bluuebunny/crossref_metadata_2025 huggingface dataset:
Postoperative Transfusions after Administration of Delayed Cold-stored Platelets versus Room Temperature Platelets in Cardiac Surgery: A Retrospective Cohort Study
Authors: Klompas Allan M. , Zec Simon , Hanson Andrew C. , Weister Tim , Stubbs James , Kor Daryl J. , Warner Matthew A.
Published: May 2023

Background

Delayed cold storage of room temperature platelets may extend shelf life from 5 to 14 days. The study hypothesized that the use of delayed cold-stored platelets in cardiac surgery would be associated with decreased postoperative platelet count increments but similar transfusion and clinical outcomes compared to room temperature-stored platelets.

Methods

This is an observational cohort study of adults transfused with platelets intraoperatively during elective cardiac surgery between April 2020 and May 2021. Intraoperative platelets were either room temperature-stored or delayed cold-stored based on blood bank availability rather than clinical features or provider preference. Differences in transfusion and clinical outcomes, including a primary outcome of allogenic transfusion exposure in the first 24 h postoperatively, were compared between groups.

Results

A total of 713 patient encounters were included: 529 (74%) room temperature-stored platelets and 184 (26%) delayed cold-stored platelets. Median (interquartile range) intraoperative platelet volumes were 1 (1 to 2) units in both groups. Patients receiving delayed cold-stored platelets had higher odds of allogeneic transfusion in the first 24 h postoperatively (81 of 184 [44%] vs. 169 of 529 [32%]; adjusted odds ratio, 1.65; 95% CI, 1.13 to 2.39; P = 0.009), including both erythrocytes (65 of 184 [35%] vs. 135 of 529 [26%]; adjusted odds ratio, 1.54; 95% CI, 1.03 to 2.29; P = 0.035) and platelets (48 of 184 [26%] vs. 79 of 529 [15%]; adjusted odds ratio, 1.91; 95% CI, 1.22 to 2.99; P = 0.005). There was no difference in the number of units administered postoperatively among those transfused. Platelet counts were modestly lower in the delayed cold-stored platelet group (−9 × 109/l; 95% CI, −16 to −3]) through the first 3 days postoperatively. There were no significant differences in reoperation for bleeding, postoperative chest tube output, or clinical outcomes.

Conclusions

In adults undergoing cardiac surgery, delayed cold-stored platelets were associated with higher postoperative transfusion utilization and lower platelet counts compared to room temperature-stored platelets without differences in clinical outcomes. The use of delayed cold-stored platelets in this setting may offer a viable alternative when facing critical platelet inventories but is not recommended as a primary transfusion approach.

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Early neurologic complications after liver transplant are associated with reduced long-term survival and increased rates of rejection
Authors: Khalid Mian B. , Nagorna Agnieszka , Rippel Noa , Ezaz Ghideon , Schiano Thomas D. , Crismale James F.
Published: May 2023

Neurologic complications (NCs) are common following liver transplantation (LT) and have been associated with impaired short-term survival. The impact of NC on long-term survival is less defined. We aimed to characterize these outcomes and assess for risk factors for post-LT NC. We performed a single-center, retrospective review of 521 patients with LT from 2016 to 2020. Baseline clinical and laboratory factors, intraoperative events, and outcomes were compared between patients with and without NC. The 5-year overall and rejection-free survival was estimated using the Kaplan-Meier analysis. Multivariable logistic regression assessed for an independent relationship between risk factors and the development of NC. Among 521 LT recipients, 24% experienced post-LT NC. Overall and rejection-free survival at 5 years was, respectively, 69% and 75% among those with NC versus 87% and 88% among those without NC (log-rank < 0.001). Among those who survived the first 3 months after LT, overall survival but not rejection-free survival was reduced among patients with NC. Risk factors for developing NC included peri-LT serum sodium (ΔSNa) ≥ 6 (29.4% vs. 20.5%, p = 0.04), grade 3 or 4 HE pre-LT, SNa < 125 pre-LT, and more intraoperative transfusions. In a multivariable logistic regression model controlling for described variables, SNa < 125 (or 0.21, 95% CI, 0.06–0.74) at LT and pre-LT HE grade 3 or 4 (or 0.45, 95% CI, 0.26–0.76) was independently associated with NC. Long-term survival was reduced among patients who developed NC in the immediate post-transplant period, even when censoring those who died in the first 3 months. Post-LT NC was associated with perioperative ΔSNa ≥ 6. Optimization of SNa pre-LT > 125 and limiting perioperative ΔSNa <6 mEq/L might have a beneficial impact in decreasing NC post-LT, which may improve long-term post-LT survival.
Enhancing Fairness and Accuracy in Diagnosing Type 2 Diabetes in Young Population
Authors: Pias Tanmoy Sarkar , Su Yiqi , Tang Xuxin , Wang Haohui , Faghani Shahriar , Yao Danfeng (Daphne)
Published: May 2023

