bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the genetic diversity in RNA-directed RNA polymerase sequences: implications for an automated RNA virus classification system
Authors: Tian Zhongshuai , Hu Tao , Holmes Edward C , Ji Jingkai , Shi Weifeng
Published: July 2024

RNA viruses are characterized by a broad host range and high levels of genetic diversity. Despite a recent expansion in the known virosphere following metagenomic sequencing, our knowledge of the species rank genetic diversity of RNA viruses, and how often they are misassigned and misclassified, is limited. We performed a clustering analysis of 7801 RNA-directed RNA polymerase (RdRp) sequences representing 1897 established RNA virus species. From this, we identified substantial genetic divergence within some virus species and inconsistency in RNA virus assignment between the GenBank database and The International Committee on Taxonomy of Viruses (ICTV). In particular, 27.57% virus species comprised multiple virus operational taxonomic units (vOTUs), including Alphainfluenzavirus influenzae, Mammarenavirus lassaense, Apple stem pitting virus, and Rotavirus A, with each having over 100 vOTUs. In addition, the distribution of average amino acid identity between vOTUs within single assigned species showed a relatively low threshold: <90% and sometimes <50%. However, when only exemplar sequences from virus species were analyzed, 1889 of the ICTV-designated RNA virus species (99.58%) were clustered into a single vOTU. Clustering of the RdRp sequences from different virus species also revealed that 17 vOTUs contained two distinct virus species. These potential misassignments were confirmed by phylogenetic analysis. A further analysis of average nucleotide identity (ANI) values ranging from 70% to 97.5% revealed that at an ANI of 82.5%, 1559 (82.18%) of the 1897 virus species could be correctly clustered into one single vOTU. However, at ANI values >82.5%, an increasing number of species were clustered into two or more vOTUs. In sum, we have identified some inconsistency and misassignment of the RNA virus species based on the analysis of RdRp sequences alone, which has important implications for the development of an automated RNA virus classification system.
Overdose Deaths Drop in the United States
Authors: Roush Karen
Published: July 2024

It is the first annual decrease in five years.
The Women: A Rarely Told War Story
Authors: Brown Theresa
Published: July 2024

A gripping read about U.S. Army nurses during the Vietnam War
A Case of Symptomatic Bradycardia After Valve Replacement
Authors: Kupchik Nicole , Vance Sarah
Published: July 2024

Editor's note: This is the next installment in a series on electrocardiogram (ECG) interpretation. Nurses in all settings should know the basics, as medications and physiological changes can cause cardiac arrhythmias. Each article will start with a brief case scenario and an ECG strip and then take you step by step through analyzing the heart rhythm.
The UN Commission on the Status of Women: Highlights from Parallel Events
Authors: McSpedon Corinne
Published: July 2024

How nurses are advancing gender equity and women's empowerment globally
Video-Based Coaching for Laparoscopic Salpingectomy
Authors: Muir Teale M. , Pruszynski Jessica , Kho Kimberly A. , Ramirez Christina I. , Donnellan Nicole M. , Chao Lisa
Published: July 2024

OBJECTIVE:

To evaluate the effect of video-based coaching on the gynecology resident performance of laparoscopic salpingectomy.

METHODS:

PGY-1 and PGY-2 residents were randomized before their gynecology rotations to standard gynecology curriculum (control group) or standard curriculum plus two video-coaching sessions by a fellowship-trained minimally invasive gynecologic surgeon (VBC group). Residents were video recorded intraoperatively performing three unilateral laparoscopic salpingectomies. Participants in the VBC group were coached between the procedures. The primary outcome was the improvement in modified GOALS (Global Operative Assessment of Laparoscopic Skills) and OSA-LS (Objective Structured Assessment of Laparoscopic Salpingectomy) scores, compared with baseline, in the VBC and control groups, with videos independently graded by three blinded minimally invasive gynecologic surgeons. A minimum sample size of 18 participants (nine per group) was needed to achieve 90% power to detect a difference of 5.0 points.

RESULTS:

From October 2021 to December 2022, 28 PGY-1 and PGY-2 residents completed the study with 14 participants per group. Baseline characteristics were similar between groups. In the VBC group, modified GOALS scores significantly improved by 3.0 points from video 1 to video 2 (P=.04) and by 3.2 points from video 1 to video 3 (P=.02). Modified OSA-LS scores also increased significantly in the VBC group, by 6.1 points from video 1 to video 3 (P=.02). In the control group, modified GOALS and OSA-LS scores improved from baseline but were not significant (P=.2, P=.5). Video-based coaching also enhanced resident comfort and confidence in performing laparoscopic surgery.

