bluuebunny/crossref_metadata_2025_split huggingface dataset:
CR1variants contribute to FSGS susceptibility across multiple populations
Authors: Skitchenko Rostislav , Modrusan Zora , Loboda Alexander , Kopp Jeffrey B. , Winkler Cheryl A. , Sergushichev Alexey , Gupta Namrata , Stevens Christine , Daly Mark J. , Shaw Andrey , Artomov Mykyta 
Published: November 2023

AbstractFocal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome with an annual incidence in the United States in African-Americans compared to European-Americans of 24 cases and 5 cases per million, respectively. Among glomerular diseases in Europe and Latin-America, FSGS was the second most frequent diagnosis, and in Asia the fifth. We expand previous efforts in understanding genetics of FSGS by performing a case-control study involving ethnically-diverse groups FSGS cases (726) and a pool of controls (13,994), using panel sequencing of approximately 2,500 podocyte-expressed genes. Through rare variant association tests, we replicated known risk genes –KANK1,COL4A4,andAPOL1. A novel significant association was observed for the gene encoding complement receptor 1 (CR1). High-risk rare variants inCR1in the European-American cohort were commonly observed in Latin-and African-Americans. Therefore, a combined rare and common variant analysis was used to replicate theCR1association in non-European populations. TheCR1risk variant, rs17047661, gives rise to the Sl1/Sl2 (R1601G) allele that was previously associated with protection against cerebral malaria. Pleiotropic effects of rs17047661 may explain the difference in allele frequencies across continental ancestries and suggest a possible role for genetically-driven alterations of adaptive immunity in the pathogenesis of FSGS.
The use of a deep learning model in the histopathological diagnosis of actinic keratosis: A case control accuracy study
Authors: Balkenhol J. , Schmidt M. , Schnauder T. , Langhorst J. , Arrastia J. Le’Clerc , Baguer D. Otero , Gilbert G. , Schmitz L. , Dirschka T. 
Published: November 2023

AbstractActinic Keratosis (AK) is a frequent dermatological diagnosis which contributes to a large proportion of routine dermatopathology. A current development in histopathology is in the digitization of specimens by creating whole slide images (WSI) with slide scanners. Deep Learning Models (DLM) have been introduced to radiology or pathology for image recognition but dermatopathology lacks available solutions. Building on previous work about skin pathologies, this paper proposes a DLM following the U-Net architecture to detect AK in histopathological samples. In total, 297 histopathological slides (269 with AK and 28 without AK) have been retrospectively selected. They were randomly assigned to training, validation, and testing groups. Performance was evaluated by conducting a Case Control Accuracy Study on three levels of granularity. The DLM model achieved an overall accuracy of 99.13% on the WSI level, 99.02% on the patch level and an intersection over union (IoU) of 83.88%. The proposed DLM reliably recognizes AK in histopathological images, supporting the implementation of DLMs in dermatopathology practice. Given existing technical capabilities and advancements, DLMs could have a significant influence on dermatopathology routine in the future.
A protracted cholera outbreak in Nairobi City County associated with mass gathering events, Kenya, 2017
Authors: Ngere Philip , Langat Daniel , Ngere Isaac , Dawa Jeanette , Okunga Emmanuel , Nasimiyu Carolyne , Kiama Catherine , Lokamar Peter , Ngunu Carol , Makayotto Lyndah , Njenga M. Kariuki , Osoro Eric 
Published: November 2023

