bluuebunny/crossref_metadata_2025 huggingface dataset:
Microtubule polymerization tuned by macromolecular crowdant size and density
Authors: Basu Jashaswi , Soni Aman , Athale Chaitanya A
Published: February 2024

Microtubule (MT) polymerization is regulated by biochemical as well as physical factors such as macromolecular crowding. Crowding agents or crowdants affect MT elongation rates differently depending on crowdant size due to opposing effects on polymerization: microviscosity reduces polymer elongation, while volume exclusion increases reaction rates by local concentration. In order to address how crowdant size and concentration collectively affect MT populations, we combine in vitro MT polymerization experiments with kinetic Monte Carlo simulations. Our experiments in bulk with nucleators validate decreasing MT elongation rates with increasing concentrations of small molecular weight crowdants in bulk assays and a corresponding increase for large crowdants. Kinetic Monte Carlo simulations can explain the result with packing fractions dependence of small as compared to large crowdants increasing microviscosity more dramatically. In contrast MT bulk polymerization rates in absence of nucleators increased with crowdant concentration, irrespective of their size, with a corresponding decrease in the critical concentration. Microscopy of filament growth dynamics demonstrates that small crowdants result in shorter filaments in a concentration dependent manner, consistent with their role in reducing elongation rates, but this decrease is compensated by increased number of filaments. Large crowdants increase the filament numbers while elongation is slightly decreased. Our results provide evidence for MT nucleation being rate-limited and elongation diffusion limited, resulting in differences in the effect of crowdant sizes on nucleation and elongation. These results are of general relevance to understand physical effects of crowding on collective cytoskeletal polymerization dynamics.
A Novel, Open-Source Virtual Reality Platform for Dendritic Spine Analysis
Authors: Reimer Marike L , Kauer Sierra D , Benson Curtis A , King Jared F , Patwa Siraj , Feng Sarah , Estacion Maile A , Bangalore Lakshmi , Waxman Stephen G , Tan Andrew M
Published: February 2024

Neuroanatomy is fundamental to understanding the nervous system, particularly dendritic spines, which are vital for synaptic transmission and change in response to injury or disease. Advancements in imaging have allowed for detailed 3D visualization of these structures. However, existing tools for analyzing dendritic spine morphology are limited. To address this, we developed an open-source, virtual reality (VR) Structural Analysis Software Ecosystem (coined “VR-SASE”) that offers a powerful, intuitive approach for analyzing dendritic spines. Our validation process confirmed the method’s superior accuracy, outperforming recognized gold standard neural reconstruction techniques. Importantly, the VR-SASE workflow automatically calculates key morphological metrics such as dendritic spine length, volume, and surface area, and reliably replicates established datasets from published dendritic spine studies. By integrating the Neurodata Without Borders (NWB) data standard and DataJoint, VR-SASE also aligns with FAIR principles--guidelines aimed at improving the findability, accessibility, interoperability, and reusability of digital assets--enhancing data usability and longevity in neuroscience research.

Motivation

Technological limitations of available image-analysis tools for analyzing 3D fine-structure hinders effective research and is often costly. An accessible and efficient solution is crucial to overcome these research challenges. We addressed this by integrating the NWB data standard and DataJoint technology into an open-source, virtual reality workflow, enhancing dendritic spine analysis.
Genome-wide diversity in lowland and highland maize landraces from southern South America: population genetics insights to assist conservation
Authors: Dominguez Pia Guadalupe , Gutierrez Angela Veronica , Fass Monica Irina , Filippi Carla Valeria , Vera Pablo , Puebla Andrea , Defacio Raquel Alicia , Paniego Norma Beatriz , Lia Veronica Viviana
Published: February 2024

Maize (Zea maysssp.mays L.) landraces are traditional American crops with high genetic variability that conform a source of original alleles for conventional maize breeding. Northern Argentina, one the southernmost regions of traditional maize cultivation in the Americas, harbours around 57 races traditionally grown in two regions with contrasting environmental conditions, namely the Andean mountains in the Northwest and the tropical grasslands and Atlantic Forest in the Northeast. These races encounter diverse threats to their genetic diversity and persistence in their regions of origin, with climate change standing out as one of the major challenges. In this work, we use genome-wide SNPs derived from ddRADseq to study the genetic diversity of individuals representing the five groups previously described for this area. This allowed us to distinguish two clearly differentiated gene pools, the Highland Northwestern maize (HNWA) and the Floury Northeastern maize (FNEA). Subsequently, we employed Essential Biodiversity Variables at the genetic level, as proposed by the Group on Earth Observations Biodiversity Observation Network (GEO BON), to evaluate the conservation status of these two groups. This assessment encompassed genetic diversity (Pi), inbreeding coefficient (F), and effective population size (Ne). FNEA showed low Ne values and high F values, while HNWA showed low Ne values and low Pi values, indicating that further genetic erosion is imminent for these landraces. Outlier detection methods allowed identification of putative adaptive genomic regions, consistent with previously reported flowering-time loci and chromosomal regions displaying introgression from the teosinteZea maysssp.mexicana. Finally, species distribution models were obtained for two future climate scenarios, showing a notable reduction in the potential planting area of HNWA and a shift in the cultivation areas of FNEA. Taken together, these results suggest that maize landraces from Northern Argentina may not be able to cope with climate change. Therefore, active conservation policies are advisable.
PKSmart: An Open-Source Computational Model to Predictin vivoPharmacokinetics of Small Molecules
Authors: Seal Srijit , Trapotsi Maria-Anna , Subramanian Vigneshwari , Spjuth Ola , Greene Nigel , Bender Andreas
Published: February 2024