CONCLUSION:

Video-based coaching improves resident performance of laparoscopic salpingectomy and can be used as an adjunct to resident surgical training.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT05103449.
Quality of Care and Quality of Life
Authors: Minkoff Howard , O'Brien Joselle , Berkowitz Richard
Published: July 2024

Since the publication of the Institute of Medicine's landmark report on medical errors in 2000, a large number of safety programs have been implemented in American hospitals. Concurrently, there has been a dramatic increase in the rate of burnout among physicians. Although there are many unrelated causes of burnout (eg, loss of autonomy), and multiple safety programs that are applauded by physicians (eg, The Safe Motherhood Initiative), other programs created in the name of safety improvements may be contributing to physician distress. In this piece, we review several of those programs, describe their limitations and costs to physician well-being, and discuss the manner in which they might be modified to retain their benefits while mitigating the burdens they place on physicians.
Positional End-Point Nystagmus in Patients with Diagnosis of Acute Unilateral Vestibulopathy
Authors: Domínguez-Durán Emilio , Prieto-Sánchez-de-Puerta Lucía , Tena-García Beatriz , Acosta-Mosquera María Eugenia , Sánchez-Gómez Serafín
Published: July 2024

Introduction

Recently, end-point nystagmus, traditionally observed in an upright position, has been identified in the Dix–Hallpike position among healthy subjects, suggesting a physiological origin.

However, its characteristics in individuals with vestibular hypofunction remain unexplored.

Objective

To elucidate the impact of vestibular hypofunction on the characteristics of positional end-point nystagmus.

Methods

Thirty-one patients diagnosed with acute unilateral vestibulopathy according to Bárány Society criteria were selected. A video head impulse test was conducted in all participants, followed by McClure and Dix–Hallpike maneuvers with and without gaze fixation, and with the initial position of the eye in the straight-ahead position or in the horizontal end-point position. Nystagmus direction, sense, latency, slow-phase velocity, and duration were recorded. The relationship between these characteristics and video head impulse test values was analyzed.

Results

Positional end-point nystagmus was observed in 92.6% of subjects with vestibular hypofunction, significantly more than in healthy individuals. Nystagmus direction varied depending on the performed positional test and on the vestibulo-ocular reflex gains. Gaze occlusion and the initial horizontal end-point position increased its frequency.

Conclusion

Vestibular hypofunction influences the manifestation of positional end-point nystagmus. Recognizing this nystagmus can aid in resolving diagnostic uncertainties and preventing the misdiagnosis of benign paroxysmal positional vertigo in subjects with acute unilateral vestibulopathy.
Urethral Bulking
Authors: Fleischmann Nicole , Chughtai Bilal , Plair Andre , Hurtado Eric , Jacobson Nina , Segal Saya , Panza Joseph , Cichowski Sara B.
Published: July 2024

Objective

This Clinical Practice Statement aims to provide clinicians with evidence-based guidance for the use of urethral bulking agents (UBAs) in the treatment of stress urinary incontinence (SUI).

Methods

We conducted a structured search of the English literature published from January 1960 to November 2022. Search terms identified studies of both current and historic UBAs. Data extracted at the time of full-text review included type of study, research setting, number of participants, age group, bulking agent, primary outcome, secondary outcome, efficacy, and complications.

Results

One thousand five hundred ninety-four nonduplicate articles were identified using the search criteria. After limiting the article types to randomized control led trials, prospective studies, guideline documents, reviews, meta-analyses, and case reports of complications, 395 studies were screened.

Conclusions

Based on our findings, we propose the following recommendations for clinicians when considering UBA: First, UBA is indicated in cases of demonstrable SUI. Intrinsic sphincter deficiency is not predictive of patient outcomes. Second, patients should be counseled on the risks, lack of long-term efficacy data, potential need for repeat injections, possible need for surgery for recurrent SUI, implications for future procedures, and pelvic imaging findings that may be observed after UBA. Third, UBA may be considered for initial management of SUI. Fourth, UBA is an option for patients with persistent or recurrent SUI after a sling procedure. Fifth, clinicians may prioritize UBA over surgery in specific patient populations. Sixth, polyacrylamide hydrogel demonstrates marginally improved safety and durability data over other available agents.
Impact of Donor Warm Ischemia Time on Graft Survival for Donation After Circulatory Death Kidney Transplantation
Authors: Chumdermpadetsuk Ritah R. , Alvino Donna Marie L. , Kaul Sumedh , Fleishman Aaron , Eckhoff Devin E. , Pavlakis Martha , Lee David D.
Published: July 2024

Background.

The utilization of kidneys donated after circulatory death (DCD) is an important strategy to address the ongoing shortage of organs suitable for transplantation in the United States. However, the nonuse rate of DCD kidneys remains high compared with kidneys donated after brain death (DBD) because of concerns regarding the injury incurred during donor warm ischemia time (DWIT). Therefore, we investigated the impact of DWIT on the risk of death-censored graft failure after DCD kidney transplantation (KT).

Methods.

Retrospective analysis was conducted on DCD KTs using the Standard Transplant Analysis and Research data set. The association of DWIT with death-censored graft failure was evaluated using multivariable Cox proportional hazard regression, with reference to DCD KTs with Kidney Donor Risk Index (KDRI) of ≤0.78 and the median DWIT of 26 min.

Results.

A total of 28 032 DCD kidney-alone transplants between January 2010 and December 2021 were studied. When stratified by KDRI, increasing DWIT was associated with a clinically significant increased risk for death-censored graft failure only in the subset of kidneys with KDRI >1.14 but not in those with KDRI >0.78–≤0.94 and >0.94–≤1.14, compared with the reference group.

