bluuebunny/crossref_metadata_2025 huggingface dataset:
UniGEN-DDI: Computing drug-drug interactions using a unified graph embedding network
Authors: Mondal Somnath , Datta Debarghya , Pramanik Soumajit , Mehra Rukmankesh
Published: October 2024

Finding drug-drug interaction is crucial for patient safety and treatment efficacy. Two drugs may show a synergistic effect but may sometimes cause a severe health issue, including lethality. Wet lab studies are often performed to understand such interactions but are limited by cost and time. However, the biochemical data generated can be explored to compute unknown interactions. Here, we developed a computational model named UniGEN-DDI (UnifiedGraphEmbeddingNetwork forDrug-Drug Interaction) for the estimation of interactions between drugs. It is a simple unified network model containing the biochemical information of drug association developed using the compiled data from DrugBank 5.1.0. The feature learning of the drugs was carried out using a combination of GraphSAGE and Node2Vec algorithms, which were found efficient in extracting diverse features. The simple architecture of our model led to a significant reduction in computational time compared to the baselines, while maintaining a high prediction accuracy. The model performed well on the data, which was equally distributed between interacting and non-interacting drugs. As a more challenging evaluation, we performed non-overlapping splitting of the data based on the drug action on different parts of the body, and our model performed well in both interaction estimation and time efficiency. Our model successfully identified the 12 unknown drug interactions in DrugBank 5.1.0, which were updated in DrugBank 6.0.

Highlights

UniGEN-DDI: A simple unified network model was developed for drug-drug interactions.

Node embeddings were generated using GraphSAGE and Node2Vec algorithms.

A significantly higher computational efficiency was achieved compared to baselines.

Model validated in non-overlapping splitting of data targetting multiple body parts.

UniGEN-DDI estimated unknown interactions verified in the updated DrugBank 6.0.

Graphical abstract
Distinct expression profile reveals glia involvement in the trigeminal system attributing to post-traumatic headache
Authors: Nagarajan Gurueswar , Zhang Yumin
Published: October 2024

Post-traumatic headache (PTH) is a common comorbid symptom affecting at least one-third of patients with mild traumatic brain injury (mTBI). While neuroinflammation is known to contribute to the development of PTH, the cellular mechanisms in the trigeminal system crucial for understanding the pathogenesis of PTH remain unclear. Male mice underwent a non-invasive repetitive mTBI protocol (4 impacts, 24-hour intervals) targeting either the bregma or pre-bregma region of the head. Periorbital allodynia and spontaneous pain behavior were assessed using von Frey tests and grimace scores, respectively. Quantitative PCR was used to evaluate the extent of mTBI-induced pathology in several brain regions. RNA sequencing was performed to obtain transcriptomic profile of the trigeminal ganglion (TG), trigeminal nucleus caudalis (Sp5C) and periaqueductal gray (PAG) at 7 days post-TBI. Subsequently, quantitative PCR, in situ hybridization and immunohistochemistry were used to examine mRNA and protein expression of glia specific markers and pain associated molecules. The repetitive impacts at the bregma, but not pre-bregma site led to periorbital hypersensitivity, which was correlated with enhanced inflammatory gene expression in multiple brain regions. RNA sequencing identified distinct transcriptomic profiles in the peripheral TG, central Sp5C and PAG following mTBI. Using gene set enrichment analysis, positive enrichment of non-neuronal cells in the TG and neuroinflammation in the Sp5C were identified to be essential in the pathogenesis of PTH. In situ assays also revealed that gliosis of satellite glial cells in the TG and astrocytes in the Sp5C were prominent days after injury. Furthermore, immunohistochemical study revealed a close interaction between activated microglia and reactive astrocytes correlating with increased calretinin interneurons in the Sp5C. Transcriptomics analysis indicated that non-neuronal cells in peripheral TG and successive in situ assays revealed that glia in the central Sp5C are crucial in modulating headache-like symptoms. Thus, selective targeting of glia cells can be a therapeutic strategy for PTH attributed to repetitive mTBI.
Neuronally differentiated endothelial cell subtype regulates organ blood flow and immune balance
Authors: Gyarmati Georgina , Rust Ruslan , Calderon Alejandra Becerra , Izuhara Audrey , Trogen Greta , Deepak Sachin , Chen Yibu , Ruffins Seth Walter , Junge Jason A. , Zlokovic Berislav V. , Fraser Scott , Peti-Peterdi János
Published: October 2024

Vascular endothelial cells (ECs) perform key pleiotropic functions to maintain body homeostasis via the regulation of organ blood flow, vascular permeability, tissue growth and inflammation, and angiogenesis. Recent transcriptomic studies uncovered many EC subtypes across organs; however their specific functions are incompletely understood. Here we identified and characterized a novel, minority subtype of scattered ECs with a well-defined arteriovenous zonal localization exclusively in small resistance (strain) arterioles, and with the highest density in the brain>retina>kidney. Due to their expression of both endothelial and neuron-like functional and gene transcriptomic signatures, they were termed neuro-endothelial cells (NECs). High resolution single-cell transcriptome analysis of mouse brain and kidney ECs identified neuronal nitric oxide synthase (Nos1) and cytokine-like 1 (Cytl1) as top NEC biomarkers. Intravital multiphoton imaging of optogenetic mouse models with NEC gain/loss-of-function revealed NEC and Nos1-dependent vasodilation/vasoconstriction of intact brain and kidney arterioles and elevation/reduction in blood flow. Silencing NEC Nos1 and Cytl1 gene expression in vivo caused marked segmental arteriolar vasoconstrictions, reductions in vascular density and organ blood flow, increased vascular permeability and immune cell homing. Cytl1 administration triggered vasodilation and increased blood flow acutely, and increased capillary density and clonal EC remodeling chronically. NECs play major vasodilatory, angiogenic and anti-inflammatory functions that may be therapeutically targeted for vascular and inflammatory diseases.
Methylomes reveal recent evolutionary changes in populations of two plant species
Authors: Korfmann Kevin , Zauchner Andreas , Huo Bing , Grünke Corinna , Wang Yitong , Tellier Aurélien , Arunkumar Ramesh
Published: October 2024

