bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of Rural and Urban Differences in Geographic Proximity to Outpatient Stroke Rehabilitation Services in Tennessee
Authors: Tran Phoebe M. , Fogelson Benjamin , Heidel Robert E. , Baljepally Raj
Published: September 2024

Purpose:

Great travel distances and long travel times can be barriers to outpatient stroke rehabilitation services (OSR) receipt, but there is limited information on differences in proximity to specific OSR services between urban and potentially medically underserved rural areas. Accordingly, we compared travel distance and time to the nearest service for different OSR services between rural and urban counties in Tennessee.

Methods:

We conducted data scraping on Google Maps to locate Tennessee facilities offering any of the 13 American Heart Association recognized OSR services. We conducted manual validation by calling located facilities and visiting facility websites. We used the Wilcoxon rank sum test to examine if mean travel distance and time to a specific OSR service differed significantly between rural and urban counties.

Results:

All OSR services but audiology were available in Tennessee. In rural counties, social work had the highest median of mean travel distance (135.2 km), chaplaincy the highest median of mean travel time (113.5 min), and physical therapy the lowest distance (37.7 km) and time (36.3 min). Except for social work, rural counties had significantly higher travel distance and time than urban counties (P < .01) for all OSR services.

Conclusions:

Rural Tennessee counties had significantly higher travel distance and time for almost all OSR services compared to urban areas. These findings from a largely rural state with high stroke risk factor prevalence suggest that additional focus on establishing maximum travel limits for OSR are warranted to overcome transportation barriers to enhance post-stroke services access in similar areas.
Exploring Demographic and Cognitive Predictors of Self-Management in Quasi-Randomized Fall Prevention Intervention for Older Adults With and Without Traumatic Brain Injury
Authors: Kemp Amy M. , Love Kim , O’Brien Katy H.
Published: September 2024

Objective: Changes in health behavior are key to maintaining health, safety, and independence of older adults. The purpose of this study was to explore factors impacting training in self-management and behavior change in older adults with and without traumatic brain injury (TBI), informing efforts to improve safety and independent function. Methods: Forty-one older adults, 19 with TBI, completed a self-regulation intervention (mental contrasting with implementation intentions; MCII) to promote fall prevention behavior change. Participant outcomes were related to single and recurring behavior changes; implementation outcomes were measured as modifications to treatment. Results: Although participants with TBI performed more poorly on tests of neurocognitive function, there were no differences in behavior change rates following MCII, suggesting the treatment worked similarly for participants with and without TBI. Across both groups, those with higher executive function scores were more likely to complete recurring behavior changes. Participants with higher stress, higher Fall Risk Scores, or history of TBI were more likely to need modifications to treatment. Conclusions: This quasi-experimental pilot study describes cognitive and psychosocial predictors that may be critical for participation and success in health behavior change and self-management of fall prevention for older adults with and without TBI.
Role and Outcomes of Supported Community Living Programs in Post-Hospital Brain Injury Rehabilitation Programs
Authors: Logan Daniel M. , Parrott Devan , Altman Irwin M. , Eicher Vicki , McGrath Claire , Salisbury David B. , Walters G. Joseph , Malec James F.
Published: September 2024

Objectives:

(1) To determine the proportion of participants admitted to supported community living (SCL) programs over the course of 5 years who improve, decline, or maintain functioning and community integration and (2) to examine the associations of time since injury, time in program, and age to their functional trajectory.

Setting:

Data from SCL programs serving individuals with acquired brain injury (ABI).

Participants:

104 individuals with traumatic brain injury (TBI), stroke, or other ABI.

Main Measures:

Sex, age, time since injury, Mayo-Portland Adaptability Inventory (4th edition; MPAI-4).

Design:

Retrospective analyses of MPAI-4 total and MPAI-4 indices using Linear Mixed Models (LMM) of Rasch-derived T-scores from admission to 5 years into service delivery.

Results:

MPAI-4 total, index, and subscale scores for yearly intervals of SCL services from admission to 5 years showed a high degree of stability in function (defined using the standard error of measurement (SEM) for the MPAI-4, defined as change ≥3 T-score points) with all intervals showing at least 89% of patients with improved scores or no change. The rate of change over time did not significantly vary by time since injury, time in the program, or age.

Conclusions:

The expectations for services in the SCL portion of the care continuum for ABI are unique. Unlike intensive rehabilitation programs which focus on improvement often earlier in the course of recovery, the goal of SCL services is sustained functioning over the long term. Analyses reported here indicate this can be achieved for at least 5 years, potentially mitigating the increased risk for rehospitalization and increased care needs in the ABI population. This study highlights a key finding of MPAI-4 stability within these understudied brain injury service lines. Additional exploration of comorbidities and more nuanced delineation of diagnostic information could further clarify factors influencing outcome stability over time.
Global analysis of vasoactive agents in septic shock management: Exploring trends and bridging knowledge gaps
Authors: Sharifan Amin
Published: September 2024

Background:

The swift administration of vasoactive agents is essential for effectively managing septic shock. However, the unavailability of norepinephrine—the primary recommended agent—in certain clinical settings necessitates the exploration of alternative solutions. This study aimed to identify both the key focus areas and the under-researched aspects related to this topic.