While type 2 diabetes is predominantly found in the elderly population, recent publications indicate an increasing prevalence in the young adult population. Failing to predict it in the minority younger age group could have significant adverse effects on their health. The previous work acknowledges the bias of machine learning models towards different gender and race groups and proposes various approaches to mitigate it. However, prior work has not proposed any effective methodologies to predict diabetes in the young population which is the minority group in the diabetic population. In this paper, we identify this deficiency in traditional machine learning models and implement double prioritization (DP) bias correction techniques to mitigate the bias towards the young population when predicting diabetes. Deviating from the traditional concept of one-model-fits-all, we train customized machine-learning models for each age group. The DP model consistently improves recall of diabetes class by 26 to 40 in the young age group (30-44). Moreover, the DP technique outperforms 7 commonly used whole-group sampling techniques such as random oversampling, SMOTE, and AdaSyns techniques by at least 36 in terms of diabetes recall in the young age group. We also analyze the feature importance to investigate the source of bias in the original model. Our code is publicly available at an anonymous reposi- tory - https://anonymous.4open.science/r/Diabetes-BRFSS- DP-C847
Tenecteplase 0.4 mg/kg in moderate and severe acute ischemic stroke: A pooled analysis of NOR-TEST & NOR-TEST 2A
Authors: Novotny Vojtech , Kvistad Christopher Elnan , Naess Halvor , Logallo Nicola , Fromm Annette , Khanevski Andrej Netland , Thomassen Lars
Published: May 2023

Background

The optimal dose of tenecteplase in acute ischaemic stroke remains to be defined. We present a pooled analysis of the two NOR-TEST trials exploring the efficacy and safety of tenecteplase 0.4 mg/kg in acute ischemic stroke.

Methods

We retrospectively reviewed two multi-center PROBE trials, NOR-TEST and NOR-TEST 2A, conducted in Norway. The patients were randomized to either 0.4 mg/kg single bolus tenecteplase or standard 0.9 mg/kg alteplase. The primary endpoint was favorable functional outcome at three months (mRS 0-1) or return to baseline if pre-stroke mRS was 2. The secondary endpoints included favorable functional outcome at three months (Modified Rankin Scale 0-2), major neurological improvement and safety data. The pooling project includes a pooled analysis of patients with moderate to severe stroke (NIHSS ≥6) from both trials and an additional post-hoc analysis of patients with mild stroke (NIHSS ≤5) from NOR-TEST.

Results

The per-protocol analysis contains 483 patients, of which 235 were assigned to tenecteplase and 248 to alteplase. In per-protocol analysis, functional outcome was better in the alteplase arm with cut-off mRS 2 (OR 0.52, 95% CI 0.33-0.80, p=0.003) and expressed by ordinal shift analysis (OR 1.64, 95% CI 1.17-2.28, p=0.004). Mortality at 3 months was higher in the tenecteplase arm (OR 2.48, 95% CI 1.20-5.10, p=0.014). Mortality and intracranial hemorrhage rates were higher in the severe stroke group randomized to tenecteplase, whereas these rates were similar for alteplase and tenecteplase in moderate and mild stroke. High age was not associated with either higher mortality or intracranial hemorrhage rates.

Conclusions

Tenecteplase 0.4 mg/kg is unsafe in moderate and severe stroke and the risk of death and intracranial hemorrhage probably increases with stroke severity. A lower tenecteplase dose should be tested in future trials.

Trial Registration

ClinicalTrials.govIdentifiers:NCT01949948,NCT03854500https://clinicaltrials.gov/ct2/show/NCT01949948https://clinicaltrials.gov/ct2/show/NCT03854500
A Series of Composited Tumor DNA Reference Materials Containing Three Genes and Ten Mutation Positions for CNV and SNV Detection
Authors: Fan Weijian , Shi Runyu , Zhang Hongyun , Li Cuicui , Zhang Jiawen , Su Shuixiu , Wu Ping , Tang Meifang
Published: May 2023

Processes in clinic for tumors diagnosis and treatment need reference materials (RMs) to evaluate and calibrate. However, no RMs can provides properties of copy number variation (CNV) and single nucleotide variants (SNV) of genesEGFR, HER2, MET, PIK3CA, KRAS, BRAF, NRASsimultaneously. In this study, we used commercial cell lines to construct a series of tumor RMs containing property mentioned above. Furthermore, we evaluated their stability, homogeneity, and commutability by droplet digital PCR and next generation sequencing technology. The results showed that, for tumor CNV gDNA RM, the copy number is 7.3 copies/μL (EGFR), 5.3 copies/μL (HER2) and 8.2 copies/μL (MET). For tumor 5% SNV gDNA RM, the mutation frequency of each mutation position showed as follow:EGFR-E746A750 (24.6%),EGFR-L858R (5.8%),EGFR-T790M (5.5%),EGFR-G719S (6.6%),PIK3CA-E545K (4.7%),PIK3CA-H1047R (5.8%),KRAS-G13D (8.2%),KRAS-G12D (6.5%),BRAF-V600E (4.6%),NRAS-Q61K (8.5%). All variable coefficient (CV) of tumor gDNA RM for homogeneity were less than 7%, that of CNV+SNV ctDNA RM were less than 17%. Besides, the CV for commutability of the all types of RMs were less than 17%. These RMs can be applied into a wide range type of sequencing panels and provides a closer simple background.
Imperfect gold standard gene sets yield inaccurate evaluation of causal gene identification methods
Authors: Wang Lijia , Wen Xiaoquan , Morrison Jean
Published: May 2023