Conclusions.

We suggest that clinicians should not decline kidneys on the basis of DWIT in favor of potential offers of DBD or other DCD kidneys with shorter DWIT, provided that their KDRI scores are within an acceptable limit. Our study highlights opportunities for more efficient usage of DCD kidneys and improving the shortage of transplantable organs.
V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging
Authors: Hashmi Fiza , Kane Patricia M.
Published: July 2024

Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification and V- ATPase activity is regulated by reversible disassembly in many different settings. Using the yeastSaccharomyces cerevisiaeas a replicative aging model, we demonstrate that V-ATPases disassemble into their V1 and V0 subcomplexes in aging cells, with release of V1 subunit C (Vma5) from the lysosome-like vacuole into the cytosol. Disassembly is observed after>5 cell divisions and results in overall vacuole alkalinization. Caloric restriction, an established mechanism for reversing many age-related outcomes, prevents V-ATPase disassembly in older cells and preserves vacuolar pH homeostasis. Reversible disassembly is controlled in part by the activity of two opposing and conserved factors, the RAVE complex and Oxr1. The RAVE complex promotes V-ATPase assembly and arav1Δmutant shortens replicative lifespan; Oxr1 promotes disassembly and anoxr1Δmutation extends lifespan. Importantly, the level of Rav2, a subunit of the RAVE complex, declines in aged cells, and Rav2 overexpression delays V-ATPase disassembly with age. These data indicate that reduced V-ATPase assembly contributes to the loss of lysosome acidification with age, which affects replicative lifespan.
PairK: Pairwise k-mer alignment for quantifying protein motif conservation in disordered regions
Authors: Halpin Jackson C. , Keating Amy E.
Published: July 2024

Protein-protein interactions are often mediated by a modular peptide recognition domain binding to a short linear motif (SLiM) in the disordered region of another protein. The ability to predict domain-SLiM interactions would allow researchers to map protein interaction networks, predict the effects of perturbations to those networks, and develop biologically meaningful hypotheses. Unfortunately, sequence database searches for SLiMs generally yield mostly biologically irrelevant motif matches or false positives. To improve the prediction of novel SLiM interactions, researchers employ filters to discriminate between biologically relevant and improbable motif matches. One promising criterion for identifying biologically relevant SLiMs is the sequence conservation of the motif, exploiting the fact that functional motifs are more likely to be conserved than spurious motif matches. However, the difficulty of aligning disordered regions has significantly hampered the utility of this approach. We present PairK (pairwise k-mer alignment), an MSA-free method to quantify motif conservation in disordered regions. PairK outperforms both standard MSA-based conservation scores and a modern LLM-based conservation score predictor on the task of identifying biologically important motif instances. PairK can quantify conservation over wider phylogenetic distances than MSAs, indicating that SLiMs may be more conserved than is implied by MSA-based metrics. PairK is available as open-source code athttps://github.com/jacksonh1/pairk.
Polygenic Risk Score predicts QTc-prolongation and Short-Term Mortality in Patients using QT-prolonging Psychoactive Medications
Authors: Altaraihi Mays
Published: July 2024

Background

There is a genetic component to the QT-interval. This study investigated whether a polygenic risk score for QTc (PRSQTc) could predict ΔQTc and short-term mortality in first-time users of QT-prolonging medications (QTPM) with a known risk of Torsade de Pointes.

Methods

First-time users of psychoactive QTPM in the Copenhagen Hospital Biobank and the Danish Blood Donor Study from 2009-2021 were included. ΔQTc was calculated and all-cause 30-day mortality following initiation of treatment was explored. All models were adjusted for conventional QT-prolonging risk factors, and models investigating death were additionally adjusted for potential comorbidity confounders.

Results

The PRSQTccould predict ΔQTc (2.88 milliseconds (ms) for every increase of standard deviation in PRSQTc(P <0.001)) following treatment initiation. Individuals in the top ≥ 80 % of PRSQTchad a higher risk of ΔQTc of ≥60 ms compared to individuals in <80 % PRSQTc(OR = 4.88 P = 0.019). Furthermore, the study has also shown that the shorter QTc before initiation of QTPM, the higher the risk of greater ΔQTc.

A high PRSQTccould also predict short-term mortality following treatment initiation: Individuals in the top PRSQTc≥90 % had an odds ratio of 1.84 (P-value = 0.002) for short-term mortality compared to individuals with PRSQTc<90 %. Individuals in the top PRSQTc≥99 % had an odds ratio of 4.95 (P-value = 0.009) for short-term mortality compared to individuals in the <99 % PRSQTc

It could be replicated that PRSQTc≥90 % was a predictor of short-term mortality with OR 1.52 (P-value = 0.002) compared to PRSQTc<90 % in a bigger cohort (N=15.249).

Conclusion

PRSQTcseems to be predictive of ΔQTc following initiation of treatment. PRSQTcproves to be a sufficient predictor of 30-day mortality after initiation of QT-prolonging psychoactive drugs with a known risk of Torsade de Pointes.