Methods:

The Scopus database was searched from inception until August 2, 2024, using a comprehensive list of keywords related to the topics of “septic shock”, “vasopressors”, and “hypotension”. Articles lacking original data, namely narrative reviews, errata, corrections, and conference papers, were excluded from the analysis. No language restrictions were applied. The retrieved search results were examined for publication and citation trends, international contributions by countries and institutions, keyword usage, and funding sources. Data visualization was accomplished using VOSviewer, the built-in Scopus analyzer, the bibliometrix R package, and Microsoft Excel.

Results:

A total of 7474 publications were retrieved. These studies were published between 1958 and 2024, with the year 2022 representing the highest number of publications, and 2016 having the most citations. While publications had raised until 2022 and dwindled since then, citations had fluctuating patterns throughout the years. The research landscape was marked by contributions from 207 countries, with 160 institutions publishing at least 22 studies each. The United States emerged as the leader in both publications and international collaborations in this field, followed by France, the United Kingdom, China, and Germany. Notably, all of the top 20 countries in terms of publication volume were classified as high-income or upper-middle-income nations, except India. This disparity can largely be explained by the differences in funding allocated to studies in these countries. Furthermore, 28,442 keywords relevant to this topic were collected. The demographic representation in the studies showed a predominance of males and older adults compared to their counterparts and a significant proportion of the studies were clinical investigations. Among the various vasopressors examined, terlipressin, angiotensin II, methylene blue, and selepressin were identified as the least studied agents.

Conclusion:

Consensus definitions and statements in critical care, particularly for controversial topics, are essential for enhancing communication and improving patient care. There is a need for prioritized research and funding in the Global South regarding enhanced septic shock management. Further studies on vasoconstrictor agents with limited evidence are warranted to strengthen the body of knowledge in this area.
The role of new inflammatory indices in the prediction of endoscopic and histological activity in inflammatory bowel disease patients
Authors: Cesaro Nicola , Valvano Marco , Monaco Sabrina , Stefanelli Gianpiero , Fabiani Stefano , Vernia Filippo , Necozione Stefano , Viscido Angelo , Latella Giovanni
Published: September 2024

Background and aim

Inflammatory indices are promising indicators that can be used to evaluate inflammation in inflammatory bowel diseases (IBDs). The present study aimed to investigate the test accuracy of several inflammatory indices to identify endoscopic, and histological activity in a cohort of IBD patients.

Study:

All IBD patients who underwent colonoscopy and blood examination (within 4 weeks and without therapeutic change) were included. For these patients, 10 different inflammatory biomarkers were collected. Our primary outcome was the assessment of accuracy [evaluated with a receiver operating characteristics (ROC) analysis] of each inflammatory biomarker and indices. Furthermore, we tried to establish the optimal cutoff to identify patients with endoscopic and histologic activity among the inflammatory biomarkers and indices with higher performance.

Results

Regarding endoscopic activity, at the ROC analysis, the systemic inflammation response index (SIRI) showed the best accuracy [area under the curve (AUC), 0.627; confidence interval (CI), 0.552–0.698]. Whereas the ROC analysis showed a suboptimal AUC for the neutrophil-to-lymphocytes ratio (NLR) and platelets-to-lymphocytes ratio; (AUC, 0.620; CI, 0.545–0.691 and AUC, 0.607; CI, 0.532–0.679, respectively). Concerning histological activity, the C-reactive protein albumin ratio (CAR) presented a higher accuracy among the calculated inflammatory biomarkers (AUC, 0.682; CI, 0.569–0.781) while SIRI and NLR presented a subdued diagnostic performance.

Conclusion

SIRI and CAR presented the best test accuracy in an IBD outpatient setting to identify endoscopic and histological activity. However, the test accuracy of all the evaluated Inflammatory indices appeared suboptimal. Fecal calprotectin has still the highest accuracy in predicting endoscopic and histological activity in patients with IBD.
Clinical and biochemical factors for bacteria in bile among patients with acute cholangitis
Authors: Zhao Jin , Wang Bin , Zhao Meidan , Pan Xinling
Published: September 2024

Background

Acute cholangitis is a clinical syndrome caused by a bacterial infection in the biliary system. The bacteria could exist in the bile before bile drainage despite empirical antibiotic treatment.

Methods

Patients with acute cholangitis admitted to a tertiary hospital in Southeastern China from August 2011 to September 2021 were involved when bile cultures were performed. Patient information before bile cultures and during hospitalization was extracted from the clinical record database. The risk factors related to bacteria in bile were assessed by univariable and multivairable logistic regression analysis, respectively.