Drug exposure is a key contributor to the safety and efficacy of drugs. It can be defined using human pharmacokinetics (PK) parameters that affect the blood concentration profile of a drug, such as steady-state volume of distribution (VDss), total body clearance (CL), half-life (t½), fraction unbound in plasma (fu) and mean residence time (MRT). In this work, we used molecular structural fingerprints, physicochemical properties, and predicted animal PK data as features to model the human PK parameters VDss, CL, t½, fu and MRT for 1,283 unique compounds. First, we predicted animal PK parameters [VDss, CL, fu] for rats, dogs, and monkeys for 372 unique compounds using molecular structural fingerprints and physicochemical properties. Second, we used Morgan fingerprints, Mordred descriptors and predicted animal PK parameters in a hyperparameter-optimised Random Forest algorithm to predict human PK parameters. When validated using repeated nested cross-validation, human VDss was best predicted with an R2of 0.55 and a Geometric Mean Fold Error (GMFE) of 2.09; CL with accuracies of R2=0.31 and GMFE=2.43, fu with R2=0.61 and GMFE=2.81, MRT with R2=0.28 and GMFE=2.49, and t½ with R2=0.31 and GMFE=2.46 for models combining Morgan fingerprints, Mordred descriptors and predicted animal PK parameters. We evaluated models with an external test set comprising 315 compounds for VDss (R2=0.33 and GMFE=2.58) and CL (R2=0.45 and GMFE=1.98). We compared our models with proprietary pharmacokinetic (PK) models from AstraZeneca and found that model predictions were similar with Pearson correlations ranging from 0.77-0.78 for human PK parameters of VDss and fu and 0.46-0.71 for animal (dog and rat) PK parameters of VDss, CL and fu. To the best of our knowledge, this is the first work that publicly releases PK models on par with industry-standard models. Early assessment and integration of predicted PK properties are crucial, such as in DMTA cycles, which is possible with models in this study based on the input of only chemical structures. We developed a webhosted application PKSmart (https://broad.io/PKSmart) which users can access using a web browser with all code also downloadable for local use.

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Automated pupillometry to detect residual consciousness in acute brain injury
Authors: Othman Marwan H. , Olsen Markus Harboe , Tanderup Hansen Karen Irgens , Amir Moshgan , Jensen Helene Ravnholt , Nyholm Benjamin , Møller Kirsten , Kjærgaard Jesper , Kondziella Daniel
Published: February 2024

Background

Identifying residual consciousness in patients with disorders of consciousness (DoC) in the intensive care unit (ICU) is crucial for treatment decisions, but sensitive low-cost bedside markers are missing. We investigated whether automated pupillometry combined with passive and active cognitive paradigms can identify residual consciousness in ICU patients with traumatic or non-traumatic DoC.

Methods

In a prospective observational cohort study, clinically low- or unresponsive ICU patients with traumatic and non-traumatic DoC were enrolled from neurological and non-neurological ICUs at a tertiary referral center (Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark). Age- and sex-matched healthy volunteers served as controls. Participants with eye disorders were excluded. Patients were categorized into those without (coma or unresponsive wakefulness syndrome, ≤UWS) or with (minimally conscious state or better, ≥MCS) clinical signs of residual consciousness. Using automated pupillometry, we recorded pupillary dilation as a response to passive (visual and auditory stimuli) and active (mental arithmetic) cognitive paradigms, with success criteria depending on the specific task (e.g., ≥3 of 5 pupillary dilations on 5 consecutive mental arithmetic tasks).

Results

We obtained 699 pupillometry recordings at 178 time points from 91 brain-injured ICU patients (mean age 60±13.8 years; 31% women; 49.5% non-traumatic brain injuries). Recordings were also obtained from 26 matched controls (59±14.8 years, 38% women). Passive paradigms yielded limited distinctions between patient groups and controls. However, active paradigms involving mental arithmetic enabled discrimination between different states of consciousness. With mental arithmetic of moderate complexity, ≥3 pupillary dilations were seen in 50.0% ≥MCS patients and 17.8% ≤UWS patients (OR 4.56; 95% CI 2.09-10.10,p<0.001). In comparison, 76.9% healthy controls responded with ≥3 pupillary dilations (p=0.028). Results remained consistent across sensitivity analyses using different thresholds for success. Spearman’s Rank analysis underscored the robust association between pupillary dilations during mental arithmetic and consciousness levels (rho=1,p=0.017). Notably, one behaviorally unresponsive patient demonstrated persistent command-following behavior two weeks before overt signs of awareness, suggesting a state of prolonged CMD.

