bluuebunny/crossref_metadata_2025 huggingface dataset:
Disparities in Naltrexone Prescriptions to Medicaid Enrollees During the COVID-19 Pandemic
Authors: Subervi Hemmy A. , Varghese Lysine E. , Piper Brian J.
Published: October 2022

Background

The COVID-19 pandemic strained healthcare facilities and the isolation and uncertainty associated with the pandemic compromised mental health around the world. The pandemic has also been associated with an exacerbation of the opioid crisis in the United States (US), and previous studies have reported changing trends in opioid misuse during the pandemic. Our study investigated naltrexone, a prescription drug used to treat alcohol and opioid use disorders by blocking opioid receptors to reduce cravings. We sought to investigate the changes in naltrexone prescriptions issued to Medicaid enrollees in light of the COVID-19 pandemic.

Methods

The total number of naltrexone, generic and brand name, prescriptions across the US were obtained from the Medicaid.gov database, expressed as prescriptions per state corrected for the number of enrollees, and organized into two time periods - the pre-pandemic period from January 2019 to December 2019 and the pandemic period from January 2020 to March 2021. Statistical analyses included a paired t-test, a heat map to depict state level variation, and waterfall figures. Procedures were approved by the IRB of Geisinger.

Results

There were increases in total naltrexone prescriptions throughout the time frame studied, but a decrease in prescriptions per 100,000 Medicaid enrollees. A paired t-test revealed a significant decrease in naltrexone prescriptions during the pandemic period. There was a 398-fold difference between the highest and lowest states in 2019 Quarter 1 and 424-fold in 2021 Quarter 1. Percent change calculations indicated South Dakota (+141%) and Oregon (+172%) showed a significant increase in total naltrexone prescriptions from pre-pandemic to post-pandemic from the national mean (−23.57%+5.60%).

Conclusions

The results of this study were significant and indicated a relationship between the COVID-19 pandemic and declining naltrexone prescription rates. Naltrexone prescriptions per 100,000 enrollees decreased in most states during the pandemic and fell by over 32% nationally from 2019 to 2021 despite a slight increase in total prescription numbers and an increase in Medicaid enrollees. These data suggest wide variation in access to substance use disorder treatment during the pandemic. Further research with privately insured patients may be beneficial.
Gyroscope Vector Magnitude: A proposed measure for accurately measuring angular velocities
Authors: Chen Howard , Schall Mark , Fethke Nathan
Published: October 2022

High movement velocities are among the primary risk factors for work-related musculoskeletal disorders (MSDs). Ergonomists have commonly used two methods to calculate angular movement velocities of the upper arms using inertial measurement units (accelerometers and gyroscopes). Generalized velocity is the speed of movement traveled on the unit sphere per unit time. Inclination velocity is the derivative of the postural inclination angle relative to gravity with respect to time. Neither method captures the full extent of upper arm angular velocity. We propose a new method, the gyroscope vector magnitude (GVM), and demonstrate how GVM captures angular velocities around all motion axes and more accurately represents the true angular velocities of the upper arm. We use optical motion capture data to demonstrate that the previous methods for calculating angular velocities capture 89% and 77% relative to our proposed method. We propose GVM as the standard metric for reporting angular arm velocities in future research.
COVID-19: impact of original, Gamma, Delta, and Omicron variants of SARS-CoV-2 in vaccinated and unvaccinated pregnant and postpartum women
Authors: Serra Fabiano Elisei , Rosa Elias Ribeiro , de Rossi Patricia , Vieira Francisco Rossana Pulcineli , Rodrigues Agatha Sacramento
Published: October 2022

Introduction

This study compares the clinical characteristics and disease progression of vaccinated and unvaccinated pregnant and postpartum women positive for the original, Gamma, Delta, and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using Brazilian epidemiological data.

Methods

Data of pregnant or postpartum patients with coronavirus disease 2019 (COVID-19) SARS-CoV-2 confirmed using polymerase chain reaction from February 2020 to July 2022 were extracted from a Brazilian national database. The patients were divided based on vaccination status and viral variant (original, Gamma, Delta, and Omicron). The patients’ demographic data, clinical characteristics, comorbidities, signs, symptoms, and outcomes were retrospectively compared.

Results

Data from 10,003 pregnant and 2,361 postpartum women were extracted from the database. Among unvaccinated patients, postpartum women were more likely to be admitted to the intensive care unit (ICU). These patients were more likely to require invasive ventilation when infected with the original, Gamma, and Omicron variants and were more likely to die when infected with the original and Gamma variants. Patients who were vaccinated had reduced adverse outcomes including ICU admission, requirement for invasive ventilation, and death.

Conclusion

Postpartum women were more likely to develop severe COVID-19 that required ICU admission or invasive ventilatory support or led to death, among all variants, especially when the patients were unvaccinated. Therefore, the risk of severe COVID-19 should not be underestimated after delivery. Vaccinated patients had a lower risk of severe outcomes. Vaccination should be a top priority in pregnant and postpartum patients.

WHAT IS ALREADY KNOWN ON THIS TOPIC

The obstetric population has a higher risk of adverse outcomes due to coronavirus disease 2019 (COVID-19). Few studies have compared the outcomes of pregnant and postpartum patients or vaccinated and unvaccinated patients; however, no studies have separately investigated the effects of each viral variant.