Results

A total of 533 patients (66.05%) had bacterial growth in bile. Alanine aminotransferase concentration [odds ratio (OR) = 0.998, P < 0.001], absolute monocyte count (OR = 0.335, P = 0.001), and duration of antibiotic use (OR = 0.933, P = 0.026) were negatively correlated with bacteria in bile. In contrast, C-reactive protein (OR = 1.006, P = 0.003), thrombin time (OR = 1.213, P = 0.033), prothrombin time (OR = 1.210, P = 0.011), and age (OR = 1.025, P < 0.001) were positively correlated with bacteria in bile. Based on an area under the receiver operating characteristic curve of 0.737 (95% CI, 0.697–0.776, P < 0.001), combining these seven variables could efficiently predict the presence of bacteria in bile among patients with acute cholangitis.

Conclusion

The combination of clinical indicators before bile drainage could predict the risk of bacteria in bile for patients with acute cholangitis.
How Super Is Supertrack? Expediting Care of Fast-track Patients through a Pediatric Emergency Department
Authors: Lam Daniel , Braund Cortney , Schmidt Sarah , Johnson Bernadette , Spencer Sandra P. , Agbim Chisom
Published: September 2024

Background:

Fast-track models decrease patient crowding in emergency departments (EDs) by redirecting low-acuity patients to an expedited care pathway. In 2016, this institution’s pediatric ED created a fast-track pathway for patients evaluated in a rapid assessment triage area who needed further management in the primary ED. This “Supertrack” designation was intended for patients requiring up to 1 hour of additional care, though means of ensuring these patients were discharged within their anticipated timeframe were lacking.

Methods:

We aimed to increase the percentage of Supertrack patients discharged within 1 hour of their ED bed assignment from 17% to 50%. Interventions included the creation of objective Supertrack criteria, departmental-wide progress reports, personalized reminders, intake huddles, and documentation prompts. We visualized data from Plan, Do, Study, Act (PDSA) cycles with statistical process control charts to determine special cause variation.

Results:

The percentage of Supertrack patients discharged within their anticipated timeframe increased from 17% to 27% without an increase in return ED visits. The average time Supertrack patients spent in the ED decreased from 121 to 103 minutes. Personalized reminders demonstrated a significant but short-lived improvement.

Conclusions:

We improved the flow of Supertrack patients by decreasing their length of stay and increasing how many were discharged within their anticipated timeframe. Limitations included an unexpected surge in patients with respiratory complaints and staffing and structural constraints preventing the designation of a discrete Supertrack assessment space with dedicated providers. These findings are helpful for institutions seeking to develop an effective fast-track model with limited space and resources.
Brief Report: Preexposure Prophylaxis Use Among U.S. Veterans Using Veterans Health Administration Services, 2014─2022
Authors: Huang Ya-Lin A. , Lowy Elliott , Zhu Weiming , Yu Lei , Wei Wei , Maier Marissa M. , Hoover Karen W. , Beste Lauren A.
Published: September 2024

Objectives:

It is important to monitor national HIV preexposure prophylaxis (PrEP) use in the United States. However, PrEP use data in the Veterans Health Administration (VHA) system are not included in the current monitoring surveillance. To address this gap, we examined the trends in PrEP use among U.S. Veterans receiving health services in the VHA system.

Methods:

We analyzed 2014–2022 VHA data to identify the annual number and prevalence of persons aged ≥18 years prescribed PrEP, stratified by sex, age, race/ethnicity, and region. We also assessed trends by calculating the estimated annual percent change and 95% confidence intervals using Poisson models.

Results:

The number of Veterans prescribed PrEP increased from 361 in 2014 to 6050 in 2022 with an estimated annual percent change of 29.6% (95% CI: 22.6 to 37.1). Of 6050 Veterans with PrEP prescriptions in 2022, 95.2% were men, 4.8% were women, 50.4% were White, 24.5% Black or African American (Black), and 14.0% Hispanic or Latino. The prevalence of Black and Hispanic or Latino individuals prescribed PrEP increased significantly from 2014 to 2022.

Conclusions:

VHA data fill a gap in monitoring PrEP use in the United States. We observed an increasing trend in the number of Veterans prescribed PrEP similar to trends among persons with commercial or public health insurance.
FDG PET/CT Findings of Rapidly Progressive Interstitial Lung Disease in a Patient With Anti-MDA5 Dermatomyositis
Authors: Zhang Jun , Dong Aisheng
Published: September 2024

Anti-MDA5 dermatomyositis is associated with an increased risk of developing rapidly progressive interstitial lung disease with a high mortality. We describe FDG PET/CT findings in a case of rapidly progressive noninfectious interstitial lung disease associated with anti-MDA5 dermatomyositis. The lung disease showed bilateral diffuse ground-glass opacities with diffuse heterogeneous FDG activity predominantly in middle and lower zones, mimicking infectious pneumonia. Familiarity with the imaging features of this rapidly progressive noninfectious interstitial lung disease can help to suggest the diagnosis and guide appropriate management.
Comparative study of the catalytic performance of physically mixed and sequentially utilized γ-alumina and zeolite in methanol-to-propylene reactions
Authors: Mortazavi-Manesh Anahita , Safari Nasser , Golbodaqi Mojtaba , Latifi Shirin , Fatehi Haghighat Mohammad , Bahadoran Farzad
Published: September 2024