If used in a clinical setting, PRSQTmay help prevent sudden cardiac deaths associated with QTPM.
Size control and oscillations of active droplets in synthetic cells
Authors: Sastre Judit , Thatte Advait , Bergmann Alexander M. , Stasi Michele , Tena-Solsona Marta , Weber Christoph A. , Boekhoven Job
Published: July 2024

Oscillations in the formation and dissolution of molecular assemblies inside living cells are pivotal in orchestrating various cellular functions and processes. However, designing such rhythmic patterns in synthetic cells remains a challenge. Here, we demonstrate the spontaneous emergence of spatio-temporal oscillations in the number of droplets, size, and position within a synthetic cell. The coacervate-based droplets in these synthetic cells sediment and fuse at the cell’s bottom. Through a newly discovered size control mechanism, the sedimented, large droplets shrink by expelling droplet material. The expelled molecules nucleate new droplets at the top of the synthetic cell, which grow and sediment again. These oscillations are sustained by converting chemical fuel into waste and can continue for hundreds of periods without evidence of fatigue. Strikingly, the period of the oscillation is in the minute’s regime and tunable. The design of oscillating organelles in synthetic cells brings us closer to creating more life-like materials andde novolife.
Refinement of theBrassica napusNLRome using RenSeq
Authors: Wu Jiaxu , Mukhopadhyay Soham , Pérez-López Edel
Published: July 2024

Canola (Brassica napusL.), a valuable oilseed crop, faces significant challenges from diseases such as clubroot and blackleg, threatening global yields. To improve disease resistance, it’s crucial to accurately annotate nucleotide-binding leucine-rich repeat receptors (NLRs), which are key components of plant immune systems. This study focuses on refining the NLR repertoire (NLRome) of the Westar cultivar using Resistance gene enrichment sequencing (RenSeq). Initially, only 345 NLR genes were identified in the Westar genome annotation, a figure significantly lower than other canola cultivars. By employing RenSeq, we expanded the annotated NLR genes to 715, including 287 full NLRs and 428 partial NLRs, thus providing a more comprehensive understanding of the NLR diversity in this cultivar. Our findings reveal crucial genomic regions with previously misannotated NLR genes and identify key integrated domains that may contribute to enhanced disease resistance. This refined NLRome not only advances the fundamental understanding ofB. napusgenetics but also offers valuable insights for breeding programs and biotechnological applications aimed at improving crop resilience. The data generated in this study is available in public repositories for further research and application.
Cerebellar systems consolidation driven by the temporal dynamics of Purkinje cell excitability
Authors: Seo Jewoo , Kim Yong Gyu , Lee Yong-Seok , Kim Sang Jeong
Published: July 2024

Systems consolidation, essential for long-term memory formation, orchestrates the reorganization of newly encoded memories from the cortex into subsequent neural circuitry. While the role of synaptic mechanism in consolidation is well understood, the contribution of neuronal intrinsic excitability (IE) remains relatively unexplored. Herein, we adopted the optokinetic reflex, a cerebellum-dependent learning model, and manipulated IE of the sole output of the cerebellar cortex, Purkinje cells (PCs), to corroborate the direct causality between neuronal IE and memory consolidation. Optogenetic modulation of PC-IE post-learning uncovered a critical temporal window for its role in systems consolidation. Specifically, increasing PC-IE within 90 minutes after learning disrupted memory consolidation, while outside this window, memory retention remained unaffected. Under physiological conditions, PC-IE naturally decreased during this time frame and returned to baseline thereafter. Moreover, abnormally heightened PC-IE eliminated intrinsic plasticity in flocculus-targeting neurons (FTNs) within the medial vestibular nucleus (MVN), a key downstream circuit involved in long-term memory storage. These findings highlight the precise temporal dynamics of IE as a pivotal mechanism in systems consolidation, emphasizing its vulnerability to disruptions.
The presenting HLA determines fidelity of SARS-CoV-2 spike protein epitope prediction
Authors: Schutt Charles R , Birol Deren , Lu Xiuyuan , Yamasaki Sho
Published: July 2024

During the course of the COVID-19 pandemic, multiple studies used prediction methods to identify potential epitopes. While additional studies identified epitopes from convalescent and vaccinated subjects, few studies have compared the predicted to identified epitopes. Here we used three methods alone and in combination to predict helper T cell epitopes and compared the results to experimentally determined peptide binding. The correspondence between the results predicted from each method or combination and experimental results depends on the HLA being investigated. We were also able identify the prediction methods which lead to the most consistent results. Lastly, these observations were extended to more HLAs to predict epitopes which may be globally presented. All the predicted epitopes were previously identified as helper T cell epitopes. These results suggest predicting the binding to a larger number of HLAs may lead to higher fidelity identification of epitopes.
Broad substrate scope C-C oxidation in cyclodipeptides catalysed by a flavin-dependent filament
Authors: Sutherland Emmajay , Harding Christopher J. , De Bergendal Tancrede Martin Y Du Monceau , Florence Gordon J. , Ackermann Katrin , Bode Bela E. , Synowksy Silvia , Sundaramoorthy Ramasubramanian , Czekster Clarissa Melo
Published: July 2024