Plant DNA methylation changes occur hundreds to thousands of times faster than DNA mutations and can be transmitted transgenerationally, making them useful for studying population-scale patterns in clonal or selfing species. However, a state-of-the-art approach to use them for inferring population genetic processes and demographic histories is lacking. To address this, we compare evolutionary signatures extracted from CG methylomes and genomes inArabidopsis thalianaandBrachypodium distachyon. While methylation variants (SMPs) are less effective than single nucleotide polymorphisms (SNPs) for identifying population differentiation inA. thaliana, they can classify phenotypically divergentB. distachyonsubgroups that are otherwise genetically indistinguishable. The site frequency spectra generated using methylation sites from varied genomic locations and evolutionary conservation exhibit an excess of rare alleles. Nucleotide diversity estimates were three orders of magnitude higher for methylation variants than for SNPs in both species, driven by the higher epimutation rate. Correlations between SNPs and SMPs in nucleotide diversity and allele frequencies at gene exons are weak or absent inA. thaliana, possibly because the two sources of variation reflect evolutionary forces acting at different timescales. Linkage disequilibrium quickly decays within 100 bp for methylation variants in both plant species. Finally, we developed a deep learning-based demographic inference approach. We identified recent population expansions inA. thalianaandB. distachyonusing methylation variants that were not identified when using SNPs. Our study demonstrates the unique evolutionary insights methylomes provide that SNPs alone cannot reveal.
Better confidence intervals in simulation-based inference of historical demography from population genetic data
Authors: Rousset François , Leblois Raphaël , Estoup Arnaud , Marin Jean-Michel
Published: October 2024

We describe and evaluate a method of statistical inference of model parameters, which revisits the idea of inferring a likelihood surface using simulation when the likelihood function cannot be evaluated. The method aims in particular to provide confidence intervals with controlled coverage, and its performance is assessed accordingly. It is based on a combining the random forest machine learning method, and multivariate Gaussian mixture (MGM) models, in an effective inference workflow, here used to fit models with up to 15 variable parameters. Masked autoregressive flows, a deep learning technique, is also tested as an alternative to MGM models. The method is compared to that of approximate Bayesian computation (ABC) with random forests, with which it shares some technical features, on scenarios of inference of historical demography from population genetic data. These comparisons highlight the importance of an iterative workflow for exploring the parameter space efficiently. For equivalent simulation effort of the data-generating process, the new summary-likelihood method provides better control of coverage than ABC with random forests, and than generally reported for ABC methods.
Neuronal loss ofGalnt2Impairs O-glycosylation and Leads to Neurobehavioral Deficits Mimicking GALNT2-CDG
Authors: Edmondson Andrew C. , Yu Melody , Villarosa Alvin , Shiplett Emily J. , Schjoldager Katrine T. , Zhou Zhaolan
Published: October 2024

GALNT2-CDG is a multi-system genetic disorder due to biallelic pathogenic mutations inGALNT2, which encodes a ubiquitously expressed Golgi-localized glycosyltransferase that initiates mucin-type O-glycosylation. Affected individuals exhibit dysmorphic facial features, short stature, decreased HDL-C, and notable impairments in brain function. GALNT2-CDG patients show global developmental delay without speech development, childhood epilepsy, autistic-like features, and white-matter brain abnormalities. The extent of O-glycosylation in brain development and function remains poorly understood. To address this question, we selectively ablatedGalnt2from pan-neuronal cells in the brain and found that conditional knockout mice exhibit deficits across numerous behavioral domains, including locomotion, motor coordination, sociability, learning, and memory, as well as experience spontaneous seizures, recapitulating characteristic neurological manifestations of GALNT2-CDG. Given the catalytic activity of GALNT2 to initiate mucin-type O-glycosylation, we used glycoproteomics to identify disrupted O-glycosylation in synaptosomes purified from cortical tissues. We ascertained a non-redundant, isoform-specific contribution of GALNT2 to the cortical synaptosomal O-glycoproteome, identifying candidate glycoproteins and disrupted O-glycosites that accompany behavioral abnormalities in knockout mice. These findings demonstrate functional impact of O-glycosylation in neurons, implicating roles of O-glycosylation in diverse molecular and cellular pathways related to neuronal function and provide new opportunities to gain insights into the neurological pathophysiology of GALNT2-CDG.
A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases
Authors: Qiao Longliang , Niu Lingxue , Wang Meiyan , Wang Zhihao , Kong Deqiang , Yu Guiling , Ye Haifeng
Published: October 2024