This study aimed to investigate the catalytic performance of H-ZSM-5 zeolite compared with physically mixed and sequentially used synthesized γ-alumina and zeolite in the methanol-to-propylene (MTP) reaction. A facile, green and cost-effective method was first applied to prepare a mesoporous γ-Al
2
O
3
support using a combination of sol–gel and hydrothermal methods via a few consecutive steps. This process was carried out using aluminium nitrate and polyethylene glycol with different molecular weights as non-ionic surfactants. X-ray diffraction, transmission electon microscopy, thermogravimetric analysis, ammonia temperature programmed desorption and Brunauer–Emmett–Teller analysis were then used to characterize the prepared γ-Al
2
O
3
catalyst. Afterwards, the catalytic activity of the commercial H-ZSM-5 zeolite (Si/Al = 200) and the effect of the presence of the γ-alumina physically mixed and unmixed with the zeolite were also researched in the MTP reaction. Accordingly, methanol conversion and product selectivity were monitored via gas chromatography. The physically mixed mesoporous γ-Al
2
O
3
and H-ZSM-5 zeolite exhibited the highest catalytic activity in terms of both conversion and selectivity at 400°C. To our knowledge, this research represents the first documented use of γ-alumina and zeolite simultaneously as catalysts in the MTP reaction within the English literature. It is hoped that this work will offer valuable insights for advancing the development of catalytic systems in methanol conversion processes.
SARS-CoV-2 infection and transmission via the skin to oro-nasal route with the production of bioaerosols in the ferret model
Authors: Shipley Rebecca , Seekings Amanda H. , Byrne Alexander M.P. , Shukla Shweta , James Joe , Goharriz Hooman , Lean Fabian Z.X. , Núñez Alejandro , Fooks Anthony R. , McElhinney Lorraine M. , Brookes Sharon M.
Published: September 2024

Direct and indirect transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been attributed to virus survival in droplets, bioaerosols and on fomites including skin and surfaces. Survival of SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, and Delta) on the skin and virus transference following rounds of skin-to-skin contact were assessed on porcine skin as a surrogate for human skin. SARS-CoV-2 variants were detectable on skin by RT-qPCR after 72 h at biologically relevant temperatures (35.2 °C) with viral RNA (vRNA) detected after ten successive skin-to-skin contacts. Skin-to-skin virus transmission to establish infection in ferrets as a model for mild/asymptomatic SARS-CoV-2 infection in mustelids and humans was also investigated and compared to intranasal ferret inoculation. Naïve ferrets exposed to Delta variant SARS-CoV-2 in a ‘wet’ or ‘dry’ form on porcine skin resulted in robust infection with shedding detectable for up to 14 days post-exposure, at comparable viral loads to ferrets inoculated intranasally. Transmission of SARS-CoV-2 to naïve ferrets in direct contact with infected ferrets was achieved, with environmental contamination detected from ferret fur swabs and air samples. Genetic substitutions were identified in bioaerosol samples acquired following single contact passage in ferrets, including Spike, ORF1ab, and ORF3a protein sequences, suggesting a utility for monitoring host adaptation and virus evolution via air sampling. The longevity of SARS-CoV-2 variants survival directly on the skin and skin-to-skin transference, enabling subsequent infection via the skin to oro-nasal contact route, could represent a pathway for SARS-CoV-2 infection with implications to public and veterinary health.
Effects of periodic bottlenecks on the dynamics of adaptive evolution in microbial populations
Authors: Izutsu Minako , Lake Devin M. , Matson Zachary W. D. , Dodson Jack P. , Lenski Richard E.
Published: September 2024

Population bottlenecks can impact the rate of adaptation in evolving populations. On the one hand, each bottleneck reduces the genetic variation that fuels adaptation. On the other hand, each founder that survives a bottleneck can undergo more generations and leave more descendants in a resource-limited environment, which allows surviving beneficial mutations to spread more quickly. A theoretical model predicted that the rate of fitness gains should be maximized using ~8-fold dilutions. Here we investigate the impact of repeated bottlenecks on the dynamics of adaptation using numerical simulations and experimental populations of Escherichia coli. Our simulations confirm the model’s prediction when populations evolve in a regime where beneficial mutations are rare and waiting times between successful mutations are long. However, more extreme dilutions maximize fitness gains in simulations when beneficial mutations are common and clonal interference prevents most of them from fixing. To examine these predictions, we propagated 48 E. coli populations with 2-, 8-, 100-, and 1000-fold dilutions for 150 days. Adaptation began earlier and fitness gains were greater with 100- and 1000-fold dilutions than with 8-fold dilutions, consistent with the simulations when beneficial mutations are common. However, the selection pressures in the 2-fold treatment were qualitatively different from the other treatments, violating a critical assumption of the model and simulations. Thus, varying the dilution factor during periodic bottlenecks can have multiple effects on the dynamics of adaptation caused by differential losses of diversity, different numbers of generations, and altered selection.
Capturing sclera anisotropy using direct collagen fiber models. Linking microstructure to macroscopic mechanical properties
Authors: Ji Fengting , Islam Mohammad R. , Sebastian Frederick , He Xuehuan , Schilpp Hannah , Wang Bingrui , Hua Yi , Amini Rouzbeh , Sigal Ian A.
Published: September 2024