Cyclic dipeptides are produced by organisms in all domains of life. Many possess biological activities as anticancer and antimicrobial compounds. Oxidations are frequently present in these biologically active peptides. C-C bond oxidation is catalysed by tailoring enzymes, including cyclodipeptide oxidases. These flavin-dependent enzymes are underexplored due to their complex three-dimensional arrangement involving multiple copies of two distinct small subunits and unclear mechanistic features underlying substrate selection and catalysis. Here, we determined the structure and mechanism of the cyclodipeptide oxidase from the halophileNocardiopsis dassonvillei(NdasCDO), part of the biosynthetic pathway for nocazine natural products. We showNdasCDO forms filaments in solution with a covalently bound FMN cofactor in the interface between three distinct subunits. The enzyme is promiscuous, using many cyclic dipeptides as substrates in a distributive manner. The reaction is optimal at high pH, involving the formation of a radical intermediate. Pre-steady state kinetics, a sizeable solvent kinetic isotope effect and lack of viscosity effects support that a step coupled to FMN regeneration determines the rate of the reaction. Our work dissects the complex mechanistic and structural features of this dehydrogenation reaction. This sets the stage to utilizingNdasCDO as a biocatalyst and expands the FMN-dependent oxidase family to include enzyme filaments.
MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer
Authors: Murphy Katherine C. , DeMarco Kelly D. , Zhou Lin , Lopez-Diaz Yvette , Ho Yu-jui , Li Junhui , Bai Shi , Simin Karl , Zhu Lihua Julie , Mercurio Arthur M. , Ruscetti Marcus
Published: July 2024

Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted and immunotherapies. Whether genetic alterations acquired during the evolution of CRPC impact immune and immunotherapy responses is largely unknown. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors withMYCamplification andp53disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which by signaling through VEGFR2 expressed on CD8+T cells, could directly inhibit T cell activity. Targeting VEGF-VEGFR2 signalingin vivoled to CD8+T cell-mediated tumor and metastasis growth suppression and significantly increased overall survival inMYCandp53altered CPRC. VEGFR2 blockade also led to induction of PD-L1, and in combination with PD-L1 immune checkpoint blockade produced anti-tumor efficacy in multiple preclinical CRPC mouse models. Thus, our results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC.

Significance

Though immune checkpoint blockade (ICB) therapies can achieve curative responses in many treatment-refractory cancers, they have limited efficacy in CRPC. Here we identify a genetic mechanism by which VEGF contributes to T cell suppression, and demonstrate that VEGFR2 blockade can potentiate the effects of PD-L1 ICB to immunologically treat CRPC.
ETV4 and ETV5 Orchestrate FGF-Mediated Lineage Specification and Epiblast Maturation during Early Mouse Development
Authors: Simon Claire S. , Garg Vidur , Kuo Ying-Yi , Niakan Kathy K. , Hadjantonakis Anna-Katerina
Published: July 2024

Cell fate decisions in early mammalian embryos are tightly regulated processes crucial for proper development. While FGF signaling plays key roles in early embryo patterning, its downstream effectors remain poorly understood. Our study demonstrates that the transcription factorsEtv4andEtv5are critical mediators of FGF signaling in cell lineage specification and maturation in mouse embryos. We show that loss ofEtv5compromises primitive endoderm formation at pre-implantation stages. Furthermore,Etv4/5deficiency delays naïve pluripotency exit and epiblast maturation, leading to elevated NANOG and reduced OTX2 expression within the blastocyst epiblast. As a consequence of delayed pluripotency progression,Etv4/5deficient embryos exhibit anterior visceral endoderm migration defects post-implantation, a process essential for coordinated embryonic patterning and gastrulation initiation. Our results demonstrate the successive roles of these FGF signaling effectors in early lineage specification and embryonic body plan establishment, providing new insights into the molecular control of mammalian development.

Summary statement

FGF signaling effectors ETV4/5 regulate lineage specification and embryo patterning in mice, affecting primitive endoderm formation and pluripotency exit.
Thioether-functionalized cellulose for the fabrication of oxidation-responsive biomaterial coatings and films
Authors: DuBois Eric M. , Herrema Kate E. , Simkulet Matthew G. , Hassan Laboni F. , O’Connor Payton R. , Sen Riya , O’Shea Timothy M.
Published: July 2024