WHAT THIS STUDY ADDS

Postpartum women are more likely to have adverse outcomes, including the requirements for intensive care and invasive ventilation and death, compared with pregnant women. Vaccinated women had fewer adverse outcomes. The viral variants did not significantly affect the outcomes of these patients.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY

The risks of COVID-19 infection should not be underestimated in postpartum women. Postpartum women infected with COVID-19, especially those who are not vaccinated, should be monitored carefully. Vaccination should be a top priority in pregnant and postpartum women.
Multi-omic Analysis of Primary Human Kidney Tissues Identifies Medulla-Specific Gene Expression Patterns
Authors: Haug Stefan , Muthusamy Selvaraj , Li Yong , Köttgen Anna , Akilesh Shreeram
Published: October 2022

The renal medulla is a specialized region of the kidney with important homeostatic functions. It has also been implicated in genetic and developmental disorders and ischemic and drug-induced injuries. Despite its role in kidney function and disease, the medulla’s baseline gene expression and epigenomic signatures have not been well described in the adult human kidney. Here we generate and analyze gene expression (RNA-seq), chromatin accessibility (ATAC-seq) and chromatin conformation (Hi-C) data from adult human kidney cortex and medulla. Using data from our carefully annotated specimens, we assign samples in the larger public GTEx database to cortex and medulla, thereby identifying several misassignments and extracting meaningful medullary gene expression signatures. Using integrated analysis of gene expression, chromatin accessibility and conformation profiles, we reveal insights into medulla development and function. Our datasets will also provide a valuable resource for researchers in the GWAS community for functional annotation of genetic variants.
The vertical position of visual information conditions spatial memory performance in healthy aging
Authors: Durteste M. , Van Poucke L. , Combariza S. , Benziane B. , Sahel J-A. , Ramanoël S. , Arleo A.
Published: October 2022

Memory for objects and their location is a cornerstone of adequate cognitive functioning across the lifespan. Considering that human visual perception is dependent upon the position of stimuli within the visual field, we posit that the position of objects in the environment may be a determinant aspect of mnemonic performance. In this study, a population of young and older adults completed a source monitoring task with objects presented either in the upper or lower visual field. Using multinomial processing tree modeling, we revealed that while item memory remained intact in older age, spatial memory was impaired but only for objects that had been presented in the upper visual field. Spatial memory is therefore conditioned by the vertical position of information. These findings put into question the traditional view that age-related spatial mnemonic deficits are primarily attributable to high-order associative dysfunctions and suggest that they could also originate from altered encoding of object attributes.
The first complete mitochondrial genome ofDiadema antillarum(Diadematoida, Diadematidae)
Authors: Majeske Audrey J. , Mercado Capote Alejandro J. , Komissarov Aleksey , Bogdanova Anna , Schizas Nikolaos V. , Castro Márquez Stephanie O. , Hilkert Kenneth , Wolfsberger Walter , Oleksyk Tarás K.
Published: October 2022

The mitochondrial genome of the long-spined black sea urchin,Diadema antillarum, was sequenced using Illumina next generation sequencing technology. The complete mitogenome is 15,708 bp in length, containing 2 rRNA, 22 tRNA and 13 protein-coding genes, plus a non-coding control region of 133 bp. The nucleotide composition includes 18.37% G, 23.79% C, 26.84% A and 30.99% T. The A + T bias is 57.84%. Phylogenetic analysis based on 12 complete mitochondrial genomes of sea urchins including four species of the family Diadematidae supported familial monophyly, however the twoDiademaspecies,D. antillarumandD. setosumwere not recovered as sister taxa.
Activin A promotes bone fracture repair and acts through a novel myofibroblastic cell population in callus
Authors: Yao Lutian , Zhong Leilei , Wei Yulong , Gui Tao , Wang Luqiang , Ahn Jaimo , Boerckel Joel , Rux Danielle , Mundy Christina , Qin Ling , Pacifici Maurizio
Published: October 2022

Insufficient bone fracture repair represents a significant clinical burden, and identification of novel therapeutics enhancing repair would have substantial clinical and societal impact. Activin A is a TGF-β protein superfamily member known to stimulate ectopic bone formation, but its roles in fracture repair and its therapeutic potentials remain unclear. Using two mouse tibia fracture repair models, here we mapped activin A expression at the tissue and single cell levels, tested its requirement for normal repair and evaluated its ability to enhance repair when provided exogenously. Activin A was minimally expressed in periosteum of intact bones but was markedly upregulated in developing callus soon after fracture. Single cell RNA-sequencing revealed that the activin A-encoding gene Inhba marked a unique, highly proliferative progenitor cell (PPC) population with a myofibroblast character which emerged over repair time and lay at the center of a developmental trajectory bifurcation producing cartilage and bone cells within callus. Systemic administration of a neutralizing activin A antibody impaired fracture repair and its endochondral and intramembranous phases, whereas local delivery of recombinant activin A enhanced repair. Activin A delivery also induced SMAD2 phosphorylation in vivo and increased the fraction of αSMA+ myofibroblasts within fracture callus. Gain- and loss-of-function experiments in vitro showed that activin A directly stimulated myofibroblast differentiation, chondrogenesis and osteogenesis in periosteal progenitor cells. Together, these data identify a unique population of Inhba-expressing proliferative progenitor cells that give rise to chondrocytes and osteoblasts during fracture healing and establish activin A as a potential new therapeutic tool to enhance it.