Conclusions

Automated pupillometry combined with mental arithmetic can identify cognitive efforts, and hence residual consciousness, in ICU patients with acute DoC.
Brain Age Analysis and Dementia Classification using Convolutional Neural Networks trained on Diffusion MRI: Tests in Indian and North American Cohorts
Authors: Chattopadhyay Tamoghna , Joshy Neha Ann , Ozarkar Saket S. , Buwa Ketaki , Feng Yixue , Laltoo Emily , Thomopoulos Sophia I. , Villalon Julio E. , Joshi Himanshu , Venkatasubramanian Ganesan , John John P. , Thompson Paul M.
Published: February 2024

Deep learning models based on convolutional neural networks (CNNs) have been used to classify Alzheimer’s disease or infer dementia severity from T1-weighted brain MRI scans. Here, we examine the value of adding diffusion-weighted MRI (dMRI) as an input to these models. Much research in this area focuses on specific datasets such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which assesses people of North American, largely European ancestry, so we examine how models trained on ADNI, generalize to a new population dataset from India (the NIMHANS cohort). We first benchmark our models by predicting “brain age” - the task of predicting a person’s chronological age from their MRI scan and proceed to AD classification. We also evaluate the benefit of using a 3D CycleGAN approach to harmonize the imaging datasets before training the CNN models. Our experiments show that classification performance improves after harmonization in most cases, as well as better performance for dMRI as input.
Knowledge, Attitudes, and Practices Regarding Urinary Tract Infections Among Women in the United Arab Emirates
Authors: Alhaj Shaikha Salah , Allami Sajad , Mohamadiyeh Amjad , Agha Ammar , Ali Abdul Kareem Abu , Habbal Joudi M Bassam , Saeed Balsam Qubais
Published: February 2024

Background

Urinary tract infections (UTIs), which are infections of the kidneys, ureters, bladder, or urethra, are a worldwide public health concern. As compared to men, women are more prone to UTIs. There have been several studies that explore the knowledge, attitudes, and practices of women regarding UTIs in different countries, but no such study has been conducted in the UAE; therefore, we conducted this study in the UAE setting.

Methods

This study was conducted using an online survey created on Microsoft Forms. The minimum sample size required for our study was 385. This study was conducted after obtaining ethical approval from the Research Ethics Committee at the University of Sharjah (Reference Number: REC-23-09-19-01-F). A personally designed questionnaire consisting of 21 items, derived from previous research was used to record data. The data was analyzed using SPSS.

Results

A total of 475 females were included in the study. Most respondents were aged 18-30 years (47.4%). Our study found that a majority of the participants (69.7%) correctly identified bacteria as the most common cause of UTIs. With regards to practices undertaken during UTIs, among the participants with a history of UTI episodes, 32.6% waited 24-48 hours before seeking medical attention at a hospital or clinic, while 10% did not visit a hospital at all. Distinct trends were found when comparing demographic factors with knowledge levels. Most notably, the age group of 18-30 years showed the highest percentage of high-knowledge individuals (49%) compared to other age groups (p < 0.05). Education level was significantly (p = 0.003) associated with UTI knowledge. Going to the hospital/clinic was reported by 41% with high knowledge but only by 20% of those with poor knowledge. Moreover, a higher proportion of individuals with high knowledge sought medical attention immediately within 24 hours (47%).

Conclusion

Most of the participants possessed adequate knowledge regarding UTIs. Higher knowledge levels were associated with more proactive & appropriate health behaviors, such as seeking medical attention promptly & drinking more water.
Early altered directionality of resting brain network state transitions in the TgF344-AD rat model of Alzheimer’s disease
Authors: De Waegenaere Sam , van den Berg Monica , Keliris Georgios A. , Adhikari Mohit H. , Verhoye Marleen
Published: February 2024

Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in memory loss and cognitive decline. Synaptic dysfunction is an early hallmark of the disease whose effects on whole-brain functional architecture can be identified using resting-state functional MRI (rsfMRI). Insights into mechanisms of early, whole-brain network alterations can help our understanding of the functional impact of AD’s pathophysiology. Here, we obtained rsfMRI data in the TgF344-AD rat model at the pre- and early-plaque stages. This model recapitulates the major pathological and behavioural hallmarks of AD. We used co-activation pattern (CAP) analysis to investigate if and how the dynamic organization of intrinsic brain functional networks states, undetectable by earlier methods, is altered at these early stages. We identified and characterized six intrinsic brain states as CAPs, their spatial and temporal features, and the transitions between the different states. At the pre-plaque stage, the TgF344-AD rats showed reduced co-activation of hub regions in the CAPs corresponding to the default mode-like and lateral cortical network. Default mode-like network activity segregated into two distinct brain states, with one state characterised by high co-activation of the basal forebrain. This basal forebrain co-activation was reduced in TgF344-AD animals mainly at the pre-plaque stage. Brain state transition probabilities were altered at the pre-plaque stage between states involving the default mode-like network, lateral cortical network, and basal forebrain regions. Additionally, while the directionality preference in the network-state transitions observed in the wild-type animals at the pre-plaque stage had diminished at the early-plaque stage, TgF344-AD animals continued to show directionality preference at both stages. Our study enhances the understanding of intrinsic brain state dynamics and how they are impacted at the early stages of AD, providing a nuanced characterization of the early, functional impact of the disease’s neurodegenerative process.
Crebinostat Facilitates Memory Formation
Authors: Dama Deepti , Sharma Shiv K
Published: February 2024