Biomaterial coatings and films can prevent premature failure and enhance performance of chronically implanted medical devices. However, current hydrophilic polymer coatings and films have significant drawbacks, including swelling and delamination. To address these issues, we modified hydroxyethyl cellulose with thioether groups to generate an oxidation-responsive polymer, HECMTP. HECMTPreadily dissolves in green solvents and can be fabricated as coatings or films with tunable thicknesses. HECMTPcoatings effectively scavenge hydrogen peroxide, resulting in conversion of thioether groups to sulfoxide groups on the polymer chain. Oxidation-driven, hydrophobic-to-hydrophilic transitions that are isolated to the surface of HECMTPcoating under physiologically relevant conditions increase wettability, decrease stiffness, and reduce protein adsorption to generate a non-fouling interface with minimal coating delamination or swelling. HECMTPcan be used in diverse optical applications and permits oxidation-responsive, controlled drug release. HECMTPfilms are non-resorbablein vivoand evoke minimal foreign body responses. These results highlight the versatility of HECMTPand support its incorporation into chronically implanted medical devices.
Host-derived CEACAM-laden vesicles engage enterotoxigenicE. colifor elimination and toxin neutralization
Authors: Sheikh Alaullah , Ganguli Debayan , Vickers Tim J. , Singer Bernhard , Foulke-Abel Jennifer , Akhtar Marjahan , Khatoon Nazia , Setu Bipul , Basu Supratim , Harro Clayton , Maier Nicole , Beatty Wandy L. , Chakraborty Subhra , Bhuiyan Tafiqur R. , Qadri Firdausi , Donowitz Mark , Fleckenstein James M.
Published: July 2024

abstract

EnterotoxigenicEscherichia coli(ETEC) cause hundreds of millions of diarrheal illnesses annually ranging from mildly symptomatic cases to severe, life-threatening cholera-like diarrhea. Although ETEC are associated with long-term sequelae including malnutrition, the acute diarrheal illness is largely self-limited. Recent studies indicate that in addition to causing diarrhea, the ETEC heat-labile toxin (LT) modulates the expression of many genes in intestinal epithelia, including carcinoembryonic cell adhesion molecules (CEACAMs) which ETEC exploit as receptors, enabling toxin delivery. Here however, we demonstrate that LT also enhances the expression of CEACAMs on extracellular vesicles (EV) shed by intestinal epithelia and that CEACAM-laden EV increase in abundance during human infections, mitigate pathogen-host interactions, scavenge free ETEC toxins, and accelerate ETEC clearance from the gastrointestinal tract. Collectively, these findings indicate that CEACAMs play a multifaceted role in ETEC pathogen-host interactions, transiently favoring the pathogen, but ultimately contributing to innate responses that extinguish these common infections.

Significance statement

EnterotoxigenicE. coli,characterized by the production of heat-labile (LT) and heat-stable (ST) toxins, are a very common cause of diarrhea in low-income regions responsible for hundreds of millions of infections each year, and the major cause of diarrhea in travelers to endemic areas. Although these infections may be severe and cholera-like, they are typically self-limited. These studies demonstrate that extracellular vesicles produced by host intestinal cells can capture the bacteria and its secreted toxins at a distance from the cell surface, potentially acting as molecular decoys to neutralize the enterotoxins and extinguish the infection.
Similar won’t make it: Coexistence, habitat availability and suboptimal restoration
Authors: Urioste Felipe Maresca , Borthagaray Ana Inés , Cunillera-Montcusí David , Soutullo Álvaro , Arim Matias
Published: July 2024

In the context of the looming biodiversity crisis, adding patches of habitat has been proposed as a restoration strategy in several ecosystems. However, these interventions rarely mimic the conditions of the natural habitats precisely. Consequently, not all species equally benefit from the restored habitat, fostering a difference in species fitness that could generate an imbalance in the equalizing and stabilizing mechanisms that enable species coexistence, leading to competitive exclusion. Using a metapopulation model, we explore how the introduction of habitat patches with biased fitness advantages affects species coexistence. We show that while adding habitat patches generally increases species occupancy, suboptimal patches can favor one species, disrupting the stabilizing and equalizing mechanisms that enable coexistence, leading to competitive exclusion. This impact on the coexistence regime is particularly pronounced in species with high niche overlap and high colonization-extinction ratios. Our results highlight the double-edged sword effect of suboptimal restoration, revealing potential unintended consequences that could exacerbate biodiversity loss. On the other hand, restoration favoring endangered species is also identified as a conservation tool. The present study advances in the mechanistic comprehension of habitat restoration, a necessary endeavor in the face of the challenges posed by global change.
Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation
Authors: Chen Liqiang , Chehade Hiba Douja , Chu Hong-Yuan
Published: July 2024

Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.
“Comparative Analysis of Glycoproteomic Software Using a Tailored Glycan Database”
Authors: Hogan Reuben A. , Pepi Lauren E. , Riley Nicholas M. , Chalkley Robert J.
Published: July 2024