One Sentence Summary

Deficits in bone fracture repair remain a clinical challenge and the present study provides evidence for the therapeutic potentials of activin A
WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
Authors: Hussain Tabish , Sanchez Kevin , Crayton Jennifer , Saha Dhurjhoti , Jeter Collene , Lu Yue , Abba Martin , Seo Ryan , Noebels Jeffrey L , Fonken Laura , Aldaz C Marcelo
Published: October 2022

WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12). This mutation affects the WW1 protein binding domain of WWOX, impairing its ability to interact with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T that phenocopies SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age, and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice exhibited signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. The cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions from these Wwox LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation and severe cerebellar dysfunction, activation of pathways compatible with compensatory neurogenesis along with major suppression of gene networks associated with excitability, neuronal cell differentiation and brain development. Our results show significant pathobiological effects and potential mechanisms through which WWOX LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool for the study of WWOX in common neurodegenerative conditions in which it has been identified as a novel risk factor.
Resource-efficient Neural Network Architectures for Classifying Nerve Cuff Recordings on Implantable Devices
Authors: Hwang Y. E. , Genov R. , Zariffa J.
Published: October 2022

Background

Closed-loop control of functional electrical stimulation involves using recorded nerve signals to make decisions regarding nerve stimulation in real-time. Surgically implanted devices that can implement this strategy have significant potential to restore natural movement after paralysis. Previous work demonstrated the use of convolutional neural networks (CNNs) to discriminate between activity from different neural pathways recorded by a high-density multi-contact nerve cuff electrode. Despite state-of-the-art performance, that approach required too much data storage, power and computation time for a practical implementation on surgically implanted hardware.

Objective

To reduce resource utilization for an implantable implementation, with a minimal performance loss for CNNs that can discriminate between neural pathways in multi-contact nerve cuff electrode recordings.

Methods

Neural network (NN) architectures were evaluated on a dataset of rat sciatic nerve recordings previously collected using 56-channel (7 x 8) spiral nerve cuff electrodes to capture spatiotemporal neural activity patterns. The NNs were trained to classify individual, natural compound action potentials (nCAPs) elicited by sensory stimuli. Three architecture types were explored: the previously reported ESCAPE-NET, a fully convolutional network, and a recurrent neural network. Variations of each architecture yielded NNs with a range in the number of weights and required floating-point operations (FLOPs). Each NN was evaluated based on F1-score and resource requirements.

Results

NNs were identified that, when compared to ESCAPE-NET, required 1,132-1,787x fewer weights, 389-995x less memory, and 6-11,073x fewer FLOPs, while maintaining macro F1-scores of 0.70-0.71 compared to a baseline of 0.75. Memory requirements range from 22.69 KB to 58.11 KB, falling within the range of on-chip memory sizes from several published deep learning accelerators fabricated in 65nm ASIC technology.

Conclusion

Reduced versions of ESCAPE-NET require significantly fewer resources without significant accuracy loss, thus can be more easily incorporated into a surgically implantable device that performs closed-loop real-time responsive neural stimulation.
Social investigation and social novelty in zebrafish: Roles of salience and novelty
Authors: do Nascimento Bianca Gomes , Maximino Caio
Published: October 2022

Social preference tests can be used to analyze variables that influence and modify social behaviors, and to investigate effects of substances such as medications, drugs, and hormones. They may become important tools for finding a valid model to study neuropsychiatric changes and to study human neurodevelopmental processes that have been impaired by social events. While a preference for conspecifics has been shown for different species, social novelty has been used as a model for anxiety-like behavior in rodents. The goal of this research was to understand the roles of stimulus salience (numerousness) and novelty in social investigation and social novelty tests in zebrafish (Danio rerioHamilton 1822). We used a sequential design, in which animals are exposed first to a social investigation test (with dichotomous presentation of novel conspecifics vs. empty tank) and then to a social novelty test (with dichotomous presentation of the already known conspecific and a novel conspecific). In experiment 1, animals were presented to either 1 or 3 (vs. an empty tank) conspecifics as stimuli. In experiment 2, animals were presented to 1 vs. 3 conspecifics as stimuli. In experiment 3, animals were observed in the social investigation and social novelty tests for 3 consecutive days. The results showed equivalence between 1 or 3 conspecifics in the social investigation and social novelty tests, although animals were able to discriminate between different shoal sizes. These preferences do not change with repeated test exposure, suggesting novelty to be a minor contributor to social investigation and social novelty in zebrafish.
Near Infrared Nanosensors Enable Optical Imaging of Oxytocin with Selectivity over Vasopressin in Acute Mouse Brain Slices
Authors: Navarro Nicole , Jeong Sanghwa , Ouassil Nicholas , Mun Jaewan , Leem Esther , Landry Markita P.
Published: October 2022

