bluuebunny/crossref_metadata_2025 huggingface dataset:
LOL-EVE: Predicting Promoter Variant Effects from Evolutionary Sequences
Authors: Shearer Courtney A. , Teufel Felix , Orenbuch Rose , Ritter Daniel , Spinner Aviv , Xie Erik , Frazer Jonathan , Dias Mafalda , Notin Pascal , Marks Debora S.
Published: November 2024

Genetic studies reveal extensive disease-associated variation across the human genome, predominantly in noncoding regions, such as promoters. Quantifying the impact of these variants on disease risk is crucial to our understanding of the underlying disease mechanisms and advancing personalized medicine. However, current computational methods struggle to capture variant effects, particularly those of insertions and deletions (indels), which can significantly disrupt gene expression. To address this challenge, we present LOL-EVE (Language Of Life across EVolutionary Effects), a conditional autoregressive transformer model trained on 14.6 million diverse mammalian promoter sequences. Leveraging evolutionary information and proximal genetic context, LOL-EVE predicts indel variant effects in human promoter regions. We introduce three new benchmarks for indel variant effect prediction in promoter regions, comprising the identification of causal eQTLs, prioritization of rare variants in the human population, and understanding disruptions of transcription factor binding sites. We find that LOL-EVE achieves state-of-the-art performance on these tasks, demonstrating the potential of region-specific large genomic language models and offering a powerful tool for prioritizing potentially causal non-coding variants in disease studies.
Latent encoding of movement in primary visual cortex
Authors: Cosnier-Horeau Charlie , Germaine Hannah , Van Hooser Stephen , Choi Isaiah , Ribot Jérôme , Touboul Jonathan D.
Published: November 2024

Neurons in the primary visual cortex (V1) are classically thought to encode spatial features of visual stimuli through simple population codes: each neuron exhibits a preferred orientation and preferred spatial frequency that are invariant to other aspects of the visual stimulus. Here, we show that this simple rule does not apply to the representation of major features of stimulus motion, including stimulus direction and temporal frequency (TF). We collected an extensive dataset of cat V1 responses to stimuli covarying in orientation, direction, spatial frequency, and TF to assess the extent of motion selectivity. In over half of V1, we found that the preferred direction changed with stimulus TF, revealing four distinct map motifs embedded within V1’s functional architecture. Additionally, preferred TF was mostly uniform across the cortical surface. Despite the lack of spatial modulation for the preferred TF map and the lack of invariance for the preferred direction map, we found using convolutional neural networks that direction, TF and stimulus speed can be accurately decoded from V1 responses at all cortical locations. These findings suggest that subtle modulations of V1 activity may convey fine information about stimulus motion, pointing to a novel primary sensory encoding mechanism despite complex co-variation of responses to multiple attributes across V1 neurons.

Significance Statement

Cortical maps are thought to be useful for efficient processing of sensory information. In the primary visual cortex (V1), they are believed to provide uniform coverage across the visual field, ensuring that all orientations, spatial frequencies, and other features are consistently represented at each location in visual space. This organization supports stable visual perception, but it remains unclear how V1 encodes motion, particularly speed. Here, we reveal that cat V1 represents motion speed in a distributed manner without spatially organized temporal frequency maps, and that direction maps vary with stimulus speed. Nonetheless, we show that information on speed and preferred direction is decodable at all cortical locations. These findings challenge the classical uniform coverage hypothesis for motion attributes, and suggest that V1 encodes motion information in a more flexible manner.
Salinity impacted microbial carbonate precipitation mechanisms of modern microbialites in peritidal zone
Authors: Hsieh Yunli Eric , Yang Sung-Yin , Liu Shao-Lun , Wang Shih-Wei , Wang Wei-Lung , Tang Sen-Lin , Yang Shan-Hua
Published: November 2024

