for clinical and public health laboratories. The need for developing, validating and implementing a multi-pathogen diagnostic assay able to detect a wide range of AFI-associated pathogens should be prioritized in low-resource settings. The use of the previously developed Acute Febrile Illness TaqMan Array card (AFI-TAC), which detects 26 pathogens in less than 2 hours post-sample nucleic acid extraction, was selected for evaluation in Uganda.

Methods

This was a cross-sectional retrospective study in which archived viral hemorrhagic fever (VHF)-negative blood and plasma samples were selected. Samples were previously tested and archived at the Uganda Virus Research Institute (UVRI)-Viral Hemorrhagic Fever (UVRI-VHF) Laboratory from August 2018 to March 2019 as part of the routine surveillance program. The VHF case definition included, temperature of ≥38.0 ºC, additionally with bleeding and any other febrile symptoms. Samples were then tested using an AFI-TAC for 35 potential pathogen targets. Selected positive samples were subsequently assessed using a second, pathogen-specific simplex PCR assay. Epidemiological data were linked to the laboratory findings to assess for risk factors for infection.

Results

A total of 82 samples were selected for this study, of which 152 (83.52%) were from Uganda, 22 (12.09%) from the Democratic Republic of the Congo, 7 (3.85 %) from South Sudan, and 1 (0.55%) from Kenya. The median age of the patients was 27 years, with 145 (79.67%) samples from adults >18 years. Seven pathogens were detected with the most prevalent beingPlasmodiumspp. 26.92% (49/182) of which 69.4% (34/49) werePlasmodium falciparum, Yellow fevervirus 2 (1.10 %), non-typhoidalSalmonella3 (1.65%),Salmonella enterica serovarTyphi (1.10%),Leptospiraspp. 1 (0.54%),Streptococcus pneumonia(0.55%), andRickettsiaspp. (0.55%). Epidemiological correlation revealed a significant relationship between case fatality (p=0.002) and disease while age, occupation, sex and disease were not significant. Cough was found to be the only clinical symptom associated with being infected withPlasmodium(p=0.016).

Conclusion

The use of TAC is feasible, readily adoptable diagnostic assay for use in Uganda and will be useful when incorporated into the national testing algorithm for the differential diagnosis of AFI during an outbreak and surveillance.
Negative BOLD Responses Surpass Positive Responses in Task Specificity, Reflecting Neural Reconfigurations Better Than Functional Connectivity
Authors: Gholipour Picha Saman , Hojjati Seyed Hani , Nayak Siddharth , Ozoria Sindy , Chernek Peter , Calimag Jenseric , Ghaderi Yazdi Bardiya , Razlighi Qolamreza R.
Published: November 2024

Objective

To investigate whether the Negative BOLD Response (NBR) is more task-specific than the Positive BOLD Response (PBR) during cognitive tasks and to determine whether task-evoked activity reflects brain reconfigurations during different tasks better than functional connectivity.

Methods

Functional Magnetic Resonance Imaging (fMRI) data were collected from 214 participants under 50 years old (152 in Dataset 1 and 62 in Dataset 2) performing twelve cognitive tasks spanning vocabulary, speed of processing, fluid reasoning, and memory domains. Data analysis included subject-level and group-level analyses, focusing on comparing the spatial patterns and task specificity of NBR and PBR through similarity measures using Dice coefficients. Additionally, functional connectivity was assessed using the Multi-session Hierarchical Bayesian Model (MS-HBM) to evaluate its sensitivity to task-induced brain reconfigurations compared to task-evoked activity.

Results

NBR demonstrated significantly greater task specificity compared to PBR across all cognitive tasks, with lower mean Dice coefficients for NBR maps (mean: 0.44, SD: 0.13) than for PBR maps (mean: 0.67, SD: 0.09; t(65) = 18.38, p < 0.001). Functional connectivity analyses indicated that the default mode network (DMN) remained stable across tasks, suggesting that task-evoked activity reflects task-specific brain reconfigurations better than functional connectivity.