Oxytocin plays a critical role in regulating social behaviors, yet our understanding of its role in both neurological health and disease remains incomplete. Real-time oxytocin imaging probes with the spatiotemporal resolution relevant to its endogenous signaling are required to fully elucidate oxytocin function in the brain. Herein we describe a near-infrared oxytocin nanosensor (nIROx), a synthetic probe capable of imaging oxytocin in the brain without interference from its structural analogue, vasopressin. nIROx leverages the inherent tissue-transparent fluorescence of single-walled carbon nanotubes (SWCNT) and the molecular recognition capacity of an oxytocin receptor peptide fragment (OXTp) to selectively and reversibly image oxytocin. We employ these nanosensors to monitor electrically stimulated oxytocin release in brain tissue, revealing oxytocin release sites with a median size of 3 μm which putatively represents the spatial diffusion of oxytocin from its point of release. These data demonstrate that covalent SWCNT constructs such as nIROx are powerful optical tools that can be leveraged to measure neuropeptide release in brain tissue.
Eradication of tumors with pre-existing antigenic heterogeneity by vaccine-mediated co-engagement of CAR T and endogenous T-cells
Authors: Ma Leyuan , Morgan Duncan M. , Sulkaj Ina , Yousefpour Parisa , Whittaker Charles A. , Abraham Wuhbet , Li Na , Love J. Christopher , Irvine Darrell J.
Published: October 2022

Chimeric Antigen Receptor (CAR) T-cell therapy can be effective in treating human cancer but loss of the antigen recognized by the CAR poses a major obstacle. Here, we report an approach for vaccine boosting CAR T-cells, which triggers engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T-cells promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited priming of endogenous anti-tumor T-cells (antigen spreading). This process was accompanied by a shift in toward oxidative phosphorylation in CAR T-cells and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading induced by vaccine-boosted CAR-T enabled a proportion of complete responses even when the initial tumor was 50% CAR-antigen-negative, and heterogenous tumor control was further enhanced by genetically amplifying CAR-T IFN-γ expression. Thus, CAR T-cell-derived IFN-γ plays a critical role in promoting antigen spreading, and vaccine boosting provides a clinically-translatable strategy to drive such responses against solid tumors.
Systemic inflammation impairs human myelopoiesis and interferon I responses
Authors: Keramati Farid , Leijte Guus P. , Bruse Niklas , Grondman Inge , Habibi Ehsan , Ruiz-Moreno Cristian , Megchelenbrink Wout , Peters van Ton Annemieke M. , Heesakkers Hidde , Bremmers Manita , van Grinsven Erinke , Tesselaar Kiki , van Staveren Selma , van der Velden Walter , Preijers Frank , Gerretsen Jelle , Netea Mihai G. , Stunnenberg Hendrik G. , Pickkers Peter , Kox Matthijs
Published: October 2022

Systemic inflammation (SI) plays a detrimental role in various conditions with high mortality rates1–4. SI manifests an acute hyperinflammation followed by long-lasting immunosuppression, increasing patients’ risks for secondary infections and impaired clinical outcomes5–7. Due to the extensive heterogeneity in SI etiology, the mechanisms governing these states are incompletely understood. Here, we characterized acute and late effects of lipopolysaccharide (LPS)-induced SI (LPS-SI8) on blood monocytes and bone marrow (BM) cells of healthy volunteers. Like clinical SI, LPS administration elicited a profound but transient acute response. Single-cell transcriptomic analysis of acute LPS-SI unveiled loss of BM monocytes and appearance of an inflammatory monocyte-like (i-Mono’s) population, expressing gene programs similar to early-stage sepsis patients9. In the ensuing late phase of LPS-SI, we observed reduced expression of interferon type I (IFN-I) responsive genes in monocytes and profound attenuation of in vivo response to a second LPS challenge. Furthermore, late LPS-SI led to impaired myelopoiesis with a loss of intermediate and non-classical monocytes. In accordance, we show compromised myelopoiesis also occurs in late-stage sepsis. Finally, IFNβ treatment reversed LPS-induced immunosuppression in monocytes. Our results reveal long-lasting effects of SI on myelopoiesis and substantiate the importance of IFN-I in the pathophysiology of SI-induced immunosuppression.
Antibody selection strategies and their impact in the analysis of malaria multi-sera data
Authors: Fonseca André , Spytek Mikolaj , Biecek Przemyslaw , Cordeiro Clara , Sepúlveda Nuno
Published: October 2022

Background

Nowadays, the chance of discovering the best antibody candidates for explaining naturally acquired protection to malaria and detecting exposure to malaria parasites has notably increased due to publicly available multi-sera data. The analysis of these data is typically divided into a feature selection phase followed by a predictive one where several models are constructed for the outcome of interest. A key question in the analysis is to determine which and how each feature should be included in the predictive stage.

Results

To answer this question, we developed three approaches for classifying malaria protected and susceptible groups: (i) a basic and simple approach based on selecting antibodies via the nonparametric Mann-Whitney test; (ii) a dichotomization approach where each antibody was selected according to the optimal cut-off via maximization of the χ2statistic for two-way tables; (iii) a hybrid parametric/non-parametric approach that integrates Box-Cox transformation followed by a t-test, together with the use of finite mixture models and the Mann-Whitney test as a last resort. We illustrated the application of these three approaches with published serological data for predicting clinical malaria in 121 Kenyan children. The predictive analysis was based on a Super-Learner where predictions from multiple classifiers were pooled together. Our results led to almost similar areas under the Receiver Operating Characteristic curves of 0.72 (95% CI = [0.61, 0.82]), 0.80 (95% CI = [0.71, 0.90]), 0.79 (95% CI = [0.7, 0.88]) for the simple, dichotomization and hybrid approaches, respectively.