Objectives

Protein modifications importantly contribute to memory formation. Protein acetylation is a posttranslational modification of proteins that regulates memory formation. Acetylation level is determined by the relative activities of acetylases and deacetylases. Crebinostat is a histone deacetylase inhibitor. In this study, our aim was to examine whether Crebinostat affects memory formation in object recognition task. Further, we aimed to understand regulation of plasticity-related proteins by Crebinostat.

Methods

Object recognition task was used to examine the effect of Crebinostat on memory formation. The effect of Crebinostat on plasticity-related proteins was examined using Western blot experiments.

Results

We show that Crebinostat facilitates memory formation by a weak training in object recognition task. Further, this compound enhances acetylation of α-tubulin, and reduces the level of histone deacetylase 6, an α-tubulin deacetylase.

Conclusions

The results suggest that enhanced acetylation of α-tubulin by Crebinostat contributes to its facilitatory effect on memory formation.

Protein modifications importantly contribute to memory formation. Protein acetylation is a posttranslational modification of proteins that regulates memory formation. Acetylation level is determined by the relative activities of acetylases and deacetylases. Crebinostat is a histone deacetylase inhibitor. Here we show that in object recognition task, Crebinostat facilitates memory formation by a weak training. Further, this compound enhances acetylation of α-tubulin, and reduces the level of histone deacetylase 6, an α-tubulin deacetylase. The results suggest that enhanced acetylation of α-tubulin by Crebinostat contributes to its facilitatory effect on memory formation.
The MYCN oncoprotein and helicases DDX17 and DDX5 have opposite effects on the production of chimeric transcripts in neuroblastoma cells
Authors: Clerc Valentine , Valat Jessica , Grand Xavier , Fontrodona Nicolas , Bazire Matéo , Rama Nicolas , Auboeuf Didier , Gibert Benjamin , Mortreux Franck , Bourgeois Cyril F.
Published: February 2024

DEAD box helicases DDX17 and DDX5 control the termination of transcription and the associated cleavage of the 3’ end of transcripts. Here we show that the transcriptional readthrough induced by their depletion in neuroblastoma cells also results in increased production of chimeric transcripts from tandemly oriented genes. Analysis of neuroblastoma tumours in which chimeric transcripts are abundant revealed that low expression of the DDX17 and DDX5 genes is associated with poor overall patient survival. Low DDX17 expression is also significantly associated with high-risk tumours and is inversely correlated with MYCN oncogene amplification, suggesting a link between these two factors. We demonstrate that changes in MYCN expression do not affect the expression of either helicase, but alter transcription termination leading to the production of chimeric transcripts. We provide evidence that MYCN acts on termination through its direct binding to the 3’ region of genes and that it interacts with DDX17, suggesting that it may inhibit the activity of the helicase. Collectively, our work reveals a novel function of MYCN in transcription termination and suggests that the deregulation of MYCN and DDX17/DDX5 expression in neuroblastoma may lead to the expression of non-canonical and potentially harmful RNA molecules.
Multimodal brain age prediction using machine learning: combining structural MRI and 5-HT2AR PET derived features
Authors: Dörfel Ruben P. , Arenas-Gomez Joan M. , Svarer Claus , Ganz Melanie , Knudsen Gitte M. , Svensson Jonas E. , Plavén-Sigray Pontus
Published: February 2024

To better assess the pathology of neurodegenerative disorders and the efficacy of neuroprotective interventions, it is necessary to develop biomarkers that can accurately capture age-related biological changes in the human brain. Brain serotonin 2A receptors (5-HT2AR) show a particularly profound age-related decline and are also reduced in neurodegenerative disorders, such as Alzheimer’s disease.

This study investigates whether the decline in 5-HT2AR binding, measured in vivo using positron emission tomography (PET), can be used as a biomarker for brain aging. Specifically, we aim to 1) predict brain age using 5-HT2AR binding outcomes, 2) compare 5-HT2AR-based predictions of brain age to predictions based on gray matter (GM) volume, as determined with structural magnetic resonance imaging (MRI), and 3) investigate whether combining 5-HT2AR and GM volume data improves prediction.

We used PET and MR images from 209 healthy individuals aged between 18 and 85 years (mean=38, std=18), and estimated 5-HT2AR binding and GM volume for 14 cortical and subcortical regions. Different machine learning algorithms were applied to predict chronological age based on 5-HT2AR binding, GM volume, and the combined measures. The mean absolute error (MAE) and a cross-validation approach were used for evaluation and model comparison.