Conclusion

The findings confirm that NBR is inherently more task-specific than PBR and that task-evoked activity provides a more sensitive measure of task-specific neural reconfigurations than functional connectivity. This enhances our understanding of the neural mechanisms underlying cognitive processes and highlights the importance of considering NBR in cognitive neuroscience research.
TRAIT: A Comprehensive Database for T-cell Receptor-Antigen Interactions
Authors: Wei Mengmeng , Wu Jingcheng , Bai Shengzuo , Zhou Yuxuan , Chen Yichang , Zhang Xue , Zhao Wenyi , Chi Ying , Pan Gang , Zhu Feng , Chen Shuqing , Zhou Zhan
Published: November 2024

Comprehensive and integrated resources on interactions between T-cell receptors and antigens are still lacking for adoptive T-cell-based immunotherapies, highlighting a significant gap that must be addressed to fully comprehend the mechanisms of antigen recognition by T-cells. In this study, we present TRAIT, a comprehensive database that profiles the interactions between T-cell receptors (TCRs) and antigens. TRAIT stands out due to its comprehensive description of TCR-antigen interactions by integrating sequences, structures and affinities. It provides nearly 8 million experimentally validated TCR-antigen pairs, resulting in an exhaustive landscape of antigen-specific TCRs. Notably, TRAIT emphasizes single-cell omics as a major reliable data source for TCR-antigen interactions and includes millions of reliable non-interactive TCRs. Additionally, it thoroughly demonstrates the interactions between mutations of TCRs and antigens, thereby benefiting affinity maturation of engineered TCRs as well as vaccine design. TCRs on clinical trials were innovatively provided. With the significant efforts made towards elucidating the complex interactions between TCRs and antigens, TRAIT is expected to ultimately contribute superior algorithms and substantial advancements in the field of T-cell-based immunotherapies. TRAIT is freely accessible athttps://pgx.zju.edu.cn/traitdb.
Human internal exposures of bisphenol A and six data-poor analogues predicted by physiologically based kinetic models with multimodal parameterization
Authors: Bigonne Hélène , Rolof Amrei , Potapova Inga , Sturla Shana J. , Aichinger Georg
Published: November 2024

Background

Bisphenols (BP) AF, B, E, F, M, and S have been introduced as substitutes for bisphenol A (BPA) and are increasingly used in consumer products. Despite widespread human exposure and potential adverse health outcomes related to BPF, BPB, BPS, and BPAF, their physiological disposition in humans is poorly characterized, which hinders assessment of associated risks.

Objectives

Our goal was to simulate the kinetic behavior of prevalent bisphenol analogs in organs of toxicological interest. To enable predictions of physiologically relevant internal concentrations of a family of structurally similar compounds with limited available human data, we aim to establish a reproducible framework using multimodal parameterization methods.

Methods

Herein we developed physiologically based kinetic (PBK) models, following oral exposure. Their parametrization was primarily based on structural, physiological and experimental values, as well as quantitative structure-activity relationship (QSAR) predictions. Outputs were evaluated against available biomonitoring data for BPA and BPS. Critical parameters were identified by sensitivity analysis and iteratively re-sampled in Monte Carlo (MC) simulations to quantify uncertainties.

Results

Among human models parametrized for males and females of different ages, we predicted that bisphenols reached the highest concentrations in 5-year-old males. Environmentally relevant exposure levels resulted in maximum concentrations in the blood and testes for BPS, and in the thyroid for BPM. After 96 hours, steady-state concentrations were not yet reached in the breasts for BPA, BPAF, BPB, BPE, BPF and BPM.

Conclusions

The data from this study suggest significant variability in internal concentrations for identical exposures to different bisphenols analogs that further depend on age, sex and organ. This diversity in toxicokinetic behavior should be considered for health risk assessment of these substitutes.
Self-organized patterning of peristaltic waves by suppressive actions in a developing gut
Authors: Kawamura Koji , Kato Soichiro , Utsunomiya Shota , Takahashi Yoshiko , Inaba Masafumi
Published: November 2024