Causal gene discovery methods are often evaluated using gold-standard (GS) sets of causal genes. However, GS gene sets are always incomplete, leading to mis-estimation of sensitivity, specificity, AUC. Labeling biases in GS gene sets can also lead to inaccurate ordering of discovery methods. We argue that evaluation of these methods should rely on statistical techniques like those used for variant discovery, rather than on comparison with GS gene sets.
Testing a candidate meiotic drive locus identified by pool sequencing
Authors: Barbash Daniel A. , Jin Bozhou , Wei Kevin H-C , Dion-Côté Anne-Marie
Published: May 2023

Meiotic drive biases the transmission of alleles in heterozygous individuals, such that Mendel’s law of equal segregation is violated. Most examples of meiotic drive have been discovered over the past century based on causing sex-ratio distortion or the biased transmission of easily scoreable genetic markers that were linked to drive alleles. More recently, several approaches have been developed that attempt to identify distortions of Mendelian segregation genome-wide. Here we test a candidate female meiotic drive locus inDrosophila melanogaster, identified previously as causing a ∼54:46 distortion ratio using sequencing of large pools of backcross progeny. We inserted fluorescent visible markers near the candidate locus and scored transmission in thousands of individual progeny. We observed a small but significant deviation from the Mendelian expectation, however it was in the opposite direction to that predicted based on the original experiments. We discuss several possible causes of the discrepancy between the two approaches, noting that subtle viability effects are particularly challenging to disentangle from potential small-effect meiotic drive loci. We conclude that pool sequencing approaches remain a powerful method to identify candidate meiotic drive loci, but that genotyping of individual progeny at early developmental stages may be required for robust confirmation.
TDP-43 pathology inDrosophilainduces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1
Authors: Krupp S. , Tam O , Gale Hammell M , Dubnau J
Published: May 2023

Accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43) is seen in both neurons and glia in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Disease progression involves non-cell autonomous interactions among multiple cell types, including neurons, microglia and astrocytes. We investigated the effects inDrosophilaof inducible, glial cell type-specific TDP-43 overexpression, a model that causes TDP-43 protein pathology including loss of nuclear TDP-43 and accumulation of cytoplasmic inclusions. We report that TDP-43 pathology inDrosophilais sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown ofSF2/SRSF1in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan andSF2/SRSF1knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism.
Chaotic neural dynamics facilitate probabilistic computations through sampling
Authors: Terada Yu , Toyoizumi Taro
Published: May 2023

Cortical neurons exhibit highly variable responses over trials and time. Theoretical works posit that this variability arises potentially from chaotic network dynamics of recurrently connected neurons. Here we demonstrate that chaotic neural dynamics, formed through synaptic learning, allow networks to perform sensory cue integration in a sampling-based implementation. We show that the emergent chaotic dynamics provide neural substrates for generating samples not only of a static variable but also of a dynamical trajectory, where generic recurrent networks acquire these abilities with a biologically-plausible learning rule through trial and error. Furthermore, the networks generalize their experience in the stimulus-evoked samples to the inference without partial or all sensory information, which suggests a computational role of spontaneous activity as a representation of the priors as well as a tractable biological computation for marginal distributions. These findings suggest that chaotic neural dynamics may serve for the brain function as a Bayesian generative model.
Identification of Pain-Associated Effusion-Synovitis from Knee Magnetic Resonance Imaging by Deep Generative Networks
Authors: Lian Pin-Hsun. , Chuang Tzu-Yi , Yen Yi-Hsuan , Chang Gary Han
Published: May 2023

Objectives

To identify the source and location of osteoarthritis-induced pain symptoms, we used deep learning techniques to identify imaging abnormalities associated with pain from magnetic resonance imaging (MRI) of knees with symptoms of symptoms of osteoarthritis pain.

Methods

Pain-associated areas were detected from the difference between the MRI images of symptomatic knees and their respective counterfactual asymptomatic images generated by a Generative adversarial network. A total of 2,225 pairs of 3D MRI images were extracted from patients with unilateral pain symptoms in the baseline and follow-up cohorts of the Osteoarthritis Initiative. Subsequently, pain-associated effusion-synovitis were characterized into subregions (patellar, central, and posterior) using an anatomical segmentation model.