Conclusions

The three feature selection strategies provided a better predictive performance of the outcome when compared to the previous results solely relying on Random Forests alone (AUC=0.68). Given the similar predictive performance, we recommended the three strategies should be used in conjunction in the same data set and selected according to their complexity.
Predicting the combined effects of case isolation, safe funeral practices, and contact tracing during Ebola virus disease outbreaks
Authors: Bouba Aliou , Helle Kristina Barbara , Schneider Kristan Alexander
Published: October 2022

Background

The recent outbreaks of Ebola virus disease (EVD) in Uganda and the Marburg virus disease in Ghana reflect a persisting threat of Filoviridae to the global health community. Characteristic of Filoviridae are not just their high case fatality rates, but also that corpses are highly contagious and prone to cause infections in the absence of appropriate precautions. Vaccines against the most virulent Ebolavirus species, the Zaire ebolavirus (ZEBOV) are approved. However, there exists no approved vaccine or treatment against the Sudan ebolavirus (SUDV) which causes the current outbreak of EVD. Hence, the control of the outbreak relies on case isolation, safe funeral practices, and contact tracing. So far, the effectiveness of these control measures was studied only separately by epidemiological models, while the impact of their interaction is unclear.

Methods and findings

To sustain decision making in public health-emergency management, we introduce a predictive model to study the interaction of case isolation, safe funeral practices, and contact tracing. The model is a complex extension of an SEIR-type model, and serves as an epidemic preparedness tool. The model considers different phases of the EVD infections, the possibility of infections being treated in isolation (if appropriately diagnosed), in hospital (if not properly diagnosed), or at home (if the infected do not present to hospital for whatever reason). It is assumed that the corpses of those who died in isolation are buried with proper safety measures, while those who die outside isolation might be buried unsafely, such that transmission can occur during the funeral. Furthermore, the contacts of individuals in isolation will be traced. Based on parameter estimates from the scientific literature, the model suggests that proper diagnosis and hence isolation of cases has the highest impact in reducing the size of the outbreak. However, the combination of case isolation and safe funeral practices alone are insufficient to fully contain the epidemic under plausible parameters. This changes if these measures are combined with contact tracing. In addition, shortening the time to successfully trace back contacts contribute substantially to contain the outbreak.

Conclusions

In the absence of an approved vaccine and treatment, EVD management by proper and fast diagnostics in combination with epidemic awareness are fundamental. Awareness will particularly facilitate contact tracing and safe funeral practices. Moreover, proper and fast diagnostics are a major determinant of case isolation. The model introduced here is not just applicable to EVD, but also to other hemorrhagic diseases such as the MVD or the Lassa fever.
Comparative Efficacy and Safety of Tenecteplase and Alteplase in Acute Ischemic Stroke: A Pairwise and Network Meta-analysis of Randomized Controlled Trials
Authors: Rehman Aqeeb Ur , Mohsin Aleenah , Cheema Huzaifa Ahmad , Zahid Afra , Rehman Muhammad Ebaad Ur , Ameer Muhammad Zain , Ayyan Muhammad , Ehsan Muhammad , Shahid Abia , Ur Rehman Muhammad Aemaz , Shah Jaffer , Khawaja Ayaz
Published: October 2022

Background

Studies on tenecteplase have been yielding mixed results on several important variables at different doses, thus hampering objective guideline recommendations in acute ischemic stroke management. This meta-analysis stratifies doses in order to refine our interpretation of outcomes and quantify the benefits and harms of tenecteplase at different doses.

Methods

PubMed/MEDLINE, the Cochrane Library, and reference lists of the included articles were systematically searched. Several efficacy and safety outcomes were pooled and reported as risk ratios (RRs) with 95% confidence intervals (CIs). Network meta-analysis was used to find the optimal dose of tenecteplase. Meta-regression was run to investigate the impact of baseline NIHSS scores on functional outcomes and mortality.

Results

Ten randomized controlled trials with a total of 4140 patients were included. 2166 (52.32%) patients were enrolled in the tenecteplase group and 1974 (47.68%) in the alteplase group. Tenecteplase at 0.25 mg/kg dose demonstrated significant improvement in excellent functional outcome at 3 months (RR 1.14, 95% CI 1.04-1.26), and early neurological improvement (RR 1.53, 95% CI 1.03-2.26). There was no statistically significant difference between tenecteplase and alteplase in terms of good functional outcome, intracerebral hemorrhage (ICH), symptomatic intracerebral hemorrhage (sICH), and 90-day mortality at any dose. Meta-regression demonstrated superior tenecteplase efficacy with increasing stroke severity, however, the results were statistically nonsignificant.