Microbialites, ancient records of microbial activity, serve as significant indicators of environmental change. This study examined microbialites from the peritidal zone of three tide pools at Fongchueisha, Hengchun, Taiwan, to investigate the impact of salinity on microbial community composition and carbonate precipitation mechanisms. Microbial samples were collected across varying salinity gradients over multiple timepoints and analyzed using next-generation sequencing of bacterial 16S and eukaryotic 18S rRNA genes. Our findings reveal that the microbial communities in higher salinity environments exhibited significant shifts, with increased relative abundance of ureolytic bacteria and ammonifying microorganisms, such asMyxococcotaandActinobacteriota. This suggests the presence of diverse microbial carbonate precipitation mechanisms beyond photosynthesis, including ureolysis and ammonification. Furthermore, our results show that changes in the composition of cyanobacteria and diatoms were influenced by salinity, with heterocystous cyanobacteria (e.g.,Nostocales) dominating low-salinity environments, and non-heterocystous cyanobacteria (e.g.,Synechococcales) prevailing in higher salinity environments. Functional predictions reveal that microbial communities in high-salinity environments were enriched in anaerobic metabolic pathways, including pyruvate fermentation and the urea cycle. These findings highlight the significant role of salinity in influencing microbial composition and metabolic pathways, shaping carbonate precipitation processes in microbialites.

Importance

The study focuses on the impact of environmental salinity on microbial community composition and carbonate precipitation mechanisms within modern microbialites, based on an analysis of samples from three tide pools with different salinity levels collected at five time points throughout the year. Using next-generation sequencing of bacterial 16S and eukaryotic 18S rRNA genes, we identified key shifts in microbial communities along salinity gradients and explored diverse microbial processes involved in carbonate precipitation. This work enhances our understanding of microbial ecosystems within modern microbialites and their response to environmental changes. Additionally, our study provides insight into ancient biogeochemical processes, with implications for interpreting microbial metabolism in carbonate precipitation across different salinity regimes.
Structures of vertebrate R2 retrotransposon complexes during target-primed reverse transcription and after second strand nicking
Authors: Thawani Akanksha , Rodríguez-Vargas Anthony , Treeck Briana Van , Hassan Nozhat T , Adelson David L , Nogales Eva , Collins Kathleen
Published: November 2024

R2 retrotransposons are model site-specific eukaryotic non-LTR retrotransposons that copy-and-paste into gene loci encoding ribosomal RNAs. Recently we demonstrated that avian A-clade R2 proteins achieve efficient and precise insertion of transgenes into their native safe-harbor loci in human cells. The features of A-clade R2 proteins that support gene insertion are not characterized. Here, we report high resolution cryo-electron microscopy structures of two vertebrate A-clade R2 proteins, avian and testudine, at the initiation of target-primed reverse transcription and one structure after cDNA synthesis and second strand nicking. Using biochemical and cellular assays we discover the basis for high selectivity of template use and unique roles for each of the expanded A-clade zinc-finger domains in nucleic acid recognition. Reverse transcriptase active site architecture is reinforced by an unanticipated insertion motif in vertebrate A-clade R2 proteins. Our work brings first insights to A-clade R2 protein structure during gene insertion and enables further improvement and adaptation of R2-based systems for precise transgene insertion.
Deconstructing evolutionary histories of complex genomic rearrangements in lung malignancies
Authors: Hu Xiaoju , Venkat Vignesh , Riedlinger Gregory , Shen Zhiyuan , Malhotra Jyoti , De Subhajyoti
Published: November 2024