Red light optogenetic systems are in high demand for the precise control of gene expression for gene- and cell-based therapies. Here, we report ared/far-red light-induciblephotoswitch (REDLIP) system based on the chimeric photosensory protein FnBphP (Fn-REDLIP) or PnBphP (Pn-REDLIP) and their interaction partner LDB3, which enables efficient dynamic regulation of gene expression with a timescale of seconds without exogenous administration of a chromophore in mammals. We used the REDLIP system to establish the REDLIP-mediated CRISPR-dCas9 (REDLIPcas) system, enabling optogenetic activation of endogenous target genes in mammalian cells and mice. The REDLIP system is small enough to support packaging into adeno-associated viruses (AAVs), facilitating its therapeutic application. Demonstrating its capacity to treat metabolic diseases, we show that an AAV-delivered Fn-REDLIP system achieved optogenetic control of insulin expression to effectively lower blood glucose levels in type 1 diabetes model mice and control an anti-obesity therapeutic protein (thymic stromal lymphopoietin, TSLP) to reduce body weight in obesity model mice. REDLIP is a compact and sensitive optogenetic tool for reversible and non-invasive control that can facilitate basic biological and biomedical research.
Exploring New Horizons: A Novel Cdk5 Inhibitor Restoring Cognitive Function and Alleviating Type 2 Diabetes
Authors: Paul Sangita , Remya Chandran , Dileep K.V. , Bhardwaj Juhi , Singh Praveen , Poornima S , Srinivas C , Sajith A.M. , Binukumar BK
Published: October 2024

Type 2 diabetes (T2D) is a metabolic disorder frequently associated with cognitive decline, making T2D patients susceptible to dementia. Often referred to as type 3 diabetes, Alzheimer’s disease (AD) shares a close association with hyperglycemia and insulin dysregulation. Despite this, anti-diabetic medications have proven beneficial in reducing cognitive impairment induced by T2D. Previous research, including our own, has highlighted the dysregulation of Cdk5 activity in both T2D and AD, with downstream consequences contributing to the progression of pathophysiological changes in both disorders. Therefore, targeting the kinase Cdk5 may offer a more effective approach to treating T2D and cognitive deterioration. In our study, we present evidence supporting Cdk5 as a significant mediator between T2D and cognitive decline. Through the screening of the KINACore library, we identified novel brain-penetrant Cdk5 inhibitors, BLINK11 and BLINK15. Our study further validated the efficacy of these inhibitors in a high-fat diet-induced T2D model, demonstrating their rescue effects on T2D pathogenesis, including blood glucose levels, obesity, and cognitive impairment as assessed through behavioral studies. Notably, BLINK11 emerges as a promising Cdk5 inhibitor for improving the T2D phenotype and addressing cognitive impairment in T2D conditions.

Graphical abstract
Reduced Synaptic Heterogeneity in a Tetanus Toxin Model of Epilepsy: Insights from Computational Modeling
Authors: Eskikand Parvin Zarei , Cook Mark J. , Burkitt Anthony N. , Grayden David B.
Published: October 2024

A neural mass model was used to assess connectivity strength across diverse populations by fitting the model to background EEG data obtained from a Tetanus Toxin rat model of epilepsy. Our findings reveal a notable decline in the variability of estimated parameters when using EEG data recorded from rats in the Tetanus Toxin group compared with the control group. A detailed comparison of standard deviations in estimated parameters between day 1 and day 20 recordings, coinciding with a heightened number of seizures, underscores the impact of Tetanus Toxin on diminishing synaptic strength variability across recordings. This study supports electrophysiological studies suggesting that epileptogenesis induces a reduction in biophysical heterogeneity, potentially leading to an increase in network synchrony associated with epilepsy. Furthermore, our computational model establishes a foundation for future explorations of the implications of this diminished variability.
Depth diagnosis of colorectal cancer located on a colorectal fold by quantitative evaluation of a width of colorectal - fold lateral contour using a lateral split-view computed tomographic air-contrast enema image
Authors: Miyasaka Mitsutoshi , Muraki Toshio , Nishimuta Yusuke , Oki Eiji , Ishigami Kousei , Tsurumaru Daisuke
Published: October 2024

Purpose

To investigate the usefulness of quantitative evaluation of a width of lateral contour on a lateral split-view computed tomographic air-contrast enema (CT enema) image for diagnosing the invasion depth of colorectal cancer (CRC) located on a colorectal fold.

Methods

The cases of 22 patients with 22 fold-located CRCs (12 early CRCs and 10 advanced CRCs) who underwent a pretherapeutic computed tomographic colonography were retrospectively examined. T1-stage CRCs were classified into two categories according to the Japanese guideline: T1a-stage, carcinoma invading the superficial submucosa (< 1000 um); and T1b-stage, carcinoma invading the deeper submucosa (≥ 1000 um). The maximum width of a lateral contour of the colorectal fold on which the CRC was located, i.e., the gap distance between the two adjacent haustrations, was calculated from the lateral split-view CT enema image by two gastrointestinal radiologists. These values were compared between the intramucosal / T1a CRCs and the T1b / more deeply invading CRCs. The inter-rater intraclass correlation coefficients were also evaluated for reliability.

Results

The maximum widths of a lateral contour of the colorectal fold were significantly higher in the T1b / more deeply invading CRCs than in the intramucosal / T1a CRCs (p<0.0001). The optimum cut-off value of the maximum width of a lateral contour of the colorectal fold for differentiating the former from the latter was 6.0 mm, with a sensitivity and specificity of 100% and 100%, respectively. The inter-rater intraclass correlation coefficient for measurement of a lateral contour of the colorectal fold was 0.958.