Conclusions

Tenecteplase at 0.25 mg/kg dose is more efficacious and at least as safe as alteplase for stroke thrombolysis. Newer analyses need to focus on direct comparison of tenecteplase doses and whether tenecteplase is efficacious at longer needle times.
Tm-22 resistance targets a conserved cysteine essential for tobacco mosaic virus (TMV) movement
Authors: Hak Hagit , Raanan Hagai , Schwarz Shahar , Sherman Yifat , Dinesh-Kumar Savithramma P , Spiegelman Ziv
Published: October 2022

The tomato Tm-22 gene was considered one of the most durable resistance genes in agriculture, protecting against viruses of the Tobamovirus genus, such as Tomato mosaic virus (ToMV) and Tobacco mosaic virus (TMV). However, an emerging tobamovirus, Tomato brown rugose fruit virus (ToBRFV), has overcome Tm-22, damaging tomato production worldwide. Tm-22 encodes a nucleotide-binding leucine-rich repeat (NLR) class immune receptor that recognizes its effector, the tobamovirus movement protein (MP). Previously, we found that ToBRFV MP (MPToBRFV) enabled the virus to overcome Tm-22- mediated resistance. Yet, it was unknown how Tm-22 remained durable against other tobamoviruses, such as TMV and ToMV, for over 60 years. Here, we show that the presence of a conserved cysteine (C68) in the MP of TMV (MPTMV) is both sufficient to trigger Tm-22 resistance and essential for viral movement. Substitution of MPToBRFV amino acid H67 with the corresponding amino acid in MPTMV (C68) activated Tm-22-medited resistance. However, replacement of C68 in TMV and ToMV disabled the infectivity of both viruses. Phylogenetic and structural prediction analysis revealed that C68 is conserved among all Solanaceae-infecting tobamoviruses except ToBRFV, and localizes to a predicted jelly-roll fold common to various MPs. Cell-to-cell, and subcellular movement analysis showed that C68 is required for the movement of TMV, by regulating the MP interaction with the endoplasmic reticulum and targeting it to plasmodesmata. The dual role of C68 in viral movement and Tm-22 immune activation could explain how TMV was unable to overcome this resistance for such a long period.
Toxoplasma gondii importin α shows weak auto-inhibition
Authors: Bhambid Manasi , Dey Vishakha , Walunj Sujata , Patankar Swati
Published: October 2022

Importin α is a nuclear transporter that binds to nuclear localization signals (NLSs), consisting of 7-20 positively charged amino acids found within cargo proteins. In addition to cargo binding, intramolecular interactions also occur within the importin α protein due to binding between the importin β-binding (IBB) domain and the NLS-binding sites, a phenomenon called auto-inhibition. The interactions causing auto-inhibition are driven by a stretch of basic residues, similar to an NLS, in the IBB domain. Consistent with this, importin α proteins that do not have some of these basic residues lack auto-inhibition; a naturally occurring example of such a protein is found in the apicomplexan parasite Plasmodium falciparum. In this report, we show that importin α from another apicomplexan parasite, Toxoplasma gondii, harbors basic residues (KKR) in the IBB domain and exhibits auto-inhibition. This protein has a long, unstructured hinge motif (between the IBB domain and the NLS-binding sites) that does not contribute to auto-inhibition. However, the IBB domain may have a higher propensity to form an α-helical structure, positioning the wild-type KKR motif in an orientation that results in weaker interactions with the NLS-binding site than a KRR mutant. We conclude that the importin α protein from T. gondii shows auto-inhibition, exhibiting a different phenotype from that of P. falciparum importin α. However, our data indicate that T. gondii importin α may have a low strength of auto-inhibition. We hypothesize that low levels of auto-inhibition may confer an advantage to these important human pathogens.
The roles and evolution of the four LEAFY homologues in floral patterning and leaf development in woodland strawberry
Authors: Zhang Yunming , Kan Lijun , Hu Shaoqiang , Cheng Laichao , Liu Zhongchi , Kang Chunying
Published: October 2022

The plant-specific transcription factor LEAFY (LFY), generally maintained as a single copy gene in most angiosperm species, plays critical roles in flower and leaf development. However, wild strawberry Fragaria vesca possesses four LFY homologues in the genome, their respective functions and evolution remain unknown. Through chemical mutagenesis screen, we identified two allelic mutations in one of the four LFY homologues, FveLFYa, in F. vesca, causing homeotic conversion of floral organs and reiterative outgrowth of ectopic florets. Both CRISPR-knockout and transgenic rescue confirmed the identity of FveLFYa. Ectopic expression in Arabidopsis lfy-5 mutant revealed that only FveLFYa and FveLFYb can rescue the flower defects and induce solitary flowers in leaf axils. Disruption of FveLFYc, the second abundantly expressed LFY homologue, caused no obvious morphology phenotypes in F. vesca. FveLFYb and FveLFYd are barely expressed. Expression of FveAP1, homologue of the well-known LFY target AtAP1, is not changed in the fvelfya flowers, possibly caused by an absence of any FveLFYa binding site in its promoter. Loss of Axillary Meristems encodes a GRAS transcription factor essential for stamen initiation. The ectopic florets are eliminated in fvelfya lam, suggesting that LAM is required for floret production. Moreover, approximately 30% of mature leaves have smaller or fewer leaflets in fvelfya. Among these homologues, only FveLFYa is syntenic to the homologues in other species. Overall, the detailed analyses of the four LFY homologues in woodland strawberry demonstrate that only FveLFYa plays crucial roles in floral patterning with rewired gene network.
Pump-Rest-Leak-Repeat: regulation of the mammalian-brain V-ATPase via ultra-slow mode-switching
Authors: Kosmidis Eleftherios , Shuttle Christopher G. , Preobraschenski Julia , Ganzella Marcelo , Johnson Peter J. , Veshaguri Salome , Møller Mads P. , Marantos Orestis , Pedersen Jesper L. , Jahn Reinhard , Stamou Dimitrios
Published: October 2022