Somatic genomic rearrangements are hallmarks of cancer. Complex genomic rearrangements (CGRs) involving multiple intertwined structural alterations are often present in tumor genomes. CGRs frequently harbor oncogenic drivers, but their genomic architectures and etiologies are poorly understood. We used deep-coverage optical mapping technology to profile the genomic landscapes of normal lung tissues, benign pulmonary lesions, carcinoma in situ, and advanced carcinomas to examine the patterns of genome disorganization and instability in different stages of carcinogenesis in lung. Large rearrangements and CGRs were prevalent in the carcinomas. We developed omcplR to resolve the architecture of CGRs and predict their genesis from optical mapping data using genome-graph concept. We found that CGRs often arose from hierarchical combinations of multiple, localized simple structural variations, and harbored allelic heterogeneity at the affected loci. Rearrangement patterns and associated genomic signatures suggested that chromoanasynthesis was a likely prevalent mechanism driving complex genomic rearrangements. The early rearrangement junctions in intra-chromosomal CGRs were usually localized within the same chromatin domains, but the late junctions in advanced tumors had more heterogeneous contexts suggesting progressive organizational heterogeneity. The CGRs, especially the late events therein were under positive selection. A composite signature of genomic alterations including the CGRs captured the trajectory of progressive genomic disorganization and instability with carcinogenesis in lung and underscored the extent of genomic structural heterogeneity among the in-situ tumors.
Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer’s disease
Authors: Cash David M , Morgan Katy E , O’Connor Antoinette , Veale Thomas D , Malone Ian B , Poole Teresa , Benzinger Tammie LS , Gordon Brian A , Ibanez Laura , Li Yan , Llibre-Guerra Jorge J. , McDade Eric , Wang Guoqiao , Chhatwal Jasmeer P , Day Gregory S , Huey Edward , Jucker Mathias , Levin Johannes , Niimi Yoshiki , Noble James M , Roh Jee Hoon , Sánchez-Valle Racquel , Schofield Peter R , Bateman Randall J , Frost Chris , Fox Nick C ,   The Dominantly Inherited Alzheimer Network (DIAN)
Published: November 2024

INTRODUCTION

Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.

METHODS

Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes.

RESULTS

Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 22[95%CI 13,46], cortical PIB 32[20,57], CSF p-tau181 58[40,112]) for a four-year trial to have 80% power (5% statistical significance) to detect a 25% reduction in absolute levels of pathology, allowing 40% dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50% reduction in rate of change. Sample sizes ranged from 75-250 (examples precuneus volume: 137[80,284], cortical FDG: 256[100,1208], CDR-SB: 161[102,291]).

DISCUSSION

Despite the rarity of ADAD, clinical trials with feasible sample sizes given the number of cases appear possible.
Neuroimaging Insights into Brain Mechanisms of Early-onset Restrictive Eating Disorders
Authors: Moreau Clara A. , Ayrolles Anael , Ching Christopher R. K. , Bonicel Robin , Mathieu Alexandre , Stordeur Coline , Bergeret Pierre , Traut Nicolas , Tran Lydie , Germanaud David , Alison Marianne , Elmaleh-Bergès Monique , Ehrlich Stefan , Thompson Paul M. , Bourgeron Thomas , Delorme Richard
Published: November 2024

Background

Early-onset restrictive eating disorders (rEO-ED) encompass a heterogeneous group of conditions, including early-onset anorexia nervosa (EO-AN) and avoidant restrictive food intake disorders (ARFID). Almost nothing is known about the consequences of rEO-ED on brain development.

Methods

We performed the largest comparison of MRI-derived brain features in children and early adolescents (<13 years) with EO-AN (n=124), ARFID (n=50), and typically developing individuals (TD, n=112).

Results

Despite similar body mass index (BMI) distributions, EO-AN and ARFID showed divergent structural patterns, suggesting independent brain mechanisms. Half the regional brain measures were correlated with BMI in EO-AN and none in ARFID, indicating a partial mediation of EO-AN signal by BMI. EO-AN was associated with a widespread pattern of thinner cortex, while underweight ARFID patients exhibited smaller surface area and subcortical volumes than TD.