Conclusions

We demonstrated for the first time that quantitative evaluation of a width of lateral contour using a lateral split-view CT enema image can improve the diagnostic accuracy of the invasion depth for CRCs located on a colorectal fold.
Typical indicators of neighborhood change used to define gentrification have opposing associations with infant mortality
Authors: Murosko Daria , Passarella Molly , Montoya-Williams Diana , Mehdipanah Roshanak , Lorch Scott
Published: October 2024

Infant mortality (IM), or death prior to the first birthday, is a key public health metric that increases with neighborhood structural inequities. However, neighborhood exposures shift as communities undergo gentrification, a pattern of neighborhood change defined by increasing affluence (in wealth, education, and housing costs). Gentrification has inconsistent associations with infant health outcomes like IM, which may be due to differing relationships between its composite measures and such outcomes. We designed a retrospective cohort analysis of all births and deaths from 2010-2019 across 4 metropolitan areas in Michigan to determine how gentrification and its neighborhood-change components are associated with risk of IM, using multilevel multivariable logistic regression models. Among 672,432 infants, 0.52% died before 1 year. IM was not associated with gentrification. Census tracts with greater increases in income and education had lower rates of IM, but tracts with greater increases in rent costs had higher rates of IM. In unadjusted models, odds of IM were 40% and 15% lower for infants living in tracts in the top quartile increase in household income and college completion, respectively, compared to infants from tracts with the least amount of change. Odds of IM were also increased 29% in infants from tracts with the most increases in rent, though these differences were attenuated when adjusting for individual social factors. Indicators of increasing community affluence have opposing relationships with IM. Policies and interventions that address rising housing costs may reduce IM.
Spatial and temporal changes in choroid morphology associated with long-duration spaceflight
Authors: Bélanger Nzakimuena Charles , Masís Solano Marissé , Marcotte-Collard Rémy , Lesk Mark Richard , Costantino Santiago
Published: October 2024

Purpose

The development of neuro-ophthalmic symptoms during long-duration spaceflight presents major risks to astronauts and their missions. Amid efforts to understand spaceflight associated neuro-ocular syndrome (SANS), uncovering the role of the choroid in its etiology is challenged by the accuracy of image segmentation. The present study extends deep learningbased choroid quantification from optical coherence tomography (OCT) to the characterization of pulsatile and topological changes in the macular plane and investigates changes in response to prolonged microgravity exposure.

Methods

We analyzed OCT macular videos and volumes acquired from astronauts before, during and after long-duration spaceflight. Deep learning models were fine-tuned for choroid segmentation and combined with further image processing towards vascularity quantification. Statistical analysis was performed to determine changes in time-dependent and spatially averaged variables from preflight baseline for OCT data.

Results

For 13 astronauts with a mean age of 47±9 years, there were significant increases in choroid thickness (CT) and luminal area (LA) of 14±25 µm (P = 0.01) and 0.11±0.2 mm2(P = 0.009) and no significant change in choroid vascularity index (CVI) averaged over OCT macular video segments. There was no significant change in the amplitude of pulsatile CT fluctuation (ΔCT), but significant increases in both pulsatile LA (ΔLA) and CVI (ΔCVI) of 0.077±0.14 mm2(P = 0.009) and 0.03±0.06 (P = 0.01), respectively. For a subgroup of 6 astronauts for which inflight imaging was available, choroid volume, luminal volume and CVI over the macular region all increased significantly during spaceflight with the greatest differences reached at 90 days following launch.

Conclusions

The findings show that localized choroid pulsatile changes occur following prolonged microgravity exposure. They suggest that the choroid vessels expand in a manner similar to the choroid layer across the macular region during spaceflight, accompanied by a relative increase in the space they occupy. The methods developed provide new tools and avenues for studying and establishing effective countermeasures to risks associated with long-duration spaceflight.
Subphenotypes of youth-onset type 2 diabetes mellitus and their association with distal symmetrical polyneuropathy
Authors: Guo Jiali , Li Zhongyu , Carrillo-Larco Rodrigo M. , Hsia Daniel S. , Harding Jessica L , Ali Mohammed K. , Varghese Jithin Sam
Published: October 2024

Context

Individuals with youth-onset type 2 diabetes mellitus (T2DM) display substantial, but unexplained, heterogeneity in their clinical presentations and risk of complications such as diabetic neuropathy. Data-driven clustering may be useful in characterizing this heterogeneity.

Objective

To identify data-driven subphenotypes of newly diagnosed youth-onset T2DM and study their association with distal symmetric polyneuropathy (DSPN) at time of diagnosis.

Design

Cross-sectional

Setting

USA

Participants

641 individuals with newly diagnosed T2DM aged 10-19 years from the SEARCH for Diabetes in Youth Study and the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

Exposure(s)

Body mass index, HbA1c, fasting C-peptide, systolic blood pressure, diastolic blood pressure, LDL cholesterol and HDL cholesterol

Main Outcome Measures

Data-driven subphenotypes were identified from k-means clustering. The cross-sectional association of subphenotypes with DSPN, based on expert examination scores (≥2.5) from the Michigan Neuropathy Screening Instrument, were assessed using Poisson regressions with robust standard errors.

Results

Among 641 youth-onset T2DM, 58.2% were female, with 38.2% of participants ≤13 years having average BMI of 34.5 kg/m2(SD: 6.5 kg/m2), and average HbA1c of 6.1% (IQR: 5.6-7.0). Three youth-onset subphenotypes were identified: mild obesity related diabetes (yMOD, 48.5%), severe insulin deficient diabetes (ySIDD, 18.7%) and severe insulin resistant diabetes (ySIRD, 32.7%). After adjusting for covariates, the prevalence of abnormal DSPN were 2.58 (95%CI: 1.74, 3.81) and 2.02 (95%CI: 1.40, 2.93) times among those classified as the ySIDD and ySIRD subphenotypes, relative to the yMOD subphenotype.