AbstractCholera continues to cause many outbreaks in low and middle-income countries due to inadequate water, sanitation, and hygiene services. We describe a protracted cholera outbreak in Nairobi City County (NCC), Kenya in 2017. We reviewed the cholera outbreak line lists from NCC in 2017 to determine its extent and factors associated with death. A suspected case of cholera was any person aged >2 years old who had acute watery diarrhea, nausea, or vomiting, whereas a confirmed case was whereVibrio choleraewas isolated from the stool specimen. We summarized cases using for continuous variables and proportions for categorical variables. Associations between admission status, sex, age, residence, time to care seeking, and outbreak settings; and cholera associated deaths were assessed using odds ratio (OR) with 95% confidence interval (CI). Of the 2,737 cholera cases reported, we analyzed 2,347 (85.7%) cases including 1,364 (58.1%) outpatients, 1,724 (73.5%) not associated with mass gathering events (MGEs), 1,356 (57.8%) male and 2,202 (93.8%) aged ≥5 years, and 35 deaths (case fatality rate: 1.5%). Cases were reported from all the Sub Counties of NCC with an overall county attack rate of 50 per 100,000 people.Vibrio choleraeOgawa serotype was isolated from 78 (34.8%) of the 224 specimens tested and all isolates were sensitive to tetracycline and levofloxacin but resistant to amikacin. The odds of cholera-related deaths was lower among outpatient cases (aOR: 0.35; [95% CI: 0.17-0.72]), age ≥5 years old (aOR: 0.21 [95% CI: 0.09-0.55]), and MGEs (aOR: 0.26 [95% CI: 0.07-0.91]) while threefold higher odds among male (aOR: 3.04 [95% CI: 1.30-7.13]). NCC experienced a protracted and widespread cholera outbreak with a high case fatality rate in 2017.Author SummaryCholera outbreaks are common in Kenya. The highest number of cases were reported in 2015 with 10,536 cases across the country. The subsequent three years also recorded a high number of cholera cases with 6,137 cases in 2016, 4,217 cases in 2017, and 5,638 cases in 2018. During the four years (2015-2018), NCC contributed less than 20.0% of the cholera cases, except in 2017 when the county reported 56.9% (2,737) of the cases. In this study, we sought to describe the burden of cholera in NCC during the 2017 outbreak. We reviewed the cholera outbreak data from NCC in 2017 to determine its extent and risk factors for cholera-related deaths. The findings depict a prolonged and widespread cholera outbreak with the likelihood of death higher among male cases but lower among outpatients, cases aged ≥5 years old, and cases from the MGEs. More studies on the factors associated with cholera-related deaths are necessary to inform public health response.
Effects of exposure in virtual reality and in vivo on subjective symptom burden and physiological parameters of height-anxious healthy participants – A pilot study
Authors: Renner Vanessa , Witthöft Michael , Hardt Jochen , Conrad Rupert , Petrowski Katja 
Published: November 2023

AbstractExposure in vivo is a highly effective treatment for anxiety disorders and acrophobia in particular. Nevertheless, it is rarely implemented in outpatient treatment. Exposure in virtual reality (VR) might be an alternative but its effect on subjective symptom burden and physiological parameters is questionable. Therefore, in this study, N = 33 participants with fear of heights received both in vivo and VR exposure in a randomized order. Subjective symptom burden before and after each exposure as well as heart rate and heart rate variability (SDNN, LF/HF ratio) during exposure sessions were assessed. Linear mixed models were calculated with the effect of condition (VR vs. in vivo) and scenario on HR, SDNN and LF/HF ratio. Subjective symptom burden was significantly reduced after both exposure sessions (p = .002; p < .001). Heart rate was significantly higher during exposure scenarios than baseline (p < .001). SDNN and LF/HF ratio reflected a significantly higher general power of HRV and a significantly higher activation of the sympathetic nervous system during exposure sessions compared to baseline and during VR exposure compared to in vivo. All in all, VR exposure shows comparable or superior effects compared to in vivo exposure regarding acrophobic fears and physiological parameters.
Affect and post-COVID-19 symptoms in daily life: An exploratory experience sampling study
Authors: Schaap Gerko , Wensink Marleen , Doggen Carine J. M. , van der Palen Job , Vonkeman Harald E. , Bode Christina 
Published: November 2023

AbstractInsight into the daily life experiences of patients with post-COVID-19 syndrome is lacking. The current study explored temporal fluctuations of and associations between positive and negative affect and symptoms throughout the day in previously hospitalised post-COVID-19 patients using an experience sampling methodology. Ten participants (age: median = 60, interquartile range = 9 years; 50% women ; 80% ≥1 comorbidity; 8–12 months since hospital discharge) filled out brief online questionnaires, six times a day for 14 consecutive days. Positive and negative affect, and self-reported symptoms (physical and mental fatigue, cognitive functioning, dyspnoea, and pain) were assessed in real-time. Primarily, graphs were analysed to assess the individual longitudinal courses of and (concurrent and time-lagged) associations between affect and symptoms. Secondly, correlations or multilevel linear regression models were used to support these interpretations. Visual assessment showed limited temporal fluctuation in affect and symptoms. All symptoms appeared to associate positively with each other (correlations between .26 and .85). Positive affect was associated with lower symptoms severity (β’s between -.28 and -.67), and negative affect with higher symptoms severity (β’s between .24 and .66). Time-lagged analyses showed that – adjusted for residual symptom severity of prior measurements – both types of affect predicted symptom severity two hours later (β’s between -.09 and -.31 for positive affect; between .09 and .28 for negative affect). These findings suggest that positive and negative affect may play important roles in post-COVID-19 symptom experience and temporal fluctuation.
Distinct roles of dopamine and acetylcholine in delay- and effort-based decision making in humans
Authors: Abdoust Mani Erfanian , Froböse Monja Isabel , Schnitzler Alfons , Schreivogel Elisabeth , Jocham Gerhard 
Published: November 2023