Conclusion

Future studies will be required to partition the contribution of low BMIvs.ED mechanisms in neurodevelopmental disorders.
Designing a Structural Equation Model (SEM) for the Relationship between Quality of Working Life and Job Involvement among Nurses, with the Mediating Role of Job Burnout and Job Identity
Authors: Nazari Elham , Roumi Azin , Sabooteh Toomaj
Published: November 2024

Introduction

Given the issue of nursing shortages globally and in Iran, compounded by new global conditions due to the COVID-19 pandemic, the quality of working life (QWL) among nurses and the factors influencing it have become important issues. Therefore, this study aimed to investigate the relationship between QWL and job involvement among nurses, considering the mediating role of job burnout and job identity.

Methodology

This study is a cross-sectional analysis conducted in Khorramabad, Lorestan province, Iran. The statistical population comprised nurses employed in Khorramabad hospitals. The sample size was determined using Cochran’s formula, and simple random sampling was employed. To assess the variables, the Work-Related Quality of Life Scale (WRQOLS), Maslach Burnout Questionnaire, Hao’s Professional Identity Questionnaire, and the Utrecht Work Engagement Scale (UWES-9) were used. Structural Equation Modeling (SEM) was employed to examine the relationships between variables, and Smart-PLS software was used for data analysis.

Results

Results showed a significant negative correlation between job involvement, job identity, and QWL with job burnout. The correlation coefficients were -0.910, -0.878, and -0.900, respectively. Additionally, the results indicated that job identity and job burnout mediate the relationship between QWL and job involvement among nurses.

Conclusion

According to the findings of this study, job identity and job burnout have a mediating effect on the relationship between QWL and employee engagement. Therefore, when nursing managers aim to enhance the job engagement of new nurses, they should consider not only QWL but also the aspects of job identity and job burnout. Enhancing QWL can improve psychological empowerment and reduce nurse burnout. Moreover, professional training and improvement of communication skills among nursing staff can assist them in managing job burnout.
Remoscope: a label-free imaging cytometer for malaria diagnostics
Authors: Lebel Paul M. , Jeyakumar Ilakkiyan , Khoo Michelle W.L. , Charlton Chris , Saxena Aditi , Jacobsen Axel , James Emorut , Huynh Emily , Wu William , Courville Greg , Fu Pei-Chuan , Raghavan Madhura , Puccinelli Robert , Peter Olwoch , Dorsey Grant , Rosenthal Phil , DeRisi Joseph , Gomez-Sjoberg Rafael
Published: November 2024

Malaria diagnostic testing in high transmission settings remains a burden on healthcare systems. Here we present Remoscope, a portable automated imaging cytometer that scans fresh, unstained whole blood using a custom neural network on low-cost hardware. By screening up to two million red blood cells, Remoscope performs label-free quantitative stage-specific detection ofPlasmodium falciparum(Pf) in 1-12 minutes without sample fixation, staining, or slide scanning. Flow is used to achieve high cellular throughput, with blood confined to a 4.5 µm monolayer in low-cost disposable flow cartridges. Remoscope performance was benchmarkedin vitroby titration of cultured parasites into uninfected whole blood at concentrations of 17.1-710,000 parasites/µL. Counts generated by Remoscope demonstrated a linear response across the entire range. Considering drug susceptibility assays, the half-maximal effective concentration (EC50) of chloroquine (CQ) for the W2 strain ofPfwas 211 nM by Remoscope, compared to 191 nM for conventional flow cytometry. Remoscope’s real-world diagnostic accuracy was evaluated in a cohort of 500 individuals in eastern Uganda, comprising 601 unique clinic visits. Parallel measurements of parasitemia were performed using Remoscope, qPCR targeting the multicopy conserved var gene acidic terminal sequence, and microscopic evaluation of Giemsa-stained thick blood smears. Remoscope’s limit of detection with respect to qPCR was 95.1 parasites/µL. At this threshold, the system had a sensitivity of 83%, specificity of 96%, Positive Predictive Value (PPV) of 91%, and a Negative Predictive Value (NPV) of 93%. Remoscope’s speed, accuracy, low cost, and ease of use address practical challenges in malaria diagnostic settings around the world. As a general imaging flow cytometer, Remoscope may also inform the development of recognition models for the diagnosis of other infectious and noninfectious blood disorders.
Mathematical Modelling of Oxygenation Dynamics using High-Resolution Perfusion Data – Part 2: Physiological Insights
Authors: Sharabiani Mansour T. A. , Mahani Alireza S. , Issitt Richard W. , Srinivasan Yadav , Bottle Alex , Stoica Serban
Published: November 2024