Gut peristalsis is a wave-like movement of a local contraction along the gut, and plays important roles in nutrient digestion and absorption. When peristaltic waves emerge in embryonic guts, randomly distributed origins of peristaltic waves (OPWs) become progressively confined to specific sites. We have investigated how this random-to-organized positioning is achieved using the caecum as a model in chicken embryos. While prominent OPWs, recognized as active (spontaneous) contractions, are located at endpoints of the intact caecum, other regions are also found to possess latent rhythm unveiled by fragmentation of a caecum into pieces, showing that the latent rhythm is normally suppressed in the intact gut. Analyses with caecum fragments demonstrate that the latent rhythm is spatially patterned in an early gut, to which negative impact by primitive passing waves contributes; the more passing waves a region experiences to undergo forced/passive contractions, the slower latent rhythm this region acquires. This patterned latent rhythm underlies the final positioning of OPWs at later stages, where a site with faster latent rhythm dominates neighboring slower rhythm, surviving as a “winner” by macroscopic lateral inhibition. Thus, the random-to-organized patterning of OPWs proceeds by self-organization within the caecum, in which two distinct mechanisms, at least, are employed; suppressive actions by primitive waves followed by macroscopic lateral inhibition.
SIGNAL: Dataset for Semantic and Inferred Grammar Neurological Analysis of Language
Authors: Komissarenko Anna , Voloshina Ekaterina , Cheveleva Anastasia , Semenkov Ilia , Serikov Oleg , Ossadtchi Alex
Published: November 2024

Recently, the idea of comparison of models’ representations and human brain signals has been a topic of several works. Consequently, several datasets with text data and EEG representations have been published. However, most of the datasets are based on normal reading task with grammatical sentences. At the same time, in the interpretability studies of LLMs, more and more attention is paid to thoroughly designed linguistic tasks based on acceptability measures. In this paper, we present SIGNAL, a dataset for Semantic and Inferred Grammar Neurological Analysis of Language. Our dataset contains a group of sentences with a combination of a fully acceptable sentence and a grammatically or/and semantically incongruent sentences. The dataset has been approved by native speakers and later used for an EEG experiment. In total, our dataset contains recordings of 21 participants, each of whom read 600 sentences. In addition, we present a pilot study where we compare EEG analysis with simple probing experiments.
Neural networks simulating short-term memory of two inputs with varying commonality
Authors: Raman Eric , Shupe Larry , Eaton Ryan , Fetz Eberhard
Published: November 2024

The activity and connectivity of neurons in the primate brain underlying behavior cannot yet be completely specified, but neural networks provide complete models of the connectivity and activity that performs specific tasks and provide insight into the neural computations performed by the primate brain (Fetz and Shupe 2003).

Studies of neurons in the monkey cortex have shown that short-term memory of sensory events may be mediated by sustained neural activity. Short-term memory tasks have been modeled with dynamic neural networks using a single continuous variable and a gate input to create a sample-and-hold (SAH) function (Zipser 1991; Maier 2003). Networks trained to perform these short-term memory tasks develop hidden unit activity which resembles that of cortical neurons in monkeys performing memory tasks.

We here extend the investigation of single-input SAH networks to networks computing SAH for two continuous-variable inputs that have varying degrees of common mode signal. Results provide insights into computational mechanisms of associative short-term memory of sensory signals with common mode components, such as visual inputs to the two eyes, auditory inputs to the ears and proprioceptive input from multiple muscle spindle afferents.

We also examined the attractor states that these SAH networks eventually reach after sufficiently long delay periods and found that these were determined by the shapes of the input-output functions of the hidden units rather than network architecture.
Development of Non-Spatial Grid-Like Neural Codes Predicts Inference and Intelligence
Authors: Qu Yukun , Ou Jianxin , Pang Luoyao , Wu Shuqi , Luo Yuejia , Behrens Timothy E , Liu Yunzhe
Published: November 2024

Piaget's theory emphasizes children develop structured knowledge schemas for assimilating new concepts, yet the neural mechanisms and their link to intelligence remain unclear. In 203 participants aged 8-25 years, we investigated how maturation of neural representations of a two-dimensional knowledge map supports inferential reasoning and assimilation. We found that grid-cell-like neural codes in the entorhinal cortex (EC) strengthen with age, forming structured representations in non-spatial conceptual spaces. This maturation is directly linked to improved inferential reasoning. These grid-like codes support the medial prefrontal cortex (mPFC) in encoding distance relationships between concepts. As participants assimilated new information, they integrated it into existing grid patterns in the EC. Furthermore, maturation of these neural codes predicts real-world intelligence measures, particularly in abstract reasoning. Our findings show that the development of non-spatial grid-like neural codes underpins inference and knowledge assimilation, providing a neural basis for cognitive development and linking cellular neuroscience with intelligence.
RNA-Stabilized Coat Proteins for Sensitive and Simultaneous Imaging of Distinct Single mRNAs in Live Cells
Authors: Kuffner Christopher J. , Marzilli Alexander M. , Ngo John T.
Published: November 2024