AbstractIn everyday life, we encounter situations that require tradeoffs between potential rewards and associated costs, such as time and (physical) effort. The literature indicates a prominent role for dopamine in discounting of both delay and effort, with mixed findings for delay discounting in humans. Moreover, the reciprocal antagonistic interaction between dopaminergic and cholinergic transmission in the striatum suggests a potential opponent role of acetylcholine in these processes. We found opposing effects of dopamine D2 (haloperidol) and acetylcholine M1 receptor (biperiden) antagonism on specific components of effort-based decision making in healthy humans: haloperidol decreased, whereas biperiden increased the willingness to exert physical effort. In contrast, delay discounting was reduced under haloperidol, but not affected by biperiden. Together, our data suggest that dopamine, acting at D2 receptors, modulates both effort and delay discounting, while acetylcholine, acting at M1 receptors, appears to exert a more specific influence on effort discounting only.
Global functional connectivity of cognitive control network predicts task-switching performance in older adults
Authors: Madero B. , Sodoma M. , Oehler C. , Magnotta V. A. , Long J. D. , Hazeltine E. , Voss M. W. 
Published: November 2023

AbstractExecutive Function (EF) is a complex higher order cognitive process that involves integrating subprocesses of attention, working memory, inhibition, and task switching and known to be one of the first cognitive functions to be affected by age related declines. Global Functional Connectivity (GFC), a measure of whole brain connectivity in brain networks such as the Cognitive Control Network (CCN), has been shown to measure the maintained EF abilities in older adults with cognitive impairment. However, this relationship has not been explored in a sample comprised of mostly cognitively normal older adults nor with the use of an experimental EF task sensitive to sub-processes most sensitive to aging. Task-switch paradigm studies have shown age-related deficits in holding and responding to rule sets while inhibiting another rule set in working memory (i.e., mixing cost). The present study aims to elucidate the relationship seen in EF performance using GFC and leveraging a task-switch paradigm that manipulates response overlap to increase cognitive demands on switching between tasks (e.g., mixing cost). Results show that greater negative DMN GFC coincides with older adults’ lower mixing costs, not CCN GFC. Findings indicate that DMN GFC, not CCN, may be important for EF performance in older adults.
Ammonia inhibits antitumor activity of NK cells by decreasing mature perforin
Authors: Domagala Joanna , Grzywa Tomasz M. , Baranowska Iwona , Kusowska Aleksandra , Fidyt Klaudyna , Marhelava Katsiaryna , Pilch Zofia , Graczyk-Jarzynka Agnieszka , Picard Lea K. , Jastrzebski Kamil , Granica Monika , Justyniarska Magdalena , Urlaub Doris , Bobrowicz Malgorzata , Miaczynska Marta , Watzl Carsten , Winiarska Magdalena 
Published: November 2023

AbstractImmunotherapy revolutionized cancer treatment in the last decade. Natural killer (NK) cells are one of the key host immunity components against malignant cells. Thus, they are currently extensively investigated in the field of immunotherapy of cancer. Different approaches have been developed to improve the antitumor activity of NK cells. Nonetheless, tumor microenvironment remains an obstacle to effective NK cell-based therapies. Here, we demonstrated that a cancer-conditioned medium suppresses the anti-tumor activity of NK cells. Further, we found that ammonia, a by-product of cancer cell metabolism, accumulates in the cancer-conditioned medium and tumor microenvironment. We identified that ammonia impairs the cytotoxicity of NK cells as well as the effectiveness of antibody-based and chimeric antigen receptor (CAR)-NK-based therapiesin vitro. Inhibited activity of NK cells was caused by decreased levels of perforin. This effect was dependent on the lysosomotropic features of ammonia and its ability to increase pH in acidic compartments. In consequence, upon contact with ammonia the mature form of perforin was decreased in NK cells leading to their dysfunction. Our findings demonstrate that in addition to its previously described role of promoting tumor growth as a nitrogen source for tumor biomass ammonia could promote tumor escape as an NK cells immune checkpoint.Graphical abstractHighlightsCancer-conditioned medium suppresses the antitumor activity of NK cellsAmmonia accumulates in conditioned medium and in the tumor microenvironmentImpaired cytotoxicity of NK cells is caused by ammonia that decreases perforin levelsAmmonia causes NK cell dysfunction
Differential expression of core metabolic functions inCandidatusAltiarchaeum inhabiting distinct subsurface ecosystems
Authors: Esser Sarah P. , Turzynski Victoria , Plewka Julia , Moore Carrie J. , Banas Indra , Soares André R. , Lee Janey , Woyke Tanja , Probst Alexander J. 
Published: November 2023