Glycoproteomics is a rapidly developing field, and data analysis has been stimulated by several technological innovations. As a result, there are many software tools from which to choose; and each comes with unique features that can be difficult to compare. This work presents a head-to-head comparison of five modern analytical software: Byonic, Protein Prospector, MSFraggerGlyco, pGlyco3, and GlycoDecipher. To enable a meaningful comparison, parameter variables were minimized. One potential confounding variable is the glycan database that informs glycoproteomic searches. We performed glycomic profiling of the samples and used the output to construct matched glycan databases for each software. Up to 19,000 glycopeptide spectra were identified across three replicates of wild-type SH-SY5Y cells. There was substantial overlap among most software for glycoproteins identified, locations of glycosites, and glycans, although Byonic reported a suspiciously large number of glycoproteins and glycosites of questionable reliability. We show that Protein Prospector identified the most glycopeptide spectrum matches with high agreement to known glycosites in UniProt. Overall, our results indicate that glycoproteomic searches should involve more than one software to generate confidence. It may be useful to consider software with peptide-first approaches and with glycan-first approaches.
Differential Reactivation of Task-Demand-Associated Firing Patterns in Subicular and CA1 Place Cells during a Hippocampal Memory Task
Authors: Seol Jae-Min , Lee Su-Min , Lee Inah
Published: July 2024

Reactivation of place cells during sharp-wave ripples (SWRs) in the hippocampus is pivotal for memory consolidation, yet differences in SWR dynamics between the hippocampus and its neighboring subiculum remain underexplored. We examined the differential reactivations of task-demand-associated representations during SWR events in the subiculum and CA1 during a visual scene memory task in rats. In the task, the spiking activity of place cell ensembles was reactivated during a SWR event according to task demands. These reactivations were more frequent and were associated with more heterogeneous task-demand types in the subiculum compared with the CA1. Neural manifold analysis showed that the neural states of the reactivated ensemble were more clearly clustered into distinct states during subicular SWRs according to the task-demand-associated variables. These subicular characteristics were driven by multiple subfields of the subicular place field, parcellated by the theta phase precession cycle. In contrast, CA1 exhibited a higher incidence of spatial replay than the subiculum. These findings indicate that the subiculum plays a key role in transmitting task-specific variables from the hippocampus to other brain regions.
Control of tongue movements by the Purkinje cells of the cerebellum
Authors: Hage Paul , Fakharian Mohammad Amin , Shoup Alden M. , Pi Jay S. , Sedaghat-Nejad Ehsan , Orozco Simon P. , Jang In Kyu , Looi Vivian , Elseweifi Hisham Y. , Mohammadrezaei Nazanin , Vasserman Alexander N. , Arginteanu Toren , Shadmehr Reza
Published: July 2024

We use our tongue much like our hands: to interact with objects and transport them. For example, we use our hands to sense properties of objects and transport them in the nearby space, and we use our tongue to sense properties of food morsels and transport them through the oral cavity. But what does the cerebellum contribute to control of tongue movements? Here, we trained head-fixed marmosets to make skillful tongue movements to harvest food from small tubes that were placed at sharp angles to their mouth. We identified the lingual regions of the cerebellar vermis and then measured the contribution of each Purkinje cell (P-cell) to control of the tongue by relying on the brief but complete suppression that they experienced following an input from the inferior olive. When a P-cell was suppressed during protraction, the tongue’s trajectory became hypermetric, and when the suppression took place during retraction, the tongue’s return to the mouth was slowed. Both effects were amplified when two P-cells were simultaneously suppressed. Therefore, suppression of P-cells in the lingual vermis disrupted the forces that would normally decelerate the tongue as it approached the target. Notably, the population simple spike activity peaked near deceleration onset when the movement required precision (aiming for a tube), but not when the movement was for the purpose of grooming. Thus, the P-cells appeared to signal when to stop protrusion as the tongue approached its target.
No evidence of musical training influencing the cortical contribution to the speech-FFR and its modulation through selective attention
Authors: Riegel Jasmin , Schüller Alina , Reichenbach Tobias
Published: July 2024

Musicians can have better abilities to understand speech in adverse conditions such as background noise than non-musicians. However, the neural mechanisms behind such enhanced behavioral performances remain largely unclear. Studies have found that the subcortical frequency-following response to the fundamental frequency of speech and its higher harmonics (speech-FFR) may be involved since it is larger in people with musical training than in those without. Recent research has shown that the speech-FFR consists of a cortical contribution in addition to the subcortical sources. Both the subcortical and the cortical contribution are modulated by selective attention to one of two competing speakers. However, it is unknown whether the strength of the cortical contribution to the speech-FFR, or its attention modulation, is influenced by musical training. Here we investigate these issues through magnetoencephalographic (MEG) recordings of 52 subjects (18 musicians, 25 non-musicians, and 9 neutral participants) listening to two competing male speakers while selectively attending one of them. The speech-in-noise comprehension abilities of the participants were not assessed. We find that musicians and non-musicians display comparable cortical speech-FFRs and additionally exhibit similar subject-to-subject variability in the response. Furthermore, we also do not observe a difference in the modulation of the neural response through selective attention between musicians and non-musicians. Moreover, when assessing whether the cortical speech-FFRs are influenced by particular aspects of musical training, no significant effects emerged. Taken together, we did not find any effect of musical training on the cortical speech-FFR.