RNA localization and regulation are critical for cellular function, yet many live RNA imaging tools suffer from limited sensitivity due to background emissions from unbound probes. Here, we introduce conditionally stable variants of MS2 and PP7 coat proteins (which we name dMCP and dPCP) designed to decrease background in live-cell RNA imaging. Using a protein engineering approach that combines circular permutation and degron masking, we generated dMCP and dPCP variants that rapidly degrade except when bound to cognate RNA ligands. These enhancements enabled the sensitive visualization of single mRNA molecules undergoing differential regulation within various sub-compartments of live cells. We further demonstrate dual-color imaging with orthogonal MS2 and PP7 motifs, allowing simultaneous low-background visualization of distinct RNA species within the same cell. Overall, this work provides versatile, low-background probes for RNA imaging, which should have broad utility in the imaging and biotechnological utilization of MS2- and PP7-containing RNAs.
Soma-centered control of synaptic autophagy by Rab39-regulated anterograde trafficking of Atg9
Authors: Kilic Ayse , Vandekerkhove Dirk , Kuenen Sabine , Swerts Jef , Muñoz Pedrazo Esther , Calatayud Aristoy Carles , Escamilla Ayala Abril , Corthout Nikky , Hernández Varas Pablo , Plaisance Stephane , Nachman Eliana , Uytterhoeven Valerie , Verstreken Patrik
Published: November 2024

Presynaptic terminals can be located far from the neuronal cell body and are thought to independently regulate protein and organelle turnover. In this work, we report a soma-centered mechanism that regulates autophagy-driven protein turnover at distant presynaptic terminals inDrosophila. We show that this system is regulated by Rab39, whose human homolog is mutated in Parkinson’s disease. Although Rab39 is localized in the soma, its loss of function causes increased autophagy at presynaptic terminals, resulting in faster synaptic protein turnover and neurodegeneration. Using a large-scale unbiased genetic modifier screen, we identified genes encoding cytoskeletal and axonal organizing proteins, includingShortstop(Shot), as suppressors of synaptic autophagy. We demonstrate that Rab39 controls Shot-and Unc104/KIF1a-mediated transport of autophagy-related Atg9 vesicles to synapses. Under starvation conditions, Rab39 in the soma shifts its localization from endosomes to lysosomes, thereby controlling the availability of Atg9 vesicles for trafficking to synapses. Our findings indicate that Rab39-mediated trafficking in the soma orchestrates a cross-compartmental mechanism that regulates the abundance of autophagy at synapses.
Nanoparticles loaded with a CSF1R antagonist selectively depletes microglial cells and modulates inflammation in spinal cord injury
Authors: Yang Jingjing , Ucakar Bernard , Vanvarenberg Kevin , Malfanti Alessio , des Rieux Anne
Published: November 2024

Neuroinflammation is a principal event occurring after spinal cord injury (SCI). M1-like microglia are key players in the inflammatory response after injury. We hypothesize that the depletion of this microglia subtype would result in a more pro-resolutive environment, favorable to SCI repair. The colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 has been used to deplete microglia in the central nervous system. Although PLX5622 can freely cross the blood-brain barrier after systemic administration, the low drug concentration within the SCI site hampers its effectiveness. Additionally, systemic administration of PLX5622 in the scope of SCI treatment can induce side effects due to off-target accumulation. In this study, we specifically depleted M1- like microglia by designing polymeric nanoparticles loaded with PLX5622 (PLX NPs) to locally treat spinal cord contusion. PLX NP was prepared using a microfluidic-assisted approach showing high encapsulation efficiency (approx. 84%), nanosized dimensions (100 nm), and batch-to-batch reproducibility. PLX NP displayed selective activity in depleting M1-like microglial cells in both resting and lipopolysaccharide (LPS)-activated mixed microglial cell models compared with the free drug counterparts while preserving non-targeted glial cells. Furthermore, locally administered PLX NP downregulated proinflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β), increasing the M2/M1-like microglia ratio, thus reducing inflammation in a SCI contusion model. Our data support the hypothesis that local treatment with PLX NPs, a formulation with a high translational value, reduces neuroinflammation, with potential applications in SCI and central nervous system inflammatory diseases.