AbstractCandidatusAltiarchaea are widespread across aquatic subsurface ecosystems and possess a highly conserved core genome, yet adaptations of this core genome to different biotic and abiotic factors based on gene expression remain unknown. Here, we investigated the metatranscriptome of twoCa. Altiarchaeum populations that thrive in two substantially different subsurface ecosystems. In Crystal Geyser, a high-CO2groundwater system in the USA,Ca. Altiarchaeum crystalense co-occurs with the symbiontCa. Huberiarchaeum crystalense, while in the Muehlbacher sulfidic spring in Germany, an artesian spring high in sulfide concentration,Ca. A. hamiconexum is heavily infected with viruses. We here mapped metatranscriptome reads against their genomes to analyze thein situexpression profile of their core genomes. Out of 537 shared gene clusters, 331 were functionally annotated and 130 differed significantly in expression between the two sites. Main differences were related to genes involved in cell defense like CRISPR-Cas, virus defense, replication, and transcription as well as energy and carbon metabolism. Our results demonstrate that altiarchaeal populations in the subsurface are likely adapted to their environment while influenced by other biological entities that tamper with their core metabolism. We consequently posit that viruses and symbiotic interactions can be major energy sinks for organisms in the deep biosphere.(Originality-Significance StatementOrganisms of the uncultivated phylumCa. Altiarchaeota are globally widespread and fulfill essential roles in carbon cycling,e.g., carbon fixation in the continental subsurface. Here, we show that the transcriptional activity of organisms in the continental subsurface differ significantly depending on the geological and microbial setting of the ecosystem explaining many of the previously observed physiological traits of this organism group.)
Binary Discriminator Facilitates GPT-based Protein Design
Authors: Zeng Zishuo , Xu Rufang , Guo Jin , Luo Xiaozhou 
Published: November 2023

AbstractGenerative pre-trained transformers (GPT) models provide powerful tools for de novo protein design (DNPD). GPT-based DNPD involves three procedures: a) finetuning the model with proteins of interest; b) generating sequence candidates with the finetuned model; and c) prioritizing the sequence candidates. Existing prioritization strategies heavily rely on sequence identity, undermining the diversity. Here, we coupled a protein GPT model with a custom discriminator, which enables selecting candidates of low identity to natural sequences while highly likely with desired functions. We applied this framework to creating novel antimicrobial peptides (AMPs) and malate dehydrogenases (MDHs). Experimental verification pinpointed four broad-spectrum AMPs from 24 candidates. Comprehensive computational analyses on the prioritized MDHs candidates provide compelling evidence for the anticipated function. During experimental validation, 4/10 and 3/10 natural MDHs and generated-prioritized novel candidates, respectively, were expressed and soluble. All the soluble candidates (3/3) are functional in vitro. This framework is time- and data-efficient and may therefore considerably expedite the DNPD process.
Induction of apoptosis by double-stranded RNA was present in the last common ancestor of cnidarian and bilaterian animals
Authors: Kozlovski Itamar , Jaimes-Becerra Adrian , Sharoni Ton , Lewandowska Magda , Karmi Ola , Moran Yehu 
Published: November 2023