Results

We found that the volumes of pain-associated effusion-synovitis were more sensitive and reliable indicators of pain symptoms than the overall volumes in the central and posterior subregions (odds ratio [OR]:3.23 versus 1.77 in the central region, and 3.18 versus 2.66 in the posterior region for severe effusion-synovitis). For mild effusion-synovitis, only pain-associated volume was found to be associated with pain symptoms, but not with overall volume. Patients with significant pain-associated effusion-synovitis in the patellar subregion had the highest increased odds of pain symptoms (OR=4.86).

Conclusion

To the best of our knowledge, this is the first study to utilize deep-learning-based models for the detection and characterization of pain-associated imaging abnormalities. The developed algorithm can help identifying the source and location of pain symptoms and in designing targeted and individualized treatment regimens.
When population growth intensifies intergroup competition, female colobus monkeys free-ride less
Authors: Arseneau-Robar T. Jean , Teichroeb Julie A. , Macintosh Andrew J. , Saj Tania L. , Glotfelty Emily , Lucci Sarah , Sicotte Pascale , Wikberg Eva C.
Published: May 2023

In many social species, intergroup aggression is a cooperative activity that produces public goods such as a safe and stable social environment and a home range containing the resources required to survive and reproduce. In this study, we investigate temporal variation in intergroup aggression in a growing population of colobus monkeys to ask a novel question: “Who stepped-up to produce these public goods when the competitive landscape changed?”. Both whole-group encounters and male incursions occurred more frequently as the population grew. Males and females were both more likely to participate in whole-group encounters when monopolizable food resources were available, indicating both sexes engaged in food defence. However, only females increasingly did so over time, suggesting that when intergroup competition intensified, it was females who increasingly invested in home range defence. Females were also more active in male incursions at high population densities, suggesting they also worked harder to maintain a safe and stable social environment over time. This is not to say that males were chronic free-riders when it came to maintaining public goods. Males consistently participated in the majority of intergroup interactions throughout the study period, indicating they may have lacked the capacity to invest more time and effort.
A Chemical Reaction Similarity-Based Prediction Algorithm Identifies the Multiple Taxa Required to Catalyze an Entire Metabolic Pathway of Dietary Flavonoids
Authors: Gulsan Ebru Ece , Nowshad Farrhin , Yamaguchi Pomaikaimaikalani , Dong Xiaokun , Jayaraman Arul , Lee Kyongbum
Published: May 2023

Flavonoids are polyphenolic phytochemicals abundant in plant-based, health-promoting foods. They are only partially absorbed in the small intestine, and gut microbiota plays a significant role in their metabolism. As flavonoids are not natural substrates of gut bacterial enzymes, reactions of flavonoid metabolism have been attributed to the ability of general classes of enzymes to metabolize non-natural substrates. To systematically characterize this promiscuous enzyme activity, we developed a prediction tool that is based on chemical reaction similarity. The tool takes a list of enzymes or organisms to match microbial enzymes with their non-native flavonoid substrates and orphan reactions. We successfully predicted the promiscuous activity of known flavonoid-metabolizing bacterial and plant enzymes.

Next, we used this tool to identify the multiple taxa required to catalyze an entire metabolic pathway of dietary flavonoids. Tilianin is a flavonoid-O-glycoside having biological and pharmacological activities, including neuroprotection. Using our prediction tool, we defined a novel bacterial pathway of tilianin metabolism that includes O-deglycosylation to acacetin, demethylation of acacetin to apigenin, and hydrogenation of apigenin to naringenin. We predicted and confirmed using in vitro experiments and LC-MS techniques that Bifidobacterium longum subsp.animalis,Blautia coccoidesandFlavonifractor plautiican catalyze this pathway. Prospectively, the prediction-validation methodology developed in this work could be used to systematically characterize gut microbial metabolism of dietary flavonoids and other phytochemicals.

The bioactivities of flavonoids and their metabolic products can vary widely. We used an in vitro rat neuronal model to show that tilianin metabolites exhibit protective effect against H2O2through reactive oxygen species (Delepine et al.) scavenging activity and thus, improve cell viability, while the parent compound, tilianin, was ineffective. These results are important to understand the gut microbiota-dependent physiological effects of dietary flavonoids.
Energy landscapes and heat capacity signatures for peptides correlate with phase separation propensity
Authors: Nicy  , Joseph Jerelle A , Collepardo-Guevara Rosana , Wales David J.
Published: May 2023