Because of the crucial role of collagen fibers on soft tissue mechanics, there is great interest in techniques to incorporate them in computational models. Recently we introduced a direct fiber modeling approach for sclera based on representing the long-interwoven fibers. Our method differs from the conventional continuum approach to modeling sclera that homogenizes the fibers and describes them as statistical distributions for each element. At large scale our method captured gross collagen fiber bundle architecture from histology and experimental intraocular pressure-induced deformations. At small scale, a direct fiber model of a sclera sample reproduced equi-biaxial experimental behavior from the literature. In this study our goal was a much more challenging task for the direct fiber modeling: to capture specimen-specific 3D fiber architecture and anisotropic mechanics of four sclera samples tested under equibiaxial and four non-equibiaxial loadings. Samples of sclera from three eyes were isolated and tested in five biaxial loadings following an approach previously reported. Using microstructural architecture from polarized light microscopy we then created specimen-specific direct fiber models. Model fiber orientations agreed well with the histological information (adjusted R2’s>0.89). Through an inverse-fitting process we determined model characteristics, including specimen-specific fiber mechanical properties to match equibiaxial loading. Interestingly, the equibiaxial properties also reproduced all the non-equibiaxial behaviors. These results indicate that the direct fiber modeling method naturally accounted for tissue anisotropy within its fiber structure. Direct fiber modeling is therefore a promising approach to understand how macroscopic behavior arises from microstructure.
An Iterative Approach to Polish the Nanopore Sequencing Basecalling for Therapeutic RNA Quality Control
Authors: Wang Ziyuan , Tu Mei-Juan , Liu Ziyang , Wang Katherine K. , Fang Yinshan , Hao Ning , Zhang Hao Helen , Que Jianwen , Sun Xiaoxiao , Yu Ai-Ming , Ding Hongxu
Published: September 2024

Nucleotide modifications deviate nanopore sequencing readouts, therefore generating artifacts during the basecalling of sequence backbones. Here, we present an iterative approach to polish modification-disturbed basecalling results. We show such an approach is able to promote the basecalling accuracy of both artificially-synthesized and real-world molecules. With demonstrated efficacy and reliability, we exploit the approach to precisely basecall therapeutic RNAs consisting of artificial or natural modifications, as the basis for quantifying the purity and integrity of vaccine mRNAs which are transcribedin vitro, and for determining modification hotspots of novel therapeutic RNA interference (RNAi) molecules which are bioengineered (BioRNA)in vivo.
FunCoup 6: advancing functional association networks across species with directed links and improved user experience
Authors: Buzzao Davide , Persson Emma , Guala Dimitri , Sonnhammer Erik L.L.
Published: September 2024

FunCoup 6 (https://funcoup6.scilifelab.se/, will behttps://funcoup.orgafter publication) represents a significant advancement in global functional association networks, aiming to provide researchers with a comprehensive view of the functional coupling interactome. This update introduces novel methodologies and integrated tools for improved network inference and analysis. Major new developments in FunCoup 6 include vastly expanding the coverage of gene regulatory links, a new framework for bin-free Bayesian training, and a new website. FunCoup 6 integrates a new tool for disease and drug target module identification using the TOPAS algorithm. To expand the utility of the resource for biomedical research, it incorporates pathway enrichment analysis using the ANUBIX and EASE algorithms. The unique comparative interactomics analysis in FunCoup provides insights of network conservation, now allowing users to align orthologs only or query each species network independently. Bin-free training was applied to 23 primary species, and in addition networks were generated for all remaining 618 species in InParanoiDB 9. Accompanying these advancements, FunCoup 6 features a new redesigned website, together with updated API functionalities, and represents a pivotal step forward in functional genomics research, offering unique capabilities for exploring the complex landscape of protein interactions.

GRAPHICAL ABSTRACT
Stigma longevity is not a major limiting factor in hybrid wheat seed production
Authors: Millan-Blanquez Marina , Simmonds James , Bird Nicholas , Manes Yann , Uauy Cristobal , Boden Scott A.
Published: September 2024

Hybrids offer a promising approach to improve crop performance because the progeny are often superior to their parent lines and they outyield inbred varieties. A major challenge in producing hybrid progeny in wheat, however, lies in the low outcrossing rates of the maternal parent. This is often attributed to suboptimal synchronisation of male and female flowering as delayed pollination can result in reproductive failure due to female stigma deterioration. To test this accepted dogma, we examined the seed set capacity of six male sterile (MS) cultivars, each varying in the onset of stigma deterioration. To mimic a hybrid seed production scenario, MS cultivars were grown during two consecutive field seasons, and open pollination was allowed up to 15 days after flowering of the female parent using a blend of seven male fertile cultivars with varying flowering times. Detailed analysis of the temporal and spatial distribution of hybrid seed set along the spike across the six MS cultivars showed that grain production remained remarkably stable during the pollination window tested. These findings suggest sustained receptivity of stigma to pollen across all tested MS cultivars throughout the entire time course. We therefore conclude that stigma longevity does not represent a limiting factor in hybrid wheat seed production, and that breeding efforts should prioritise the study of other female traits, such as enhanced access to airborne pollen.
How environment and genetic architecture of unreduced gametes shape the establishment of autopolyploids
Authors: Cheng Yu , Kolář Filip , Schmickl Roswitha , Clo Josselin
Published: September 2024