AbstractApoptosis, a major form of programmed cell death, is an essential component of host defense against invading intracellular pathogens. Viruses encode inhibitors of apoptosis to evade host responses during infection, and to support their own replication and survival. Therefore, hosts and their viruses are entangled in a constant evolutionary arms race to control apoptosis. Until now, apoptosis in the context of the antiviral immune system has been almost exclusively studied in vertebrates. This limited phyletic sampling makes it impossible to determine whether a similar mechanism existed in the last common ancestor of animals. Here, we established assays to probe apoptosis in the sea anemoneNematostella vectensis, a model species of Cnidaria, a phylum that diverged approximately 600 million years ago from the rest of animals. We show that polyinosinic:polycytidylic acid (poly I:C), a synthetic long double-stranded RNA mimicking viral RNA and a primary ligand for the vertebrate RLR melanoma differentiation-associated protein 5 (MDA5), is sufficient to induce apoptosis inN. vectensis. Furthermore, at the transcriptomic level, apoptosis related genes are significantly enriched upon poly(I:C) exposure inN. vectensisas well as bilaterian invertebrates. Our phylogenetic analysis of caspase family genes inN. vectensisreveals conservation of all four caspase genes involved in apoptosis in mammals and revealed a cnidarian-specific caspase gene which was strongly upregulated. Altogether, our findings suggest that apoptosis in response to a viral challenge is a functionally conserved mechanism that can be traced back to the last common ancestor of Bilateria and Cnidaria.
Mouse Genome Editing from Scratch
Authors: Popova J.V. , Bets V.D. , Omelina E.S. , Boldyreva L.V. , Kozhevnikova E.N. 
Published: November 2023

ABSTRACTMouse genome modification requires costly equipment and highly skilled personnel to manipulate zygotes. A number of zygote electroporation techniques were reported to be highly efficient in gene delivery. One of these methods called i-GONAD (improved Genome-editing via Oviductal Nucleic Acids Delivery) describes electroporation-based gene transfer to zygotesin utero. Here we adopted this technology for mouse genome-editing from scratch minimizing the cost of equipment, operator skill and animal use. We chose the CRISPR/Cas9 system as a genome editing tool and i-GONAD as a gene delivery method to produceIL10gene knockout in C57BL/6 mice. Four animals out of 13 delivered pups (30.8%) were genetically compromised atIL10gene locus suggesting the feasibility of the approach. This report provides one of the possible technical settings for those who aim at establishing in-house mouse transgenesis pipeline at minimal cost from scratch.For citationPopova J.V., Bets V.D., Omelina E.S., Boldyreva L.V., Kozhevnikova E.N. Mouse Genome Editing from Scratch. Journal of Experimental Biology.Year; issue (number): page. DOI
FORAGING MECHANISMS IN EXCAVATE FLAGELLATES SHED NEW LIGHT ON THE FUNCTIONAL ECOLOGY OF EARLY EUKARYOTES
Authors: Suzuki Sei , Miano Federica , Asadzadeh Seyed Saeed , Simpson Alastair G.B. , Kiørboe Thomas 
Published: November 2023

AbstractThe phagotrophic flagellates described as ‘typical excavates’ have been hypothesized to be morphologically similar to the Last Eukaryotic Common Ancestor and understanding the functional ecology of excavates may therefore help shed light on the ecology of these early eukaryotes. Typical excavates are characterized by a posterior flagellum equipped with a vane that beats in a ventral groove. Here, we combined flow visualization and observations of prey capture in representatives of the three clades of excavates with computational fluid dynamic modelling, to understand the functional significance of this cell architecture. We record substantial differences amongst species in the orientation of the vane and the beat plane of the posterior flagellum. Clearance rate magnitudes estimated from flow visualization and modelling are like that of other similarly sized phagotrophic flagellates. The interaction between a vaned flagellum beating in a confinement is modelled to produce a very efficient feeding current at low energy costs, irrespective of the beat plane and vane orientation and of all other morphological variations. Given this predicted uniformity of function, we suggest that the foraging systems of typical excavates studied here may be good proxies to understand those potentially used by our distant ancestors more than 1 billion years ago.SignificanceHuman sperm reminds us of our ancestry: flagellates, unicellular organisms equipped with a flagellum. The last common eukaryotic ancestor (LECA) was a flagellate. Phylogenetic analyses suggest that Excavates, an assemblage of flagellates, are the living organisms most similar to LECA. They have distinct characteristics in common: a ventral groove within which a vaned flagellum is beating. We show how the shared morphology and foraging behavior among 3 excavate clades is fluid dynamically efficient. A similar flagellar arrangement, potentially homologous to that found in the excavates, is found among flagellates from other deep branches of the eukaryotic tree, suggesting that the typical excavate foraging system studied here may have been used by our distant ancestors more than 1 billion years ago.