We find that both the cerebral 5-HT2AR binding (mean MAE=6.63 years, std=0.74 years) and GM volume (mean MAE=6.95 years, std=0.83 years) predict chronological age accurately. Combining the two measures improves the prediction further (mean MAE=5.54 years, std=0.68). In conclusion, 5-HT2AR binding measured using PET might be useful for improving the quantification of a biomarker for brain aging.
Dysregulation of Neuropilin-2 Expression in Inhibitory Neurons Impairs Hippocampal Circuit Development and Enhances Risk for Autism-Related Behaviors and Seizures
Authors: Subramanian Deepak , Eisenberg Carol , Huang Andrew , Baek Jiyeon , Naveed Haniya , Komatireddy Samiksha , Shiflett Michael W. , Tran Tracy S. , Santhakumar Vijayalakshmi
Published: February 2024

Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether selective dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and enhances the risk for seizures has not been evaluated. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.
Biochemical fractionation of human α-Synuclein in aDrosophilamodel of synucleinopathies
Authors: Imomnazarov Khondamir , Lopez-Scarim Joshua , Bagheri Ila , Joers Valerie , Tansey Malú Gámez , Martín-Peña Alfonso
Published: February 2024

Synucleinopathies are a group of central nervous system pathologies that are characterized by neuronal accumulation of misfolded and aggregated α-synuclein in proteinaceous depositions known as Lewy Bodies (LBs). The transition of α-synuclein from its physiological to pathological form has been associated with several post-translational modifications such as phosphorylation and an increasing degree of insolubility, which also correlate with disease progression in post-mortem specimens from human patients. Neuronal expression of α-synuclein in model organisms, includingDrosophila melanogaster,has been a typical approach employed to study its physiological effects. Biochemical analysis of α-synuclein solubility via high-speed ultracentrifugation with buffers of increasing detergent strength offers a potent method for identification of α-synuclein biochemical properties and the associated pathology stage. Unfortunately, the development of a robust and reproducible method for evaluation of human α-synuclein solubility isolated fromDrosophilatissues has remained elusive. Here, we tested different detergents for their ability to solubilize human α-synuclein carrying the pathological mutation A53T from brains of aged flies. We also assessed the effect of sonication on solubility of human α-synuclein and optimized a protocol to discriminate relative amounts of soluble/insoluble human α-synuclein from dopaminergic neurons of theDrosophilabrain. Our data established that, using a 5% SDS buffer, the 3-step protocol distinguishes between cytosolic soluble proteins in fraction 1, detergent-soluble proteins in fraction 2 and insoluble proteins in fraction 3. This protocol shows that sonication breaks down α-synuclein insoluble complexes from the fly brain, making them soluble in the SDS buffer and enriching fraction 2 of the protocol.
Dynamic phospho-proteogenomic analysis of gastric cancer cells suggests host immunity provides survival benefit
Authors: Kume Kohei , Iida Midori , Iwaya Takeshi , Yashima-Abo Akiko , Koizumi Yuka , Konta Akari , Wade Kaitlin , Hiraki Hayato , Calvert Valerie , Wulfkuhle Julia , Espina Virginia , Siwak Doris R. , Lu Yiling , Takemoto Kazuhiro , Suzuki Yutaka , Sasaki Yasushi , Tokino Takashi , Petricoin Emanuel , Liotta Lance A. , Mills Gordon B. , Nishizuka Satoshi S.
Published: February 2024

The mainstay of advanced gastric cancer (GC) therapy is DNA-damaging drugs. Using proteogenomic analysis of a panel of eight GC cell lines, we identified genetic alterations and signaling pathways, potentially associated with resistance to DNA-damaging drugs. Notably, 5-fluorouracil (5FU) resistance was associated with PD-L1 expression, but not established GC subtypes. In publicly available cohort data, PD-L1 expression was associated with a reduced risk of GC progression. In addition to PD-L1, expression of inflammatory genes induced by lymphocyte cytokines was consistently associated with prolonged survival in GC. In our validation cohort, total lymphocyte count (TLC) predicted a better relapse-free survival rate in GC patients with 5FU-based adjuvant chemotherapy than those with surgery alone. Moreover, TLC+patients who had no survival benefit from adjuvant chemotherapy were discriminated by IκBα expression. Collectively, our results suggest that 5FU resistance observed in cell lines may be overcome by host immunity or by combination therapy with immune checkpoint blockade.
Osirisgene family defines the cuticle nano-patterns ofDrosophila
Authors: Sun Zhengkuan , Inagaki Sachi , Miyoshi Keita , Saito Kuniaki , Hayashi Shigeo
Published: February 2024

Nanostructures of pores and protrusions in the insect cuticle modify molecular permeability and surface wetting and help insects sense a variety of environmental cues. The cellular mechanism specifying cuticle nanostructures is poorly understood. Here, we show that insect-specificOsirisfamily genes are expressed in various cuticle-secreting cells in theDrosophilahead in the early stage of cuticle secretion and collectively cover nearly the entire surface of the head epidermis. We show that each sense organ cell with various cuticular nanostructures expresses a unique combination ofOsirisgenes.Osirisgene mutations caused various cuticle defects in the corneal nipples of the eye and pores of the chemosensory sensilla.Osirisgenes provide an entry point for investigating cuticle nanopatterning in insects.
Local muscle pressure stimulates the principal receptors for proprioception
Authors: Torell Frida , Dimitriou Michael
Published: February 2024