Conclusions

Youth-onset T2DM consisted of heterogeneous clinical subphenotypes with differences prevalence of DSPN. Management of youth-onset T2DM may need to consider strategies tailored to each subphenotype.
Probabilistic Graphical Models for Evaluating the Utility of Data-Driven ICD Code Categories in Pediatric Sepsis
Authors: Valdez Lourdes A. , Hernandez Edgar Javier , Matthews O’Connor , Mulvey Matthew A. , Crandall Hillary , Eilbeck Karen
Published: October 2024

Electronic health records (EHRs) are digitalized medical charts and the standard method of clinical data collection. They have emerged as valuable sources of data for outcomes research, offering vast repositories of patient information for analysis. Definitions for pediatric sepsis diagnosis are ambiguous, resulting in delayed diagnosis and treatment, highlighting the need for precise and efficient patient categorizing techniques. Nevertheless, the use of EHRs in research poses challenges. EHRs, although originally created to document patient encounters, are now primarily used to satisfy billing requirements. As a result, EHR data may lack granularity, potentially leading to misclassification and incomplete representation of patient conditions. We compared data-driven ICD code categories to chart review using probabilistic graphical models (PGMs) due to their ability to handle uncertainty and incorporate prior knowledge. Overall, this paper demonstrates the potential of using PGMs to address these challenges and improve the analysis of ICD codes for sepsis outcomes research.
Separated attractors in neural landscape of motor cortex encoding motor learning
Authors: Liu Xuanting , Wu Yanzi , Ru Xiahan , Li Rongrong , Si Ke , Gong Wei
Published: October 2024

Animals gain motor learning via decrease of variation through repeated training. The secondary motor (M2) cortex shows an indispensable role in the learning process of the rotarod-learning task. Yet, it remains unclear how population decoding in M2 cortex guides the repetitive training to transform into motor enhancement. We recorded neuronal population activity using Ca2+ imaging during this enhancement revealing that neuronal population correlates of the persistent internal learning state evolves in the process of motor learning. With the behavioral micro-states analysis, we identify the growing periodicity, stability, and consistency with two gradually clearer point attractor in the M2 neural state space. The results show the evolution of attractors in M2 participate in decrease of training-acquisition behavior variation and provide a general framework for the mapping between arbitrary non-task motor learning and neural topological structure.
Effect heterogeneity reveals complex pleiotropic effects of rare coding variants
Authors: Lu Wenhan , Chen Siwei , Posthuma Danielle , Neale Benjamin M. , O’Connor Luke J. , Karczewski Konrad J.
Published: October 2024

Genome-wide association studies (GWAS) and rare-variant association studies (RVAS) have identified thousands of genes and variants that affect multiple phenotypes. Here, using rare variant association results from the UK Biobank (UKB) data, we identify pervasive gene-level pleiotropy across diverse phenotypic domains and highlight genes with apparent allelic series that provide additional association support through disease pathways. We develop a statistical test, ALLSPICE, to explore allelic heterogeneity within pleiotropic genes and identify evidence for a heterogeneous effect of a subset of missense variants in theALBgene on albumin and calcium levels, which are further validated at protein structure level. In this way, we demonstrate potential shared and trait-specific biological pathways, providing insights into the genetic basis of pleiotropy in complex human traits.
A unique bacterial family strikes again!
Authors: Shukla Gyanesh , Sharma Gaurav
Published: October 2024

In a recent study, Rolf Müller and colleagues identified a novel myxobacterial family Pendulisporaceae, encompassing four new strains with biosynthetic gene clusters (BGCs) largely distinct from known families. These strains, sourced from 1980s soil samples, display unique genomic and chemical features, suggesting significant biotechnological and pharmaceutical potential. This study underscores the value of exploring underrepresented microbial taxa for novel natural products, highlighting the potential of the family Pendulisporaceae as a source of new antimicrobial and therapeutic agents.
Computational Modeling of Proactive, Reactive, and Attentional Dynamics in Cognitive Control
Authors: Mistry Percy K. , Warren Stacie L. , Branigan Nicholas K. , Cai Weidong , Menon Vinod
Published: October 2024

We developed a novel Proactive Reactive and Attentional Dynamics (PRAD) computational model designed to dissect the latent mechanisms of inhibitory control in human cognition. Leveraging data from over 7,500 participants in the NIH Adolescent Brain Cognitive Development study, we demonstrate that PRAD surpasses traditional models by integrating proactive, reactive, and attentional components of inhibitory control. Employing a hierarchical Bayesian framework, PRAD offers a granular view of the dynamics underpinning action execution and inhibition, provides debiased estimates of stop-signal reaction times, and elucidates individual and temporal variability in cognitive control processes. Our findings reveal significant intra-individual variability, challenging conventional assumptions of random variability across trials. By addressing nonergodicity and systematically accounting for the multi-componential nature of cognitive control, PRAD advances our understanding of the cognitive mechanisms driving individual differences in cognitive control and provides a sophisticated computational framework for dissecting dynamic cognitive processes across diverse populations.
Estimating descending activation patterns from EMG in fast and slow movements using a model of the stretch reflex
Authors: Zhang Lei , Schöner Gregor
Published: October 2024