Graphical abstract.

The colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 loaded in polymeric nanoparticles (PLX NP) is delivered for the treatment of neuroinflammation in spinal cord injury.
Finding a path: Local search behavior ofDrosophilalarvae
Authors: Kromp Jessica , Triphan Tilman , Thum Andreas S.
Published: November 2024

Orientation and navigation are essential features of animals living in changing environments. Typically, animals integrate a variety of allothetic and idiothetic cues to achieve their navigational goals. Allothetic cues, such as visual or chemical landmarks from the environment, provide an external frame of reference. In contrast, idiothetic cues are based on internal proprioceptive feedback and internal copies of motor commands.

WhenDrosophilalarvae are exposed briefly to a Teflon container holding a food stimulus, they show a characteristic behavior as soon as the container is removed: They briefly crawl away from the detected resource, remain in its vicinity and then return to the area where they experienced the earlier stimulus. We quantified this behavior with respect to the chemosensory nature of the stimulus, starvation time of the larvae, and agarose concentration of the test plate substrate. We conclude that this behavior represents a centered local search. Furthermore, we exclude various external stimuli (vision and taste), which suggests that possibly idiothetic as opposed to allothetic cues have a stronger influence on the larval local search behavior.

In the long term, this behavioral description will enable us to gain insights into the comparability of larval foraging strategies. We also want to investigate whether, despite the simpler organization of the larval brain and the alleged lack of a central complex, a brain region that is important for orientation and navigation in adult Drosophila and other insects, there are common solutions for the brain circuits underlying search behavior.
Multi-modal refinement of the human heart atlas during the first gestational trimester
Authors: De Bono Christopher , Xu Yichi , Kausar Samina , Herbane Marine , Humbert Camille , Rafatov Sevda , Missirian Chantal , Moreno Mathias , Shi Weiyang , Gitton Yorick , Lombardini Alberto , Vanzetta Ivo , Mazaud-Guittot Séverine , Chédotal Alain , Baudot Anaïs , Zaffran Stéphane , Etchevers Heather C.
Published: November 2024

1.

Forty first-trimester human hearts were studied to lay groundwork for further studies of principles underlying congenital heart defects. We first sampled 49,227 cardiac nuclei from three fetuses at 8.6, 9.0, and 10.7 post-conceptional weeks (pcw) for single-nucleus RNA sequencing, enabling distinction of six classes comprising 21 cell types. Improved resolution led to identification of novel cardiomyocytes and minority autonomic and lymphatic endothelial transcriptomes, among others. After integration with 5-7 pcw heart single-cell RNAseq, we identified a human cardiomyofibroblast progenitor preceding diversification of cardiomyocyte and stromal lineages. Analysis of six Visium sections from two additional hearts was aided by deconvolution, and key spatial markers validated on sectioned and whole hearts in two- and three-dimensional space and over time. Altogether, anatomical-positional features including innervation, conduction and subdomains of the atrioventricular septum translate latent molecular identity into specialized cardiac functions. This atlas adds unprecedented spatial and temporal resolution to the characterization of human-specific aspects of early heart formation.
Effective targeting of CD19 positive primary B-ALL cells using CAR-NK cells generated with mRNA-LNPs
Authors: Salehi-Shadkami Hossein , Sedghi Mosslim , Tavoosi Shima , Alimohammadi Masoumeh , Alimohammadi Reza , Barkhordar Maryam , Mofayezi Ahmadreza , Modaresi Mohammad Sadra , Vaezi Mohammad , Dehghanizadeh Somaye , Ahmadvand Mohammad , Khoddami Vahid
Published: November 2024

1.