Proprioception plays a crucial role in motor coordination and self-perception. Muscle spindles are the principal receptors for proprioception. They are believed to encode muscle stretch and signal limb position and velocity. Here, we applied percutaneous pressure to a small area of extensor muscles at the forearm while recording spindle afferent responses, skeletal muscle activity and hand kinematics. Three levels of sustained pressure were applied on the spindle-bearing muscle when the hand was relaxed and immobile (‘isometric’ condition) and when the participant’s hand moved rhythmically at the wrist. As hypothesized to occur due to compression of the spindle capsule, we show that muscle pressure is an ‘adequate’ stimulus for human spindles in isometric conditions, and that pressure enhances spindle responses during stretch. Interestingly, release of sustained pressure in isometric conditions lowered spindle firing below baseline rates. Our findings urge a re-evaluation of muscle proprioception in sensorimotor function and various neuromuscular pathologies.

HIGHLIGHTS

Local muscle pressure is an adequate stimulus for spindles in isometric conditions

Release of pressure in isometric conditions lowers spindle firing below baseline rates

Local muscle pressure enhances spindle afferent responses during muscle stretch
Gut microbial-mediated polyphenol metabolism is restrained by parasitic whipworm infection and associated with altered immune function in mice
Authors: Andersen-Civil Audrey Inge Schytz , Arora Pankaj , Zhu Ling , Myhill Laura J. , Gökgöz Nilay Büdeyri , Castro-Mejia Josue L. , Leppä Milla M. , Hansen Lars H. , Lessard-Lord Jacob , Salminen Juha-Pekka , Thamsborg Stig M. , Nielsen Dennis Sandris , Desjardins Yves , Williams Andrew R.
Published: February 2024

Polyphenols are phytochemicals commonly found in plant-based diets which have demonstrated immunomodulatory and anti-inflammatory properties. However, the interplay between polyphenols and pathogens at mucosal barrier surfaces has not yet been elucidated in detail. Here, we show that proanthocyanidin (PAC) polyphenols interact with gut parasites to influence immune function and gut microbial-derived metabolites in mice. PAC intake inhibited mastocytosis during infection with the small intestinal roundwormHeligmosomoides polygyrus, and induced a type-1, interferon-driven mucosal immune response during infection with the large intestinal whipwormTrichuris muris.PAC also induced alterations in mesenteric lymph node T-cell populations that were dependent on infection model, with a Th2/Treg bias duringH. polygyrusinfection, and a Th1 bias duringT. murisinfection. In the absence of infection, PAC intake promoted the expansion ofTuricibactersp. within the gut microbiota, increased faecal short chain fatty acids, and enriched phenolic metabolites such as phenyl-γ-valerolactones in the caecum. However, these putatively beneficial effects were reduced in PAC-fed mice infected withT. muris,suggesting concomitant parasite infection can attenuate gut microbial-mediated PAC catabolism. Collectively, our results suggest an inter-relationship between a phytonutrient and infection, whereby PAC may augment parasite-induced inflammation (most prominently with the caecum dwellingT. muris), and infection may abrogate the beneficial effects of health-promoting phytochemicals.
DrosophilaHCN mediates gustatory homeostasis by preserving sensillar transepithelial potential in sweet environments
Authors: Lee MinHyuk , Park Se Hoon , Joo Kyeung Min , Kwon Jae Young , Lee Kyung-Hoon , Kang KyeongJin
Published: February 2024

Establishing transepithelial ion disparities is crucial for sensory functions in animals. In insect sensory organs called sensilla, a transepithelial potential, known as the sensillum potential (SP), arises through active ion transport across accessory cells, sensitizing receptor neurons such as mechanoreceptors and chemoreceptors. Because multiple receptor neurons are often co-housed in a sensillum and share SP, niche-prevalent overstimulation of single sensory neurons can compromise neighboring receptors by depleting SP. However, how such potential depletion is prevented to maintain sensory homeostasis remains unknown. Here, we find that theIh-encoded hyperpolarization-activated cyclic nucleotide gated (HCN) channel bolsters the activity of bitter-sensing gustatory receptor neurons (bGRNs), albeit acting in sweet-sensing GRNs (sGRNs). For this task, HCN maintains SP despite prolonged sGRN stimulation induced by the diet mimicking their sweet feeding niche, such as overripe fruit. We present evidence thatIh-dependent demarcation of sGRN excitability is implemented to throttle SP consumption, which may have facilitated adaptation to a sweetness-dominated environment. Thus, HCN expressed in sGRNs serves as a key component of a simple yet versatile peripheral coding that regulates bitterness for optimal food intake in two contrasting ways: sweet-resilient preservation of bitter aversion and the previously reported sweet-dependent suppression of bitter taste.
Distinct Effects of Aducanumab and Lecanemab on Intraneuronal Endogenous Aβ42 and Phosphorylated Tau in Alzheimer’s Disease Treatment
Authors: Liu Ming-Jie , Long Zhu , Li Fuyun , Shi Xiaobang , Shen Yan-Fei , Liu Meng-Lu
Published: February 2024