Due to spinal reflex loops, descending activation from the brain is not the only source of muscle activation that ultimately generates movement. This study directly estimates descending activation patterns from measured patterns of muscle activation (EMG) during human arm movements. A simple model of the spinal stretch reflex is calibrated in a postural unloading task and then used to estimate descending activation patterns from muscle EMG patterns and kinematics during voluntary arm motion performed at different speeds. We observed three key features of the estimated descending activation patterns: (1) Within about the first 15% of movement duration, descending and muscle activations are temporally aligned. Thereafter, they diverge and develop qualitatively different temporal profiles. (2) The time course of descending activation is monotonic for slow movements, non-monotonic for fast movements. (3) Varying model parameters like the spinal reflex gain or the level of co-contraction does not qualitatively change the temporal pattern of estimated descending activation. Our findings highlight the substantial contribution of spinal reflex loops to movement generation, while at the same time providing evidence that the brain must generate qualitatively different descending activation patterns for movements that vary in their mechanical dynamics.

New & Noteworthy

We propose a new method that directly estimates descending activation from measured EMG signals and arm kinematics by inverting a model of the spinal stretch reflex, without the need for muscle models or for an arm dynamics model. This approach identifies key features of the time structure of descending activation as movement speed is varied, while also revealing the significant contribution of the spinal stretch reflex to movement generation.
Tumor Priming by Ultrasound Mechanogenetics for with SynNotch CAR T Therapy
Authors: Yoon Chi Woo , Song Chunyang , Minh Nguyen Dung Ngo , Zhu Linshan , Ho Phuong , Huang Ziliang , Lu Gengxi , Zamat Ali , Lewis Alexa , Chen Ruimin , Zeng Yushun , Lee Nan Sook , Jamieson Christina , Shung K. Kirk , Zhou Qifa , Wang Yingxiao
Published: October 2024

Cell-based cancer immunotherapy holds potential as a therapeutic approach, yet its application for solid tumor treatment remains challenging. We created a system where focused ultrasound (FUS) is able to remotely stimulate gene expressions in a specific tissue area through mechanical induction, gated by a chemical inducer to minimize the background noise. This system, known as CaDox, integrates FUS-triggered mechanical and calcium stimulation with doxycycline-responsive genetic circuits, which allows the localized expression of the clinically validated and specific antigen CD19 within a subpopulation of cancer cells upon FUS stimulation. These CD19-expressing cells can then function as “training centers” that activate synNotch chimeric antigen receptor (CAR) T cells to generate CARs that recognize a less specific but widespread antigen in cancer cells, thereby attacking and suppress the whole cancer cell population nearby at the tumor site. We validated the functionality of this CaDox systemin vitro, in organoids, andin vivo, demonstrating its potential for various cell types and as a versatile platform for precisely controllable immunotherapy. Our combinatorial approach thus offers a FUS-controlled remote and non-invasive priming of solid tumors for effective and safe CAR T immunotherapy via the induced production of clinically validated antigens.
Amelioration of Oxidative Stress in Sodium Fluoride-administered Wistar Rats byTamarindus indicaFruit Pulp Ethanolic Extract
Authors: Usman Lutfat A , Ajani Emmanuel O. , Ishiaku Muhammed A , Bankole Taofeeq A , Ibrahim Rasheed B. , Saka Dauda K. , Abdulameed Hassan T. , Aladodo Raliat A.
Published: October 2024

Infertility is a significant global health issue often exacerbated by environmental toxins like sodium fluoride (NaF), which induces oxidative stress and reproductive dysfunction. Medicinal plants, such as Tamarindus indica, known for their antioxidant properties, offer potential natural remedies. This study evaluates the antioxidant potential of the ethanolic extract of Tamarindus indica fruit pulp in mitigating NaF-induced infertility in Wistar rats.

Tamarindus indicafruits were authenticated and processed into a crude extract, with phytochemical screening revealing the presence of tannins and steroids. Seventy Wistar rats were divided into seven groups, receiving various treatments including T. indica extract, NaF, and Clomid. The acute toxicity test, conducted according to WHO and OECD guidelines, showed no lethal effects up to 5000 mg/kg of the extract. Phytochemical screening indicated that the antioxidant properties of the extract could be attributed to tannins and steroids.

Experimental groups treated with T. indica extract exhibited significant improvements in oxidative stress markers such as malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) compared to control groups. The 200 mg/kg preventive group demonstrated the most notable antioxidant activity, comparable to the normal control group.

The findings suggest that the ethanolic extract of Tamarindus indica fruit pulp at 200 mg/kg body weight has significant potential as a natural therapeutic agent against oxidative stress-induced infertility. This highlights its promise as an alternative to conventional treatments, offering a safe and effective option for managing reproductive health issues related to oxidative stress.
Single Cells Signal Non-self from Self via ‘XOR’ and ‘NOT EQUALS’ Logic in a Dimer of Dimers
Authors: An Rocky , Prakash Manu
Published: October 2024

The ciliateTetrahymena thermophila’s seven mating types are defined by unique receptor-ligand pairs (Mta/Mtb). While Mta and Mtb are known to participate in a mating signal complex, how they distinguish between oneself and six non-self cell types remains unknown. AlphaFold3 predictions reveal Mta/Mtb as large glycoproteins likely derived from ancient, unisexual, intercellular adhesion molecules. Since homologous binary-type systems perform XOR by switching mtA expression, we show spectrum (n) types naturally extend XOR to multi-bit NOT EQUALS operations via differential affinities of Mta/Mtb dimers. We model kinetics begetting the ‘n+ 1th’ type, demonstrating self-inhibition bytrans-homophilic Mtb-Mtb. A computational approach reconciles recent and classical evidence for mating exclusivity, including selfing failures (same type mating). Binding kinetics enables fast, robust intercellular computation across an intermembrane mating space. Thus, Mta/Mtb families are a model system allowing us to derive a ‘calculus’ of antigenic variation and inspire synthetic designs of XOR logic underlying self/non-self recognition.