Summary paragraph

Vacuolar-type adenosine triphosphatases (V-ATPases)1–3 are electrogenic rotary mechanoenzymes structurally related to F-type ATP synthases4,5. They hydrolyze ATP to establish electrochemical proton gradients for a plethora of cellular processes1,3. In neurons, the loading of all neurotransmitters into synaptic vesicles is energized by ~1 V-ATPase molecule per synaptic vesicle6,7. To shed light into this bona fide single-molecule biological process, we investigated electrogenic proton pumping by single mammalian-brain V-ATPases, using individual synaptic vesicles fused with immobilized liposomes. We show V-ATPases do not pump continuously in time, as hypothesized by observing the rotation of bacterial homologs8 and assuming strict ATP/proton coupling. Instead, they stochastically switch between three novel ultra-long-lived proton-pumping, inactive, and proton-leaky modes. Upending conventional wisdom, direct observation of pumping revealed that physiologically relevant concentrations of ATP do not regulate the intrinsic pumping rate. Instead, ATP regulates V-ATPase activity via the switching probability of the proton-pumping mode. In contrast, electrochemical proton gradients regulate the pumping rate and the switching of the pumping and inactive modes. This work reveals and emphasises the mechanistic and biological importance of mode-switching in protein regulation.
Drug repurposing screens identifies compounds that inhibit α-synuclein oligomers’ membrane disruption and block antibody interactions
Authors: Somavarapu Arun Kumar , Kleijwegt Giulia , Nagaraj Madhu , Alam Parvez , Nielsen Janni , Otzen Daniel
Published: October 2022

Small soluble oligomers of the protein α-synuclein (αSO) have been linked to disruptions in neuronal homeostasis, contributing to the development of Parkinson’s Disease (PD). While this makes αSO an obvious drug target, the development of effective therapeutics against αSO are challenged by its low abundance and structural and morphological complexity. Here we employ two different approaches to neutralize toxic interactions made by αSOs with different cellular components. Firstly, we use available data to identify four neuronal proteins as likely candidates for αSO interactions, namely Cfl1, Uchl1, Sirt2 and SerRS. However, despite promising results when immobilized, all 4 proteins only bind weakly to αSO in solution in microfluidic assays, making them inappropriate for screening. In contrast, the formation of stable contacts formed between αSO and vesicles consisting of anionic lipids not only mimics a likely biological role of αSO but also provided a platform to screen two small molecule libraries for disruptors of these contacts. Of the 11 leads obtained in this way, 2 significantly impaired αSO contacts with other proteins in a sandwich ELISA assay using αSO-binding monoclonal antibodies and nanobodies. In addition, 5 of these leads suppressed α-synuclein amyloid formation. Thus a repurposing screening that directly targets a key culprit in PD pathogenesis shows therapeutic potential.

Highlights

The toxic oligomer formed by α-synuclein (αSO) is an important drug target.

Neuronal proteins found by pull-down assays do not bind αSOs in solution.

Liposome assay identifies 7 approved drugs reducing αSO membrane disruption.

We identify different inhibitory mechanisms used by different compounds.

Two top drug hits disrupt αSO binding to oligomer-specific antibodies.

Graphical Abstract
Convergent evolution of plant pattern recognition receptors sensing cysteine-rich patterns from three microbial kingdoms
Authors: Yang Yuankun , Steidele Christina E. , Löffelhardt Birgit , Kolb Dagmar , Leisen Thomas , Zhang Weiguo , Ludwig Christina , Felix Georg , Seidl Michael F. , Nürnberger Thorsten , Hahn Matthias , Gust Bertolt , Gross Harald , Hückelhoven Ralph , Gust Andrea A.
Published: October 2022

The Arabidopsis thaliana receptor-like protein RLP30 contributes to immunity against the fungal pathogen Sclerotinia sclerotiorum. Here we identified the RLP30-ligand as a small cysteine-rich protein (SCP) that occurs in many fungi and oomycetes and is also recognized by the Nicotiana benthamiana RLP RE02. However, RLP30 and RE02 share little sequence similarity and respond to different parts of the native/folded protein. Interestingly, some Brassicaceae other than Arabidopsis also respond to a linear SCP peptide, suggesting that SCP is an eminent immune target that led to the convergent evolution of distinct immune receptors in plants. Surprisingly, RLP30 shows a second ligand specificity for a SCP-nonhomologous protein secreted by bacterial Pseudomonads. RLP30 expression in N. tabacum resulted in lower susceptibility to bacterial, fungal and oomycete pathogens, thus demonstrating that detection of immunogenic patterns by Arabidopsis RLP30 is involved in defense against pathogens from three microbial kingdoms.
Synchronization in collectively moving inanimate and living active matter
Authors: Riedl Michael , Merrin Jack , Sixt Michael , Hof Björn
Published: October 2022