In the treatment of Alzheimer’s Disease (AD), two FDA-approved monoclonal antibodies, Aducanumab (Adu) and Lecanemab (LCN), exhibit significant differences in clinical benefits. By utilizing human-induced basal forebrain cholinergic neurons (BFCNs) derived from AD patient skin fibroblasts, we successfully recapitulated the natural endogenous neuropathologies of Aβ42 and Tau within just 21 days and revealed distinct intraneuronal effects of Adu and LCN. Both antibodies are internalized into BFCNs and localize with cytosolic Aβ42. However, LCN, selectively targeting Aβ42 oligomers and protofibrils, triggers TRIM21 pathway and significantly enhances autolysosome- and proteasome-mediated Aβ42 clearance, thereby leading to a marked reduction in phosphorylated Tau181 (pTau181) pathology. In contrast, the fibrillized Aβ42-selective Adu shows considerably weaker effects. This study not only reveals the unique intraneuronal actions of Adu and LCN but also provides a reliable and accessible human neuronal model for evaluating potential AD therapeutics, emphasizing the importance of intraneuronal pathology in the treatment of AD.
Genotypic and phenotypic characterization ofEnterococcus faecalisisolates from periprosthetic joint infections
Authors: Haeberle Amanda , Greenwood-Quaintance Kerryl , Zar Sarah , Johnson Stephen , Patel Robin , Willett Julia L. E.
Published: February 2024

Over 2.5 million prosthetic joint implantation surgeries occur annually in the United States. Periprosthetic joint infections (PJIs), though occurring in only 1-2% of patients receiving replacement joints, are challenging to diagnose and treat and are associated with significant morbidity. The Gram-positive bacteriumEnterococcus faecalis, which can be highly antibiotic resistant and is a robust biofilm producer on indwelling medical devices, accounts for 2-11% of PJIs.E. faecalisPJIs are understudied compared to those caused by other pathogens, such asStaphylococcus aureus. This motivates the need to generate a comprehensive understanding ofE. faecalisPJIs to guide future treatments for these infections. To address this, we describe a panel ofE. faecalisstrains isolated from the surface of prosthetic joints in a cohort of individuals treated at Mayo Clinic in Rochester, MN. Here, we present the first complete genome assemblage ofE. faecalisPJI isolates. Comparative genomics shows differences in genome size, virulence factors, antimicrobial resistance genes, plasmids, and prophages, underscoring the genetic diversity of these strains. These isolates have strain-specific differences inin vitrobiofilm biomass, biofilm burden, and biofilm morphology. We measured robust changes in biofilm architecture and aggregation for all isolates when grown in simulated synovial fluid (SSF). Lastly, we evaluated antibiotic efficacy of these isolates and found strain specific changes across all strains when grown in SSF. Results of this study highlight the existence of genetic and phenotypic heterogeneity amongE. faecalisPJI isolates which will provide valuable insight and resources for futureE. faecalisPJI research.

Importance

Periprosthetic joint infections (PJIs) affect ∼1-2% of those who undergo joint replacement surgery.Enterococcus faecalisis a Gram-positive opportunistic pathogen that causes ∼10% of PJIs in the United States each year, but our understanding of how and whyE. faecaliscauses PJIs is limited.E. faecalisinfections are typically biofilm associated and can be difficult to clear with antibiotic therapy. Here, we provide complete genomes for fourE. faecalisPJI isolates from the Mayo Clinic. These isolates have strain-specific differences in biofilm formation, aggregation, and antibiotic susceptibility in simulated synovial fluid. These results provide important insight into genomic and phenotypic features ofE. faecalisisolates from PJI.
Dynamics of quasiholes and quasiparticles at the edges of small lattices
Authors: Li Xikun , Jaworowski Błażej , Haque Masudul , Nielsen Anne E. B.
Published: February 2024

We study quench dynamics of bosonic fractional quantum Hall systems in small lattices with cylindrical boundary conditions and low particle density. The states studied have quasiholes or quasiparticles relative to the bosonic Laughlin state at half-filling. Pinning potentials are placed at edge sites (or sites close to the edges) to trap quasiholes and qausiparticles. The potentials are then turned off, and because the edges of fractional quantum Hall systems host chiral edge modes, we expect chiral dynamics of the quasiholes and quasiparticles. We numerically show that chiral motion of the density distribution is observed and robust for the case with positive potentials (quasiholes), but that there is no noticeable chiral motion for negative potentials (quasiparticles). The comparison of the numerical ground states with model lattice Laughlin wave functions suggests that both positive and negative potentials do create and pin anyons that are not necessarily well separated on small lattices. Initializing the dynamics with the model state also shows the lack of chiral dynamics of quasiparticles. Our results suggest that, in small lattices with low particle density, quasiparticles are strongly adversely affected in dynamical processes, whereas quasiholes are dynamically robust.