Graphical Abstract

Highlights

Within minutes, swimming cells signal compatible mating types via membrane proteins

AlphaFold insights reveal Mta/Mtb family as elongate adhesion receptors/ligands

Relative affinities of two dimers explain multi-bit intercellular signaling capacity

Dimer-of-dimers compute NOT EQUALS via homo-vs. hetero-philic interactions

In BriefFree-living ciliatesT. thermophilabreed only when two cells are different in mating type, out of seven types total. Their mating-type-specific coexpression of a receptor-ligand glycoprotein pair reveals how competitive homophilic vs. heterophilic binding computes self vs. non-self recognition with single-layer intercellular logic. Proteins perform binary XOR gates (with two mating types) that extend to multi-bit ‘NOT EQUALS’ (with multiple mating types). The work illuminates principles of eXclusivity in molecular recognition and inspires the design of synthetic cellular recognition systems.
History bias and its perturbation of the stimulus representation in the macaque prefrontal cortex
Authors: Benozzo Danilo , Ferrucci Lorenzo , Ceccarelli Francesco , Genovesio Aldo
Published: October 2024

Multiple history biases affect our representation of magnitudes, such as time, distance, and size. It is not clear whether the previous stimuli interfere with the discrimination process from the moment of stimulus presentation, during working memory retention, or even later during the decision-making phase. We used a spatial discrimination task involving two stimuli of different magnitudes, presented sequentially at various distances from the center. The monkey’s task was to select the farthest of them. We showed that the previous stimulus magnitude generated a contraction bias effect, but only when its stimulus features differed from those of the current stimulus. In this case, at the neural level we also observed that the decoding of the stimulus magnitude achieved the highest accuracy when it matched the magnitude of the preceding stimulus for which the decoder was trained. This indicates that past stimuli can affect magnitude processing already during the stimulus presentation, even before the decision process. Interestingly, this effect manifested when the trace of the previous stimulus magnitude reactivated in the second part of the stimulus presentation after an “activity-silent” period.
The MutRS quorum sensing system controls lantibiotic mutacin production in the human pathogenStreptococcus mutans
Authors: Wyllie Ryan M. , Jensen Paul A.
Published: October 2024

Microbes use quorum sensing systems to respond to ecological and environmental changes. In the oral microbiome, the pathogenic bacteriumStreptococcus mutansuses quorum sensing to control the production of bacteriocins. These antimicrobial peptides kill off ecological competetors and allowS. mutansto dominate the microenviornment of dental plaques and form dental caries. One class of bacteriocins produced byS. mutans, the lantibiotic mutacins, are particularly effective at killing due to their broad spectrum of activity. Despite years of study, the regulatory mechanisms governing production of lantibiotic mutacins I, II, and III inS. mutanshave never been elucidated. We discovered a distinct class of quorum sensing system, MutRS, that regulates mutacins and is widespread among the streptococci. We demonstrate that MutRS systems are activated by a short peptide pheromone (Mutacin Stimulating Peptide, or MSP) and show that MutRS controls production of three separate lantibiotic mutacins in three different strains ofS. mutans. Finally, we show that paralogous MutRS systems participate in inter- and intrastrain crosstalk, providing further evidence of the interplay between quorum sensing systems in the oral streptococci.
An integrative proteotranscriptomics approach reveals new ADAM9 substrates and downstream pathways
Authors: Lu Congyu , Xu Xiaolu , Sindhu Neha , Rainey Jessica , Polson Shawn W. , Qiu Jing , Wei Shuo
Published: October 2024

Membrane protein shedding is a key regulatory mechanism for cell signaling and adhesion, and dysregulated shedding is associated with diseases. Many membrane proteases can catalyze shedding, but the substrate spectra and downstream targets of these “sheddases” remain largely elusive. While secretomics-based methods have been applied to the systematic identification of sheddase substrates, these methods are not always effective and do not provide much information on downstream targets. Here we developed an integrative proteotranscriptomics approach to uncover the transcriptional and post-transcriptional targets of the disintegrin metalloproteinase ADAM9, a sheddase that has been implicated in solid tumors, autoimmunity, inflammatory diseases and COVID-19. This systematic approach revealed signaling pathways downstream of ADAM9, including the oncogenic mTOR and tumor suppressor FOXO pathways. We further identified several direct and indirect substrates for ADAM9, which may mediate the pathophysiological roles of ADAM9 in various diseases. Of note, some of these substrates are difficult to detect by secretomics. This new approach can be applied to other sheddases to systematically identify their substrates and targets.
Two-dimensional condensates of HRS drive the assembly of flat clathrin lattices on endosomes
Authors: Hakala Markku , Moparthi Satish Babu , Ganeva Iva , Bernat-Silvestre César , Espadas Javier , Kukulski Wanda , Vassilopoulos Stéphane , Kaksonen Marko , Roux Aurélien
Published: October 2024