Chimeric antigen receptor natural killer (CAR-NK) cell therapy is recognized as a promising modality for the treatment of hematologic malignancies, particularly B-cell malignancies. In this study, we developed “off-the-shelf” anti-CD19 CAR-NK cells using anti-CD19 CAR mRNAs formulated in proprietary ionizable lipid nanoparticles (LNPs). The efficiency of mRNA-LNP delivery into umbilical cord blood (UCB)-derived NK cells and primary T cells was evaluated in an in-vitro setting, demonstrating superior delivery efficiency in NK cells. Further investigation showed a probable role for an endocytic mechanism, macropinocytosis, in efficient transfection of NK cells with LNPs. Nevertheless, CAR-NK cells generated through this mRNA-LNP platform exhibited significantly enhanced cytotoxicity against CD19+target cells, such as EGFP+Raji stable cell line and primary malignant B cells derived from refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL) patients. These findings highlight the promise of the mRNA-LNP platform in advancing CAR-NK therapies against B-cell malignancies.
FocalSV: target region-based structural variant assembly and refinement using single-molecule long read sequencing data
Authors: Luo Can , Zhou Zimeng Jamie , Zhou Xin Maizie
Published: November 2024

Structural variants (SVs) play a critical role in shaping the diversity of the human genome and their detection holds significant potential for advancing precision medicine. Despite notable progress in single-molecule long-read sequencing technologies, accurately identifying SV breakpoints and resolving their sequence remains a major challenge. Current alignment-based tools often struggle with precise breakpoint detection and sequence characterization, while whole genome assembly-based methods are computationally demanding and less practical for targeted analyses. Neither approach is ideally suited for scenarios where regions of interest are predefined and require precise SV characterization. To address this gap, we introduce FocalSV, a target region assembly-based SV detection tool that combines the precision of assembly-based methods with the efficiency of region-specific approaches. FocalSV was evaluated on nine germline datasets and two paired normal-tumor cancer datasets, demonstrating superior performance in both precision and efficiency.
Lewy-MSA hybrid fold drives distinct neuronal α-synuclein pathology
Authors: Enomoto Masahiro , Martinez-Valbuena Ivan , Forrest Shelley L. , Xu Xiaoxiao , Munhoz Renato P. , Li Jun , Rogaeva Ekaterina , Lang Anthony E. , Kovacs Gabor G.
Published: November 2024

The ordered assembly of α-synuclein protein into filaments encoded by SNCA characterizes neurodegenerative diseases called synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal α-synuclein pathology and multiple system atrophy (MSA) predominantly oligodendrocytic α-synuclein pathology affecting subcortical brain structures. Based on cryo-electron microscopy, it was reported that structures of α-synuclein filaments from LBD differ from MSA and juvenile onset synucleinopathy (JOS) caused by a 21-nucleotide duplication in the second exon of one allele ofSNCAgene1-3. Importantly, a rare subtype of MSA, called atypical MSA4shows abundant neuronal argyrophilic α-synuclein inclusions in the limbic system. Current concepts indicate that disease entities are characterized by unique protofilament folds. Here we demonstrate that in addition to the MSA fold, α-synuclein can form a new Lewy-MSA hybrid fold in the same brain region, leading to the atypical histopathological form of MSA. Distinct biochemical characteristics of α-synuclein, as demonstrated by protease-sensitivity digestion assay, seed amplification assays (SAAs) and conformational stability assay (CSA), are also linked to cytopathological differences (e.g. neuronal or oligodendroglial). We expand the current structure-based classification of α−synucleinopathies and propose that cell-specific protein pathologies can be associated with distinct filament folds.
Lattice design for the Diamond-II light source storage ring
Authors: Ghasem H. , Kraljevic N. Blaskovic , Singh B. , Martin I. P. S.
Published: November 2024

To satisfy user demands for a high-brightness, high-capacity synchrotron light source, a novel multibend achromat (MBA) lattice structure has been developed for the Diamond-II storage ring upgrade. This lattice combines the high-dispersion locations characteristic of hybrid MBA lattices with newly introduced midcell straight sections to allow extra insertion devices to be installed. The resulting structure is named the modified hybrid six bend achromat (MH6BA) lattice. When adapted to fit in the existing 560.6 m Diamond storage ring tunnel, it reaches a natural emittance of 162 pm rad at 3.5 GeV. The characteristics of the MH6BA lattice, the methodology used to optimize the linear and nonlinear beam dynamics, and the lattice performance in a range of conditions are discussed.

Published by the American Physical Society
2024