Published by the American Physical Society
2024
Truncated stochastically switching processes
Authors: Bressloff Paul C.
Published: February 2024

There are a large variety of hybrid stochastic systems that couple a continuous process with some form of stochastic switching mechanism. In many cases the system switches between different discrete internal states according to a finite-state Markov chain, and the continuous dynamics depends on the current internal state. The resulting hybrid stochastic differential equation (hSDE) could describe the evolution of a neuron's membrane potential, the concentration of proteins synthesized by a gene network, or the position of an active particle. Another major class of switching system is a search process with stochastic resetting, where the position of a diffusing or active particle is reset to a fixed position at a random sequence of times. In this case the system switches between a search phase and a reset phase, where the latter may be instantaneous. In this paper, we investigate how the behavior of a stochastically switching system is modified when the maximum number of switching (or reset) events in a given time interval is fixed. This is motivated by the idea that each time the system switches there is an additive energy cost. We first show that in the case of an hSDE, restricting the number of switching events is equivalent to truncating a Volterra series expansion of the particle propagator. Such a truncation significantly modifies the moments of the resulting renormalized propagator. We then investigate how restricting the number of reset events affects the diffusive search for an absorbing target. In particular, truncating a Volterra series expansion of the survival probability, we calculate the splitting probabilities and conditional MFPTs for the particle to be absorbed by the target or exceed a given number of resets, respectively.

Published by the American Physical Society
2024
Predicting Phase Stability at Interfaces
Authors: Pitfield J. , Taylor N. T. , Hepplestone S. P.
Published: February 2024

We present the RAFFLE methodology for structural prediction of the interface between two materials and demonstrate its effectiveness by applying it to MgO encapsulated by two layers of graphene. To address the challenge of interface structure prediction, our methodology combines physical insights derived from morphological features observed in related systems with an iterative machine learning technique. This employs physical-based methods, including void-filling and n-body distribution functions to predict interface structures. For the carbon-MgO encapsulated system, we have shown the rocksalt and hexagonal phases of MgO to be the two most energetically stable in the few-layer regime. We demonstrate that monolayer rocksalt is heavily stabilized by interfacing with graphene, becoming more energetically favorable than the graphenelike monolayer hexagonal MgO. The RAFFLE methodology provides valuable insights into interface behavior, and a route to finding new materials at interfaces.

Published by the American Physical Society
2024
Tomasch Oscillations as Above-Gap Signature of Topological Superconductivity
Authors: Štrkalj Antonio , Chen Xi-Rong , Chen Wei , Xing D. Y. , Zilberberg Oded
Published: February 2024

The identification of topological superconductors usually involves searching for in-gap modes that are protected by topology. However, in current experimental settings, the smoking-gun evidence of these in-gap modes is still lacking. In this Letter, we propose to support the distinction between two-dimensional conventional s-wave and topological p-wave superconductors by above-gap transport signatures. Our method utilizes the emergence of Tomasch oscillations of quasiparticles in a junction consisting of a superconductor sandwiched between two metallic leads. We demonstrate that the behavior of the oscillations in conductance as a function of the interface barriers provides a distinctive signature for s-wave and p-wave superconductors. Specifically, the oscillations become weaker as the barrier strength increases in s-wave superconductors, while they become more pronounced in p-wave superconductors, which we prove to be a direct manifestation of the pairing symmetries. Our method can serve as a complimentary probe for identifying some classes of topological superconductors through the above-gap transport.

Published by the American Physical Society
2024
Unraveling the transformation: the three-wave time-lagged study on big data analytics, green innovation and their impact on economic and environmental performance in manufacturing SMEs
Authors: Mehmood Khalid , Jabeen Fauzia , Rashid Md , Alshibani Safiya Mukhtar , Lanteri Alessandro , Santoro Gabriele
Published: February 2024

Purpose

The firms’ adoption and improvement of big data analytics capabilities to improve economic and environmental performance have recently increased. This makes it important to discover the underlying mechanism influencing the association between big data analytics (BDA) and economic and environmental performance, which is missing in the existing literature. The present study discovers the indirect effect of green innovation (GI) and the moderating role of corporate green image (CgI) on the impact of BDA capabilities, including big data management capability (MC) and big data talent capability (TC), on economic and environmental performance.

Design/methodology/approach

A time-lagged design was employed to collect data from 417 manufacturing firms, and study hypotheses were evaluated using Mplus.

Findings

The empirical outcomes indicate that both BDA capabilities of firms significantly influence green innovation (GI), which significantly mediates the relationship between BDA and economic and environmental performance. Our findings also revealed that CgI strengthened the effect of GI on economic and environmental performance. The empirical evidence provides important theoretical and practical repercussions for manufacturing SMEs and policymakers.

Originality/value

This study contributes to the literature on BDA by empirically exploring the effects of MC and TC on improving the EcP and EnP of manufacturing firms. It does so through the indirect impact of GIs and the moderating effect of CgI, thereby extending the Dynamic capabilities view (DCV) paradigm.