Phase separation plays an important role in the formation of membraneless compartments within the cell, and intrinsically disordered proteins with low-complexity sequences can drive this compartmentalisation. Various intermolecular forces, such as aromatic–aromatic and cation–aromatic interactions, promote phase separation. However, little is known about how the ability of proteins to phase separate under physiological conditions is encoded in their energy landscapes, and this is the focus of the present investigation. Our results provide a first glimpse into how the energy landscapes of minimal peptides that containπ–πand cation–πinteractions differ from the peptides that lack amino acids with such interactions. The peaks in the heat capacity (CV) as a function of temperature report on alternative low-lying conformations that differ significantly in terms of their enthalpic and entropic contributions. The CVanalysis and subsequent quantification of frustration of the energy landscape suggest that the interactions that promote phase separation leads to features (peaks or inflection points) at low temperatures in CV, more features may occur for peptides containing residues with better phase separation propensity and the energy landscape is more frustrated for such peptides. Overall, this work links the features in the underlying single-molecule potential energy landscapes to their collective phase separation behaviour, and identifies quantities (CVand frustration metric) that can be utilised in soft material design.
PROTEOMICS OF HYPOTHERMIC ADAPTATION REVEALS THAT RBM3 ENHANCES MITOCHONDRIAL METABOLISM AND MUSCLE STEM-CELL DIFFERENTIATION
Authors: Dey Paulami , Rajalaxmi Srujanika , Thakur Purvi Singh , Hashmi Maroof Athar , Lal Heera , Saini Nistha , Muralidharan Sneha , Math Raviswamy G H , Saha Pushpita , Pundlik Swarang Sachin , Singh Nirpendra , Ramanathan Arvind
Published: May 2023

Adaptation to hypothermic stress is important for skeletal muscle cells, but a comprehensive knowledge of molecular mediators is lacking. We show that adaptation to mild hypothermia (320C) improves the ability of skeletal muscle myoblasts to differentiate into myotubesin vitro. We performed proteomic analysis of mouse myoblasts exposed to mild hypothermia for various time points and identified dynamic changes in mitochondrial metabolism and proteostasis. This revealed that RBM3, an RNA-binding protein, increases progressively with acute and chronic exposure to hypothermic stress, and is necessary for the enhanced differentiation upon hypothermic adaptation. We also demonstrate that overexpression of RBM3 at physiological temperatures is sufficient to (i) enhance mitochondrial metabolism as judged by a decrease in the AMPK energy-sensing pathway, (ii) increase levels of proteins associated with translation and increase levels of 4E-BP1 phosphorylation, (iii) increase stem cell markers (MyoD1, PAX7), and improve differentiation of myoblasts from both young and aged mice.
OneNet – One network to rule them all: consensus network inference from microbiome data
Authors: Champion Camille , Momal Raphaelle , Chatelier Emmanuelle Le , Sola Mathilde , Mariadassou Mahendra , Berland Magali
Published: May 2023

Modeling microbial interactions as sparse and reproducible networks is a major challenge in microbial ecology. Direct interactions between the microbial species of a biome can help to understand the mechanisms through which microbial communities influence the system. Most state-of-the art methods reconstruct networks from abundance data using Gaussian Graphical Models, for which several statistically grounded and computationnally efficient inference approaches are available. However, the multiplicity of existing methods, when applied to the same dataset, generates very different networks. In this article, we present OneNet, a consensus network inference method that combines seven methods based on stability selection. This resampling procedure is used to tune a regularization parameter by computing how often edges are selected in the networks. We modified the stability selection framework to use edge selection frequencies directly and combine them in the inferred network to ensure that only reproducible edges are included in the consensus. We demonstrated on synthetic data that our method generally led to slightly sparser networks while achieving much higher precision than any single method. We further applied the method to gut microbiome data from liver-cirrothic patients and demonstrated that the resulting network exhibited a microbial guild that was meaningful in terms of human health.
Context transcription factors establish cooperative environments and mediate enhancer communication
Authors: Kribelbauer Judith F. , Pushkarev Olga , Gardeux Vincent , Russeil Julie , van Mierlo Guido , Deplancke Bart
Published: May 2023

Many enhancers play a crucial role in regulating gene expression by assembling regulatory factor (RF) clusters, also referred to as condensates. This process is essential for facilitating enhancer communication and establishing cellular identity. However, how DNA sequence and transcription factor (TF) binding instruct the formation of such high RF environments is still poorly understood. To address this, we developed a novel approach leveraging enhancer-centric chromatin accessibility quantitative trait loci (caQTLs) to nominate RF clusters genome-wide. By analyzing TF binding signatures within the context of caQTLs, we discovered a new class of TFs that specifically contributes to establishing cooperative environments. These “context-only” TFs bind promiscuously with cell type-specific pioneers, recruit coactivators, and, like super enhancers, render downstream gene expression sensitive to condensate-disrupting molecules. We further demonstrate that joint context-only and pioneer TF binding explains enhancer compatibility and provides a mechanistic rationale for how a loose TF syntax can still confer regulatory specificity.
A novel bacterial signal transduction system specifically senses and responds to peptidoglycan damage
Authors: Yin Jianhua , Xu Chaoyi , Hu Xiao , Zhang Ting , Liang Yanqun , Sun Yijuan , Zhen Xiangkai , Zhu Yiling , Luo Yuke , Shen Penshan , Cheng Dan , Sun Yiyang , Cai Jingxiao , Meng Qiu , Zhu Tingheng , Wan Fen , Gao Haichun , Yu Zhiliang
Published: May 2023