Background

Accurate prediction of oxygen demand is essential for optimizing oxygen delivery during paediatric cardiopulmonary bypass (CPB), but traditional models may not fully account for the influences of temperature, age, and weight. We aimed to quantify these relationships and assess age-related variability in the oxygen extraction ratio (OER) response.

Methods

We analysed data from 334 paediatric patients undergoing CPB, developing an extended GARIX model (eGARIX) that incorporates age, weight, and nonparametric temperature modelling via splines. Subgroup analyses compared OER responses to changes in haemoglobin and arterial oxygen saturation across different age groups.

Results

eGARIX significantly improved model fit over GARIX (p < 0.001). Oxygen demand per body surface area exhibited a nonlinear relationship with age and weight, peaking around 3 years. In neonates and infants, oxygen demand positively correlated with weight; in adolescents, the correlation was negative. The temperature dependence was more complex than constant-Q10models predict, showing reduced sensitivity of oxygen demand to mild hypothermia and increased sensitivity at deep hypothermia. Younger patients showed a diminished OER response to haemoglobin changes.

Conclusions

Age and weight significantly affect oxygen demand during paediatric CPB, highlighting the need for individualized models. Our findings challenge constant-Q10assumptions, indicating that nonparametric models better capture temperature effects. Personalized oxygen delivery strategies are essential; further validation is recommended.
Bleeding Risks Associated with Antidepressant Medications Among Acute Ischemic Stroke Patients on Anticoagulation or Dual Anti-platelet Therapy
Authors: Simmonds Kent P. , Chavez Audrie , Venkatachalam Aardhra M. , Ifejika Nneka
Published: November 2024

Background

Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitors (SSRI/SNRIs) can treat post-stroke depression and improve recovery but may be withheld for acute ischemic stroke (AIS) patients over bleeding risk concerns. Study objectives were: 1) Quantify the association between early SSRI/SNRI initiation and adverse bleeding events 2) Assess bleeding risk among patients receiving concurrent anticoagulants (AC) or dual antiplatelet therapy (DAPT) and 3) Evaluate if bleeding risks were specific to SSRI/SNRIs.

Methods

AIS patients were identified from Electronic Medical Records of 76 healthcare organizations (2004-2024). Patients were assigned to one of three groups within 3 months of the indexed stroke – (1) No antidepressant (No AD), (2) SSRI/SNRI, (3) Other AD (i.e., mirtazapine, bupropion, trazodone, or tricyclic ADs). The primary outcome was 1-year risk of a major bleeding event. Secondary outcomes included hemorrhagic stroke (HS), fall/fracture and death. Baseline differences were adjusted for using 1:1 matched propensity scores.

Results

679,532 patients were included [No AD (n=612,868), SSRI/SNRI (n=40,136), Other AD (n=26,528)]. Early SSRI/SNRIs use (vs. No ADs) was not associated with an increased risk of a major bleed among all patients (n=36,838 pairs) or patients on anticoagulants (n=7,942 pairs). Concurrent use of SSRI/SNRIs and DAPT was associated with an 11% increased risk of a major bleed (RR: 1.11, 95% CI: 1.00 -1.24, n=7,536 pairs). Bleed risks were higher (RR: 1.10; 95 CI% 1.05, 1.14) for use of Other AD vs. SSRI/SNRI (n=22,789 pairs).