It is broadly assumed that polyploidy success is due to an increase in fitness associated with whole genome duplication due to higher tolerance to stressful conditions. In agreement, several theoretical models found that, among other factors, a better tolerance to new environmental conditions can promote polyploidy establishment. These models, however, often made strong hypotheses, for example considering that diploids cannot adapt to new conditions, or that unreduced gametes production is not a limiting factor and that it is of a fixed quantity. In this paper, we challenged some of these hypotheses. We developed a theoretical model in which we modeled the joint evolution of a quantitative trait under selection and the production of unreduced gametes, this trait also being a quantitative trait; both traits were pleiotropically linked. We followed the adaptation of initially diploid populations to a new environment to which neo-tetraploid individuals were directly adapted. The generation of these autotetraploid individuals was enabled by the genetic production of unreduced gametes and by the environmental change modifying the average production of these gametes. We found that for realistic values of unreduced gametes production, adaptation to new environmental conditions was mainly achieved through adaptation of diploids to the new optimum rather than the fixation of newly adapted tetraploid individuals. In broader parameter sets, we found that the adaptation process led to mixed-ploidy populations, except when the populations were swamped with unreduced gametes, and that pleiotropy and environmental effects favored the co-existence of both cytotypes.
Sex-Specific Complement and Cytokine Imbalances in Drug-Resistant Epilepsy: Biomarkers of Immune Vulnerability
Authors: Pinzon-Hoyos Nicole , Li Yibo , McGee Monnie , Poolos Nicholas P. , Marchi Nicola , Brewster Amy L.
Published: September 2024

Objective

Drug-resistant epilepsy (DRE) poses significant challenges in treatment and management. While seizure-related alterations in peripheral immune players are increasingly recognized, the involvement of the complement system, central to immune function, remains insufficiently explored in DRE. This study aimed to investigate the levels of complement system components and their association with cytokine profiles in patients with DRE.

Methods

We analyzed serum samples from DRE patients (n = 46) and age- and sex-matched healthy controls (n = 45). Complement components and cytokines were quantified using Multi- and Single-plex ELISA. Statistical analyses examined relationships between complement molecules, cytokines, and clinical outcomes including epilepsy duration, Full-Scale Intelligence Quotient (FSIQ) scores, and age.

Results

We found common alterations in all DRE cases, including significant complement deficiencies (C1q, Factor H, C4, C4b, C3, and C3b/iC3b) and detectable bFGF levels. DRE females showed significantly lower levels of TNFα and IL-8 compared to healthy females. We observed a trend towards elevated CCL2 and CCL5 levels in DRE males compared to healthy males. These findings suggest potential sex dimorphism in immune profiles. Our analysis also indicated associations between specific complement and inflammatory markers (C2, IL-8, and IL-9) and Full-Scale Intelligence Quotient (FSIQ) scores in DRE patients.

Interpretation

Our study reveals sex-specific peripheral complement deficiencies and cytokine dysregulation in DRE patients, indicating an underlying immune system vulnerability. These findings provide new insights into DRE mechanisms, potentially guiding future research on complement and cytokine signaling toward personalized treatments for DRE patients.
Affinity tag free purification of SARS-Cov-2 N protein and its crystal structure in complex with ssDNA
Authors: Maiti Atanu , Matsuo Hiroshi
Published: September 2024

The nucleocapsid (N) protein is one of the four structural proteins in SARS-CoV-2, playing key roles in viral assembly, immune evasion, and stability. One of its primary functions is to protect viral RNA by forming the nucleocapsid. However, the precise mechanisms of how the N protein interacts with viral RNA and assembles into a nucleocapsid remain unclear. Compared to other SARS-CoV-2 components, the N protein has several advantages: higher sequence conservation, lower mutation rates, and stronger immunogenicity, making it an attractive target for antiviral drug development and diagnostics. Therefore, a detailed understanding of the N protein’s structure is essential for deciphering its role in viral assembly and for developing effective therapeutics. In this study, we report the expression and purification of a soluble recombinant N protein, along with a 1.55Å resolution crystal structure of its nucleic acid-binding domain (N-NTD) in complex with ssDNA. Our structure reveals new insights into the conformation and interaction of the flexible N-arm, which could aid in understanding nucleocapsid assembly. Additionally, we identify residues that are critical for ssDNA interaction.
Brain-wide microstrokes affect the stability of memory circuits in the hippocampus
Authors: Heiser Hendrik , Kiessler Filippo , Roggenbach Adrian , Ibanez Victor , Wieckhorst Martin , Helmchen Fritjof , Gjorgjieva Julijana , Wahl Anna-Sophia
Published: September 2024