Regardless of whether one considers swarming insects, flocking birds, or bacterial colonies, collective motion arises from the coordination of individuals and entails the adjustment of their respective velocities. In particular, in close confinement, such as those encountered by dense cell populations during development or regeneration, collective migration can only arise coordinately. Yet, how individuals unify their velocities is often not understood. Focusing on a finite number of cells in circular confinements, we identify waves of polymerizing actin that function as a pacemaker governing the speed of individual cells. We show that the onset of collective motion coincides with the synchronization of the wave nucleation frequencies across the population. Employing a simpler and more readily accessible mechanical model system of active spheres, we identify the essential requirements to reach the corresponding collective state, i.e. the synchronization of the individuals’ internal oscillators. The mechanical ‘toy’ experiment illustrates that the global synchronous state is achieved by nearest neighbor coupling. We suggest by analogy that local coupling and the synchronization of actin waves are essential for emergent, self-organized motion of cell collectives.
Capsid-mediated chromatin state of the AAV vector genome controls host species range
Authors: Gonzalez-Sandoval Adriana , Tsuji Shinnosuke , Zhang Feijie , Hung King L. , Chang Howard Y. , Pekrun Katja , Kay Mark A.
Published: October 2022

Recombinant adeno-associated viral vectors (rAAVs) are among the most commonly used vehicles for in vivo based gene therapies. However, it is hard to predict which AAV capsid will provide the most robust expression in human subjects due to the observed discordance in vector-mediated transduction between species. We used a primate specific capsid, AAV-LK03, and demonstrated that the limitation of this capsid towards transduction of mouse cells was unrelated to cell entry and nuclear transport but rather due to depleted histone H3 chemical modifications related to active transcription, namely H3K4me3 and H3K27ac, on the vector DNA itself. A single-amino acid insertion into the AAV-LK03 capsid enabled efficient transduction and the accumulation of active histone marks on the vector chromatin in mouse without compromising transduction efficiency in human cells. Our study suggests that the capsid protein itself is involved in determining the chromatin status of the vector genome, most likely during the process of uncoating. Programming viral chromatin states by capsid design may enable facile DNA transduction between vector and host species.
Aquaponics versus conventional farming: effects on the growth, nutritional and chemical compositions of Celosia argentea L., Corchorus olitorius L., and Ocimum gratissimum L.
Authors: Olanrewaju Gbolaga O. , Sarpong David D. , Aremu Abiola O. , Ade-Ademilua Elizabeth O.
Published: October 2022

This study examined the practicality and sustainability of growing leafy vegetables in aquaponics instead of traditional soil-based farming systems by comparing the physiological growth patterns, nutritional compositions, and phytochemical constituents of Celosia argentea L., Corchorus olitorius L. and Ocimum gratissimum L. grown in aquaponics with those of other conventional systems. The results of this study indicate that the growth and accumulation of biomass by plants grown in aquaponics were similar to those obtained in unamended loamy soil but better than those of plants grown in inorganic hydroponics. However, plants grown in NPK-supplemented soil showed significantly (p<0.05) higher biomass accumulation than those grown in aquaponics. Likewise, C. argentea, C. olitorius, and O. gratissimum grown in aquaponics had significantly higher nutrient compositions than those grown in inorganic medium, and at the same time, similar to that of plants grown in unamended loamy soil. C. argentea and C. olitorius grown in inorganic medium had significantly higher concentrations of the observed phytochemicals than those grown in aquaponics, whereas the opposite was true for O. gratissimum. The three plant species were able to serve as filters for the effective maintenance of nitrogen dynamics in the constructed African catfish aquaponics, while utilizing nitrogenous waste for biomass production.
A plasma membrane-associated glycolytic metabolon is functionally coupled to KATPchannels in pancreatic α and β cells from humans and mice
Authors: Ho Thuong , Potapenko Evgeniy , Davis Dawn B. , Merrins Matthew J.
Published: October 2022

The ATP-sensitive K+channel (KATP) is a key regulator of hormone secretion from pancreatic islet endocrine cells. Using direct measurements of KATPchannel activity in pancreatic β cells and the lesser-studied α cells, from both humans and mice, we demonstrate that a glycolytic metabolon locally controls KATPchannels on the plasma membrane. The two ATP-consuming enzymes of upper glycolysis, glucokinase and phosphofructokinase, generate ADP that activates KATP. Substrate channeling of fructose 1,6-bisphosphate through the enzymes of lower glycolysis fuels pyruvate kinase, which directly consumes the ADP made by phosphofructokinase to raise ATP/ADP and close the channel. We further demonstrate the presence of a plasma membrane NAD+/NADH cycle, whereby lactate dehydrogenase is functionally coupled to glyceraldehyde-3-phosphate dehydrogenase. These studies provide direct electrophysiological evidence of a KATP-controlling glycolytic signaling complex and demonstrate its relevance to islet glucose sensing and excitability.

Graphical abstract

Hoet al. demonstrate that the enzymes of glycolysis, as well as lactate dehydrogenase, form a plasma membrane-associated metabolon with intrinsic ATP/ADP and NAD+/NADH cycles. The subcellular location of this signaling complex allows both ATP-consuming and ATP-producing enzymes to locally control the activity of ATP-sensitive K+channels in pancreatic α and β cells from humans and mice.

Highlights

KATPchannels are regulated by a glycolytic metabolon on the plasma membrane.

Substrate channeling occurs between the consecutive enzymes of glycolysis.

Upper glycolysis produces ADP that is used directly by lower glycolysis to make ATP.

LDH and GADPH facilitate a plasma membrane-associated NAD+/NADH redox cycle.