The peptidoglycan (PG) layer is a mesh-like structure within the cell envelope essential for maintenance of cell shape and resistance to osmotic stress, and therefore is a primary target of many important and widely used antibiotics, such as β-lactams. In Gram-negative bacteria, while signal transduction systems that monitor the state of the inner- and outer-membranes have been extensively studied and well understood, much less is known about how cells sense and respond to PG-targeting stresses. Here we show that a novel bacterial two-component system (PghKR) fromShewanella oneidensisis capable of sensing and responding to PG damage. This system is specifically activated in cells exposed to various PG-targeting antibiotics or carrying a defect in PG synthesis, resulting in induced expression ofblaAandrelV, which encode a β-lactamase conferring resistance to β-lactams and a small ppGpp synthetase responsible for antibiotic tolerance, respectively. Intriguingly, the PghKR homologs are widespread among several classes ofProteobacteriaand the periplasmic domain of sensor kinase PghK contains a family 9 carbohydrate-binding module that is required for signal perception, implying that the signals could be the glycan fragments of PG. Overall, our results provide critical insights into the regulation of PG homeostasis in Gram-negative bacteria.
Dysfunctional effector memory CD8 T cells in the bronchoalveolar compartment of people living with HIV
Authors: Mthembu Maphe , Claassen Helgard , Khuzwayo Sharon , Voillet Valentin , Naidoo Anneta , Nyamande Kennedy , Khan Dilshaad F. , Maharaj Priya , Mitha Mohammed , Mhlane Zoey , Karim Farina , Andersen-Nissen Erica , Ndung’u Thumbi , Pollara Gabriele , Wong Emily B.
Published: May 2023

Mechanisms by which HIV causes susceptibility to respiratory pathogens remain incompletely understood. We obtained whole blood and bronchoalveolar lavage (BAL) from people with latent TB infection in the presence or absence of antiretroviral-naïve HIV co-infection. Transcriptomic and flow cytometric analyses demonstrated HIV-associated cell proliferation plus type I interferon activity in blood and effector memory CD8 T-cells in BAL. Both compartments displayed reduced induction of CD8 T-cell-derived IL-17A in people with HIV, associated with elevated T-cell regulatory molecule expression. The data suggest that dysfunctional CD8 T-cell responses in uncontrolled HIV contribute to susceptibility to secondary bacterial infections, including tuberculosis.
Connectome-based prediction of functional impairment in experimental stroke models
Authors: Schmitt Oliver , Eipert Peter , Wang Yonggang , Kanoke Atsushi , Rabiller Gratianne , Liu Jialing
Published: May 2023

Experimental rat models of stroke and hemorrhage are important tools to investigate cerebrovascular disease pathophysi- ology mechanisms, yet how significant patterns of functional impairment induced in various models of stroke are related to changes in connectivity at the level of neuronal populations and mesoscopic parcellations of rat brains remain unresolved. To address this gap in knowledge, we employed two middle cerebral artery occlusion models and one intracerebral hemorrhage model with variant extent and location of neuronal dysfunction. Motor and spatial memory function was assessed and the level of hippocampal activation via Fos immunohistochemistry. Contribution of connectivity change to functional impairment was analyzed for connection similarities, graph distances and spatial distances as well as the importance of regions in terms of network architecture based on theneuroVIISASrat connectome. We found that functional impairment correlated with not only the extent but also the locations of the injury among the models. In addition, via coactivation analysis in dynamic rat brain models, we found that lesioned regions led to stronger coactivations with motor function and spatial learning regions than with other unaffected regions of the connectome. Dynamic modeling with the weighted bilateral connectome detected changes in signal propagation in the remote hippocampus in all 3 stroke types, predicting the extent of hippocampal hypoactivation and impairment in spatial learning and memory function. Our study provides a comprehensive analytical framework in predictive identification of remote regions not directly altered by stroke events and their functional implication.
SKOOTS: Skeleton oriented object segmentation for mitochondria
Authors: Buswinka Christopher J , Nitta Hidetomi , Osgood Richard T. , Indzhykulian Artur A.
Published: May 2023

The segmentation of individual instances of mitochondria from imaging datasets is informative, yet time-consuming to do by hand, sparking interest in developing automated algorithms using deep neural networks. Existing solutions for various segmentation tasks are largely optimized for one of two types of biomedical imaging: high resolution three-dimensional (whole neuron segmentation in volumetric electron microscopy datasets) or two-dimensional low resolution (whole cell segmentation of light microscopy images). The former requires consistently predictable boundaries to segment large structures, while the latter is boundary invariant but struggles with segmentation of large 3D objects without downscaling. Mitochondria in whole cell 3D EM datasets often occupy the challenging middle ground: large with ambiguous borders, limiting accuracy with existing tools. To rectify this, we have developedskeletonorientedobject segmentation (SKOOTS); a new segmentation approach which efficiently handles large, densely packed mitochondria. We show that SKOOTS can accurately, and efficiently, segment 3D mitochondria in previously difficult situations. Furthermore, we will release a new, manually annotated, 3D mitochondria segmentation dataset. Finally, we show this approach can be extended to segment objects in 3D light microscopy datasets. These results bridge the gap between existing segmentation approaches and increases the accessibility for three-dimensional biomedical image analysis.
JNplots: an R package to visualize outputs from the Johnson-Neyman technique for categorical and continuous moderators, including options for phylogenetic regressions
Authors: Toyama Ken S.
Published: May 2023