Significance statement

In previous research musicians have been found to exhibit larger subcortical responses to the pitch of a speaker than non-musicians. These larger responses may reflect enhanced pitch processing due to musical training and may explain why musicians tend to understand speech better in noisy environments than people without musical training. However, higher-level cortical responses to the pitch of a voice exist as well and are influenced by attention. We show here that, unlike the subcortical responses, the cortical activities do not differ between musicians and non-musicians. The attentional effects are not influenced by musical training. Our results suggest that, unlike the subcortical response, the cortical response to pitch is not shaped by musical training.
Enhancing Statistical Power While Maintaining Small Sample Sizes in Behavioral Neuroscience Experiments Evaluating Success Rates
Authors: Desachy Theo , Thevenet Marc , Garcia Samuel , Lightning Anistasha , Didier Anne , Mandairon Nathalie , Kuczewski Nicola
Published: July 2024

Studies with low statistical power reduce the probability of detecting true effects and often lead to overestimated effect sizes, undermining the reproducibility of scientific results. While several free statistical software tools are available for calculating statistical power, they often do not account for the specialized aspects of experimental designs in behavioral studies that evaluate success rates. To address this gap, we developed “SuccessRatePower” a free and user-friendly power calculator based on Monte Carlo simulations that takes into account the particular parameters of these experimental designs. Using “SuccessRatePower”, we demonstrated that statistical power can be increased by modifying the experimental protocol in three ways: 1) reducing the probability of succeeding by chance (chance level), 2) increasing the number of trials used to calculate subject success rates, and 3) employing statistical analyses suited for discrete values. These adjustments enable even studies with small sample sizes to achieve high statistical power. Finally, we performed an associative behavioral task in mice, confirming the simulated statistical advantages of reducing chance levels and increasing the number of trials in such studies
Non-invasive Ultrasound Deep Neuromodulation of the Human Nucleus Accumbens Increases Win-Stay Behaviour
Authors: Yaakub Siti N. , Bault Nadège , Lojkiewiez Mathilde , Bellec Elouan , Roberts Jamie , Philip Noah S. , Rushworth Matthew F.S. , Fouragnan Elsa F.
Published: July 2024

Current methods for directly modulating activity in deep human brain structures are limited and invasive. Here, we demonstrate modulation of activity in human deep brain structures using non-invasive transcranial ultrasound stimulation (TUS) and show it exerts selective effects on learning and decision making. 26 healthy adults participated in a within-subject repeated TUS– functional magnetic resonance imaging (fMRI) experiment with three sonication conditions. Participants performed a probabilistic learning task while undergoing fMRI scanning after counterbalanced 80 s 5 Hz repetitive TUS of the nucleus accumbens (NAcc), dorsal anterior cingulate cortex (dACC), or Sham. TUS-NAcc altered parametric BOLD response to reward expectation in NAcc and adjacent areas. Moreover, it induced changes specific to reward-related behaviours including in the use of win–stay strategy, learning rate following rewards, learning curve for choices of the rewarding option, and rate of repetition for rewarded choices. The results demonstrate TUS’s utility for human non-invasive deep-brain neuromodulation and the causal role of the human NAcc in learning from positive outcomes.

Precisely neuromodulating deep brain regions in humans could bring transformative advancements in both cognitive neuroscience and brain disorder treatment. In a within subject experiment, twenty-six healthy adults underwent a series of transcranial ultrasound stimulation procedures, including stimulation of the nucleus accumbens, the dorsal anterior cingulate cortex, or no sonication. Results revealed that ultrasound stimulation of the nucleus accumbens (NAcc) induced changes in reward-related behaviours, including in the tendency to stick with winning choices, the rate of learning specifically from positive feedback, and the rate of repeating rewarded choices. Functional brain scans showed corresponding neural changes in response to reward expectations in targeted and interconnected brain areas. These findings demonstrate the causal role of the human NAcc in learning from positive feedback, as well as the feasibility of using non-invasive neuromodulation deep in the human brain to modulate learning and decision making both as a research tool and as a potential component of future treatments for disorders involving reward sensitivity.
Shaping the Future: the importance of land use when projecting the future distribution of Endangered Amphibians and Reptiles.
Authors: Santostasi Nina Luisa , Serafini Chiara , Maiorano Luigi
Published: July 2024

Obtaining reliable predictions of future species distributions under global change scenarios is fundamental for identifying priority conservation sites. This requires incorporating the main drivers of distribution shifts into the modeling process. Climate change and land use change are the two primary drivers of species distributions, yet they have been considered differently in studies exploring future scenarios. Most studies focus solely on bioclimatic variables, given that climate is a major determinant of species distributions on a large spatial scale. In our study, we explored the impact of including dynamic land use variables in species distribution models, examining predicted range loss and spatial mismatch of suitable areas compared to models using only bioclimatic variables. Our findings indicate that including land cover can significantly alter model outputs. While incorporating land use and land cover variables did not enhance the predictive power for most species, it substantially affected the predicted future suitable areas for 60% of the species (mean change = 69%, range: 4% to 167%). This trend was consistent across all spatial resolutions. The two modeling approaches also differed in the spatial location of suitable areas. The level of disagreement varied across species but was generally high for both current and future scenarios, increasing with coarser resolutions. Our results underscore the significant implications of excluding land use change variables and highlight the necessity of considering these factors on a taxon-specific basis.