Cognitive deficits affect over 70% of stroke survivors, yet the mechanisms by which multiple small ischemic events contribute to cognitive decline remain poorly understood. In this study, we employed chronic two-photon calcium imaging to longitudinally track the fate of individual neurons in the hippocampus of mice navigating a virtual reality environment, both before and after inducing brain-wide microstrokes. Our findings reveal that, under normal conditions, hippocampal neurons exhibit varying degrees of stability in their spatial memory coding. However, microstrokes disrupted this functional network architecture, leading to cognitive impairments. Notably, the preservation of stable coding place cells, along with the stability, precision, and persistence of the hippocampal network, was strongly predictive of cognitive outcomes. Mice with more synchronously active place cells near important locations demonstrated recovery from cognitive impairment. This study uncovers critical cellular responses and network alterations following brain injury, providing a foundation for novel therapeutic strategies preventing cognitive decline.
Amygdala stimulation transforms short-term memory into remote memory by persistent activation of atypical PKC in the anterior cingulate cortex
Authors: Almaguer-Melian William , Mercerón-Martínez Daymara , Alacán-Ricardo Laura , Pina Arturo Bejerano , Hsieh Changchi , Bergado-Rosado Jorge A. , Sacktor Todd Charlton
Published: September 2024

Although many studies have addressed the role of the amygdala in modulating long-term memory, it is not known whether weak training plus amygdala stimulation can transform a short-term memory into a remote memory. Object place recognition (OPR) memory after strong training remains hippocampus-dependent through the persistent action of PKMζ for at least 6 days, but it is unknown whether weak training plus amygdala stimulation can transform short-term memory into an even longer memory, and whether such memory is stored through more persistent action of PKMζ in hippocampus. We trained rats to acquire OPR and 15 min or 5 h later induced a brief pattern of electrical stimulation in basolateral amygdala (BLA). Our results reveal that a short-term memory lasting < 4 h can be converted into remote memory lasting at least 3 weeks if the BLA is activated 15 min, but not 5 h after learning. To examine how this remote memory is maintained, we injected ZIP, an inhibitor of atypical PKCs (aPKCs), PKMζ and PKCι/λ, into either hippocampal CA1, dentate gyrus (DG), or anterior cingulate cortex (ACC). Our data reveal amygdala stimulation produces consolidation into remote memory, not by persistent aPKC activation and capture by synaptic tagging processes in the hippocampal formation, but in ACC. Our data establish a powerful modulating role of the BLA in forming remote memory and open a path in the search for neurological restoration of memory, based on enhancing synaptic plasticity in aging or neurodegenerative disorders such as Alzheimer’s disease.
Endothelial regulatory circuits control cranial neural crest migration and plasticity
Authors: Hu Zhiyuan , Mayes Sarah , Wang Weixu , Santos-Pereira José M. , Theis Fabian , Sauka-Spengler Tatjana
Published: September 2024

The cranial neural crest (NC) is a migratory embryonic population ideal for studying cell plasticity, motility, and fate establishment. Although NC migration has been linked to changes in cell adhesion, polarity, and signaling, the gene regulatory circuitry governing these processes remained obscure. Using time-resolved single-cell multi-omics, spatial transcriptomics, and gene regulatory network reconstruction, we identified ten programs underlying 23 NC cell states and three spatial trajectories. Using in silico perturbation and systematic CRISPR/Cas9-mediated Perturb-seq, we uncovered novel lineage drivers and an endothelial-like program controlling NC migration, distinct from the epithelial-to-mesenchymal transition (EMT) program. We show that endothelial-like regulons (fli1a, elk3) drive migration through direct or tiered activation via the “FOX:ETS-Ebf3a-targets” axis, while ETS suppressors (erf,erfl3) maintain cell plasticity. Using the newly developed SyncReg tool, we identify functional redundancy among ETS regulons, which has thus far obscured their critical roles in NC migration, and we quantify their synergy with retinoic acid receptors, also essential for this process. Our GRN model, combined with novel velocity-embedded simulations, accurately predicted the functions of all major regulons, which were confirmed by in vivo functional perturbations. This study provides a comprehensive, validated cranial NC regulatory landscape, resolving heterogeneous regulatory circuits underlying NC cell motility and plasticity.
Disruption of hippocampal-prefrontal neural dynamics and risky decision-making in a mouse model of Alzheimer’s disease
Authors: Kim Eun Joo , Park Sanggeon , Schuessler Bryan P. , Boo Harry , Cho Jeiwon , Kim Jeansok J.
Published: September 2024

This study investigates how amyloid pathology influences hippocampal-prefrontal neural dynamics and decision-making in Alzheimer’s disease (AD) using 5XFAD mice, a well-established model system characterized by pronounced early amyloid pathology. Utilizing ecologically-relevant “approach food-avoid predator” foraging tasks, we observed that 5XFAD mice exhibited persistent risk-taking behaviors and reduced adaptability to changing threat conditions, indicative of impaired decision-making. Multi-regional neural recordings revealed rigid hippocampal CA1 place-cell fields, decreased sharp-wave ripple (SWR) frequencies, and disrupted medial prefrontal-hippocampal connectivity, all of which corresponded with deficits in behavioral flexibility during spatial risk scenarios. These findings highlight the critical role of SWR dynamics and corticolimbic circuit integrity in adaptive decision-making, with implications for understanding cognitive decline in AD in naturalistic contexts. By identifying specific neural disruptions underlying risky decision-making deficits, this work provides insights into the neural basis of cognitive dysfunction in AD and suggests potential targets for therapeutic intervention.
Functional consequences of fast-spiking interneurons in striatum
Authors: Kumar Arvind , Guo Lihao
Published: September 2024