Amongst the different clathrin structures in mammalian cells, bi-layered clathrin coat colocalizing with endosomal sorting complex required for transport (ESCRT)-0 remains one of the most ambiguous. Despite being observed for the first time twenty years ago, their structure and how they are assembled remains unknown. Here, we reconstitutedin vitrothe ESCRT-0 clathrin assembly onto various types of membranes. The ESCRT-0 protein HRS, a known clathrin adaptor on endosomes, was found to form protein condensates. These condensates spread into a thin layer on PI(3)P-rich membranes. Platinum replica electron microscopy revealed that, surprisingly, the assembly of clathrin was different depending on the HRS phase. Protein droplets recruited clathrin as a dense, curved lattice, with many cage-like structures. On two-dimensional condensates, HRS recruited clathrin as a dense flat assembly. Two-dimensional HRS-clathrin condensates promoted the clustering of cholesterol in the underlying membrane, while cholesterol enhanced PI(3)P- dependent HRS recruitment on the membrane. On free-standing membranes, two-dimensional HRS-clathrin condensates promoted membrane flattening. Overall, these results show that a two- dimensional HRS condensate creates a unique membrane structure for sorting cargo molecules, defining a new mechanism in membrane trafficking processes.
Conservation of an immune homeostasis module in land plants
Authors: Dou Ruoqi , Mahboubi Karima El , Tanney Cailun A.S. , Chu Jiashu , Bredow Melissa , Rodriguez Gallo Maria Camila , Lauressergues Dominique , Keller Jean , Miguel Virginia Natali , DeFalco Thomas A. , Glen Uhrig R. , Zipfel Cyril , Delaux Pierre-Marc , Monaghan Jacqueline
Published: October 2024

Calcium-dependent protein kinases (CDPKs or CPKs) are a unique family of Ca2+-regulated kinases with diverse functions in plants1. CPK28 regulates immune homeostasis, stress responses, and growth in multiple angiosperms including tomato2,3, rice4–7, cotton8–10, andArabidopsis thaliana(hereafter, Arabidopsis)11–17. In Arabidopsis, CPK28 phosphorylates and activates the E3 ubiquitin ligases PLANT U-BOX 25 (PUB25) and PUB26 that target the major immune signaling protein BOTRYTIS-INDUCED KINASE 1 (BIK1), resulting in its turnover12,18. The CPK28-PUB25/26-BIK1 regulatory module maintains precise levels of BIK1 in the cell and is thought to optimize immune responses19. Separated from angiosperms by 450M years of evolution, the liverwortMarchantia polymorpha(hereafter, Marchantia) has emerged as a model system to study the evolution of signaling modules across land plants20. Here, we demonstrate that the function of CPK28 is conserved in Marchantia. MpCPK28 displays Ca2+-dependent protein kinase activity and is inhibited by calmodulinin vitro. Over-expression ofMpCPK28results in pronounced developmental phenotypes and decreased chitin-induced oxidative burst, andMpCPK28can functionally complement the mutant phenotypes of the Arabidopsiscpk28-1mutant. MpCPK28 associates with and phosphorylates multiple residues on Marchantia AVRPPHB SUSCEPTIBLE 1 (PBS1)-like (PBL)-a (MpPBLa), a functional ortholog of AtBIK1, as well as MpPUB20e (a putative ortholog of AtPUB25/26). MpPBLa undergoes proteasomal degradation in Marchantia and can be polyubiquitinated by MpPUB20e. The occurrence of the CPK28-PUB25/26-BIK1 module across land plants reveals that the regulation of immune amplitude has been conserved throughout plant evolution.

Highlights

MpCPK28 is a Ca2+-dependent protein kinase that regulates immune homeostasis and development in Marchantia and is functionally orthologous to AtCPK28.

MpCPK28 phosphorylates the E3 ubiquitin ligase MpPUB20e and the receptor-like cytoplasmic kinase MpPBLa.

MpPBLa is subject to proteasomal degradation and is ubiquitinated by MpPUB20e.

In Brief

Deploying robust immune responses to deter pathogens while minimizing host damage is critical to plant survival. Here, Douet al. show that optimizing the protein accumulation of receptor-like cytoplasmic kinase MpPBLa is an ancient property of the plant immune system, controlled by the MpCPK28-MpPUB20e regulatory module.
A molecular basis for plant SCAR/WAVE functional divergence
Authors: Brumm Sabine , Gavrin Aleksandr , Macleod Matthew , Chesneau Guillaume , Usländer Annika , Schornack Sebastian
Published: October 2024

Dynamic actin cytoskeleton reorganisation enables plant developmental processes requiring polarised transport such as root hair and leaf trichome formation. The SCAR/WAVE complex plays a crucial role in regulating these dynamics through ARP2/3-mediated actin branching.SCAR/WAVEgenes occur as small families across a wide range of plant species but whether and how they fulfil different functions remains unclear. We utilise a systematic chimaera approach to define the differential functionality of two closely relatedMedicago truncatulaSCAR proteins in plant development. We show that SCAR/WAVE contribution toMedicago truncatularoot hair orArabidopsis thalianatrichome formation is dependent on two central intrinsically disordered regions (IDRs). Differential functionalities ofMedicago truncatulaSCAR proteins were furthermore associated with the presence/absence of a 42-amino acid sequence within the IDR that impacted protein stability. Through uncovering a molecular basis for functional differences, we advance our understanding of plant SCAR/WAVE complexes.

One Sentence Summary

Intrinsically disordered regions in SCAR/WAVE proteins drive diverse functions in root hair and leaf trichome development.