The analysis of two-way interactions in linear models is common in the fields of ecology and evolution, being often present in allometric, macroevolutionary, and experimental studies, among others. However, the interpretation of significant interactions can be incomplete when limited to the examination of model coefficients and significance tests. The Johnson-Neyman technique represents a step forward in the interpretation of significant two-way interactions, allowing the user to examine how changes in the moderator variable, it being categorical or continuous, affect the significance of the relationship between the dependent variable and the predictor. Despite its implementation in several software since its initial development, the available options to perform the method lack certain functionality aspects, including the visualization of regions of non-significance when the moderator is categorical, the implementation of phylogenetic corrections, and more intuitive graphical outputs. Here I present the R packageJNplots, which aims to fill gaps left by previous software regarding the calculation and visualization of regions of non-significance when fitting two-way interaction models.JNplotsincludes two basic functions which allow the user to investigate different types of interaction models, including cases where the moderator variable is categorical or continuous. The user can also specify whether the model to explore should be phylogenetically informed and choose a particular phylogenetic correlation structure to be used. Finally, the functions ofJNplotsproduce plots that are largely customizable and allow a more intuitive interpretation of the interaction term. Here I provide a walkthrough on the use ofJNplotsusing three different examples based on empirical data, each representing a different common scenario in which the package can be useful. Additionally, I present the different customization options for the graphical outputs ofJNplots.
Elevated HIV viral load is associated with higher recombination ratein vivo
Authors: Romero Elena V. , Feder Alison F.
Published: May 2023

HIV’s exceptionally high recombination rate drives its intra-host diversification, enabling immune escape and multi-drug resistance within people living with HIV. While we know that HIV’s recombination rate varies by genomic position, we have little understanding of how recombination varies throughout infection or between individuals as a function of the rate of cellular coinfection. We hypothesize that denser intra-host populations may have higher rates of coinfection and therefore recombination. To test this hypothesis, we develop a new approach (Recombination Analysis via Time Series Linkage Decay, or RATS-LD) to quantify recombination using autocorrelation of linkage between mutations across time points. We validate RATS-LD on simulated data under short read sequencing conditions and then apply it to longitudinal, high-throughput intra-host viral sequencing data, stratifying populations by viral load (a proxy for density). Among sampled viral populations with the lowest viral loads (< 26,800 copies/mL), we estimate a recombination rate of 1.5×10−5events/bp/generation (95% CI: 7×10−6−2.9×10−5), similar to existing estimates. However, among samples with the highest viral loads (> 82,000 copies/mL), our median estimate is approximately 6 times higher. In addition to co-varying across individuals, we also find that recombination rate and viral load are associated within single individuals across different time points. Our findings suggest that rather than acting as a constant, uniform force, recombination can vary dynamically and drastically across intra-host viral populations and within them over time. More broadly, we hypothesize that this phenomenon may affect other facultatively asexual populations where spatial co-localization varies.
Lexical semantic content, not syntactic structure, is the main contributor to ANN-brain similarity of fMRI responses in the language network
Authors: Kauf Carina , Tuckute Greta , Levy Roger , Andreas Jacob , Fedorenko Evelina
Published: May 2023

Representations from artificial neural network (ANN) language models have been shown to predict human brain activity in the language network. To understand what aspects of linguistic stimuli contribute to ANN-to-brain similarity, we used an fMRI dataset of responses to n=627 naturalistic English sentences (Pereira et al., 2018) and systematically manipulated the stimuli for which ANN representations were extracted. In particular, we i) perturbed sentences’ word order, ii) removed different subsets of words, or iii) replaced sentences with other sentences of varying semantic similarity. We found that the lexical semantic content of the sentence (largely carried by content words) rather than the sentence’s syntactic form (conveyed via word order or function words) is primarily responsible for the ANN-to-brain similarity. In follow-up analyses, we found that perturbation manipulations that adversely affect brain predictivity also lead to more divergent representations in the ANN’s embedding space and decrease the ANN’s ability to predict upcoming tokens in those stimuli. Further, results are robust to whether the mapping model is trained on intact or perturbed stimuli, and whether the ANN sentence representations are conditioned on the same linguistic context that humans saw. The critical result—that lexical- semantic content is the main contributor to the similarity between ANN representations and neural ones—aligns with the idea that the goal of the human language system is to extract meaning from linguistic strings. Finally, this work highlights the strength of systematic experimental manipulations for evaluating how close we are to accurate and generalizable models of the human language network.
Calcium-triggered DNA-mediated membrane fusion in synthetic cells
Authors: Hsu Yen-Yu , Samuel J. Chen , Bernal-Chanchavac Julio , Sharma Bineet , Moghimianavval Hossein , Stephanopoulos Nicholas , Liu Allen P.
Published: May 2023