The striatum features a distinct network characterized by a high degree of shared feedforward inhibition (FFI) from a mere 1% of fast-spiking interneurons (FSI). We investigate the potential roles of this extensively shared FFI in striatal function beyond inducing synchrony. Our findings reveal that FSIs increase the acrosstrial variability of striatal responses to cortical stimuli and, combined with recurrent inhibition, lead to a ‘correlation attractor’ of striatal activities, i.e., weakly correlated inputs result in more correlated responses and vice versa. Thus, we uncover a mechanism by which input correlation can be bidirectionally modulated, which is possible only because of high sharing of FSI inputs. We posit that the emergence of a correlation attractor leads to non-zero correlation level and variable rate trajectories of striatal responses across trials, hence beneficial for exploration in learning. However, given their role in across-trial variability, we argue that FSIs should be ‘disengaged’ from the MSNs during performance where stability across trials is required.

Significance Statement

Striatum is a network of inhibitory neurons. Fast spiking interneurons constitute about 1% of the striatal neural population and provide feedforward inhibition (FSI). Here, we unravel two novel ways in which FSIs may shape striatal function. Given the recurrent inhibition, it is assumed that striatum can only de-correlate inputs. We show that high sharing of FSI also renders the striatum an ability to correlate inputs. Thus, recurrent and shared FSI create a ‘correlation attractor’. Besides, we show that shared FSIs give rise to high across-trial variability. Therefore, we argue that FSIs are more crucial in learning as they provide the neural basis of exploration, but they may impair learned behavior due to high across-trial variability.
Targeting FUS-ALS aggregation with Proteasome Inhibitors
Authors: Younis Amal , Yassen Kanar , Rozales Kinneret , Kadah Tahani , Saida Naseeb , Meller Anatoly , Hazra Joyeeta Dutta , Heinrich Ronit , Levy-Adam Flonia , Berlin Shai , Shalgi Reut
Published: September 2024

ALS, Amyotrophic lateral sclerosis, a devastating neurodegenerative disease (ND) with no cure, is often caused by abnormal cytosolic aggregation of RNA-binding proteins, the most well-known of which are TDP-43 and FUS. The proteasome is considered one of the major systems that degrades misfolded, including ND-associated, proteins, thereby acting to reduce aggregation, while inhibition of the proteasome increases aggregation. Unexpectedly, we found that proteasome inhibitor treatment significantly reduced ALS-associated mutant FUS aggregation in cells and in primary neurons. This is in sharp contrast to most other ND-associated aggregating proteins, including Huntingtin and TDP-43, for which proteasome inhibitors enhanced aggregation. We further found that this inhibitory effect is dependent on the transcription factor HSF1, suggesting that the underlying mechanism of this effect is transcriptionally-mediated. Since heat shock treatment did not show any effect on FUS aggregation, we hypothesized that proteasome inhibitors elicit a transcriptional program distinct of that of heat shock, which is protective of FUS aggregation. We identified BAG3, a co-chaperone that cooperates with HSP70 in reducing FUS aggregation, as a significant mediator of this effect. We therefore propose BBB-permeable proteasome inhibitors as a potential therapy specific to ALS-FUS.
A neural model for V1 that incorporates dendritic nonlinearities and back-propagating action potentials
Authors: Rentzeperis Ilias , Prandi Dario , Bertalmío Marcelo
Published: September 2024

The groundbreaking work of Hubel and Wiesel has been instrumental in shaping our understanding of V1, leading to modeling neural responses as cascades of linear and nonlinear processes in what has come to be known as the “standard model” of vision. Under this formulation, however, some dendritic properties cannot be represented in a practical manner, while extensive evidence indicates that dendritic processes are an indispensable element of key neural behaviours. As a result, current V1 models fail to explain neural responses in a number of scenarios. In this work, we propose an implicit model for V1 that considers nonlinear dendritic integration and backpropagation of action potentials from the soma to the dendrites. This is a parsimonious scheme that minimizes an energy, allows for a better conceptual understanding of neural processes, and explains several neurophysiological phenomena that have challenged classical approaches.
Sex-specific maladaptive responses to acute stress upon in utero THC exposure are mediated by dopamine
Authors: Valeria Serra , Francesco Traccis , Sonia Aroni , Laura Vidal Palencia , Luca Concas , Marcello Serra , Roberta Leone , Patrizia Porcu , Arnau Busquets Garcia , Roberto Frau , Miriam Melis
Published: September 2024

Cannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) deficits. Notably, VTA dopamine neuronal activity is required for the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-β signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent deficits of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.