In cells, membrane fusion is mediated by SNARE proteins, whose activities are calcium-dependent. While several non-native membrane fusion mechanisms have been demonstrated, few can respond to external stimuli. Here, we develop a calcium-triggered DNA-mediated membrane fusion strategy where fusion is regulated using surface-bound PEG chains that are cleavable by the calcium-activated protease calpain-1.
Low circulating choline, a modifiable dietary factor, is associated with the pathological progression and metabolome dysfunction in Alzheimer’s disease
Authors: Judd Jessica M. , Jasbi Paniz , Winslow Wendy , Serrano Geidy E. , Beach Thomas G. , Klein-Seetharaman Judith , Velazquez Ramon
Published: May 2023

Most Americans (∼90%) are deficient in dietary choline, an essential nutrient. Associations between circulating choline and pathological progression in Alzheimer’s disease (AD) remain unknown. Here, we examined these associations and performed a metabolomic analysis in blood serum from severe AD, moderate AD, and healthy controls. Additionally, to gain mechanistic insight, we assessed the effects of dietary choline deficiency (Ch-) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice. In humans, we found AD-associated reductions in choline, it’s derivative acetylcholine (ACh), and elevated pro-inflammatory cytokine TNFα. Choline and ACh were negatively correlated with Plaque density, Braak stage, and TNFα, but positively correlated with MMSE and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were associated with choline levels. In mice, Ch-paralleled AD severe, but Ch+ was protective. In conclusion, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of dietary choline consumption to offset disease.
Evolution in response to an abiotic stress shapes species coexistence
Authors: Fragata Inês , Godinho Diogo P. , Rodrigues Leonor R. , Cruz Miguel A. , Zélé Flore , Godoy Oscar , Magalhães Sara
Published: May 2023

Adaptation to abiotic stresses is pervasive and generally relies on traits that are not independent from those affecting species interactions. Still, how such evolution affects species coexistence remains elusive. We addressed this using populations of two herbivorous spider mite species (Tetranychus urticaeandT. evansi) evolving separately on tomato plants hyper-accumulating cadmium, a stressful environment for the mites, or on control plants with no-cadmium. Combinations of phenotypic analyses with structural stability theory predicted that adaptation of both species to cadmium allow them to coexist in that environment, whereas for cadmium-naïve mite populations the most likely outcome is competitive exclusion. The shift from exclusion to coexistence was due to an increase in structural niche differences caused by a simultaneous increase in intra and a decrease in interspecific competition. However, adaptation to cadmium did not affect species interactions and competitive outcomes in the cadmium-free environment, indicating that such evolutionary changes were environment-specific. Experimental outcomes of population dynamics with populations of the two species from each selection regime in each environment were fully compatible with model predictions. Therefore, evolution of single species in a new environment, even in absence of interspecific competitors, shapes species coexistence. Hence, population shifts to novel environments may have unforeseen evolutionary consequences for community composition and the maintenance of species diversity.

Significance Statement

The evolutionary consequences of strong selective pressures imposed by environmental changes on species interactions and their subsequent coexistence remain largely unknown. To fill this knowledge gap, we combined the power of experimental evolution and structural stability to analyze how evolution of two spider mite species on plants with or without cadmium affected their ability to coexist. We found that evolution in the high cadmium environment led to changes in growth rates, but also in the strength of intra-and interspecific competition, such that coexistence became possible, but only when the two species evolved in the new environment. Our study highlights that evolution under high pollutant concentrations, even in the absence of competitors, can shape long-term coexistence between species.
The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta-analysis
Authors: Almulla Abbas F. , Thipakorn Yanin , Tunvirachaisakul Chavit , Maes Michael
Published: May 2023

Background

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. In ASD, studies show activated immune-inflammatory and nitro-oxidative pathways which are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acids (CAAs) and activation of the TRP catabolite (TRYCAT) pathway.

Objectives

This study aims to systematically review and meta-analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in blood and urine of ASD patients.

Methods

After searching PubMed, Google Scholar, and SciFinder extensively, a total of 25 full-text papers were included in the analysis, with a total of 6653 participants (3,557 people with ASD and 30,96 healthy controls).

Results

Blood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD= −0.227, 95% confidence interval, CI: −0.540; 0.085 and SMD= 0.158, 95%CI: −0.042; 0.359) respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD= 0.001, 95%CI: −0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD.

Conclusions

Our study demonstrates that there are no abnormalities in peripheral blood TRP metabolism, IDO activity, and TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASD’s pathophysiology.