Discussion

SSRI/SNRIs treat post-stroke depression, promote recovery and are generally safe, however, bleed risks among patients on current DAPT should be considered.
Development of a pipeline to evaluate YAP-TEAD inhibitor potential-direct TEAD inhibition represses cancerous growth in aNF2-mutant model of mesothelioma
Authors: Cunningham Richard , Jia Siyang , Purohit Krishna , Fairley Michaela Noskova , Lin Yue , Hui Ning Sze , Graham Rebecca E. , Rossi Adriano G. , Cholewa-Waclaw Justyna , Carragher Neil O. , Hansen Carsten Gram
Published: November 2024

As the core, tumorigenic downstream effectors of the Hippo signalling pathway, YAP/TAZ and the TEAD family of transcription factors represent attractive targets for drug discovery efforts within cancer research. This is particularly true within the context of pleural mesothelioma, in which there are many recent preclinical developments and clinical trials evaluating the efficacy of TEAD inhibitors. The range of inhibitors have shown great promise, but comparisons of their performances are so far limited. Here we develop a high content pipeline that enables a comparative analysis of currently developed YAP/TAZ-TEAD inhibitors. We take advantage of isogenic cellular models that enable us to examine inhibitor specificity. We identify genetic compensation of the Hippo pathway transcriptional module, with implications for therapeutic targeting, and implement Cell Painting to develop a detailed morphological profiling pipeline that enables further characterisation, quantification, and analysis of off-target effects. Our pipeline is scalable and allows us to establish specificity and comparative potency within cancer relevant assays in a clinically relevant cellular model.
Overexpression ofβTrCP1elicits cell death in cisplatin-induced senescent cells
Authors: Belmonte-Fernández Alejandro , Herrero-Ruíz Joaquín , Limón-Mortés M. Cristina , Sáez Carmen , Japón Miguel Á. , Mora-Santos Mar , Romero Francisco
Published: November 2024

Senescence is a non-proliferative cellular state derived from aging or in response to exogenous insults, such as those that cause DNA damage. As a result of cancer treatments like cisplatin, certain tumor cells may undergo senescence. However, rather than being beneficial for patients, this is detrimental because these cells might proliferate again under specific conditions and, more importantly, because they synthesize and secrete molecules that promote the proliferation of nearby cells. Therefore, to achieve complete tumor remission, it is necessary to develop senolytic compounds to eliminate senescent cells. Here, we studied the role of βTrCP1 in cell proliferation and senescence and found that lentiviral overexpression ofβTrCP1induces the death of senescent cells obtained after cisplatin treatment in both two-dimensional cell cultures and tumorspheres. Mechanistically, we demonstrated that overexpression ofβTrCP1triggers proteasome- dependent degradation of p21 CIP1, allowing damaged cells to progress through the cell cycle and consequently die. Furthermore, we identified nucleophosmin 1 (NPM1) as the intermediary molecule involved in the effect of βTrCP1 on p21 CIP1. We determined that increased amounts of βTrCP1 partially retains NPM1 in the nucleoli, preventing it from associating with p21 CIP1, thus leaving it unprotected from degradation by the proteasome. These results have allowed us to discover a potential new target for senolytic drugs, as retaining NPM1 in the nucleoli under senescent conditions induces cell death.
Lipid-driven SRC self-association modulates its transformation capacity
Authors: Mohammad Irrem-Laareb , Giannotti Marina I. , Fourgous Elise , Boublik Yvan , Fernándz Alejandro , Le Roux Anabel-Lise , Sirvent Audrey , Taulés Marta , Roche Serge , Pons Miquel
Published: November 2024

Src tyrosine kinase is anchored to the plasma membrane, however, the contribution of membrane lipids to its regulation remains elusive. Here we report Src self-association through a lysine cluster in the Src SH4 region mediated by lipids in human cells and in vitro. Mutation of the lysine cluster to arginine modulates Src self-association and its transforming function in human cells. This mechanism may also apply to other membrane-associated signaling proteins that have similar lysine clusters in their unstructured regions.

Lipid-anchored micron-sized condensates of full length Src are formed in supported homogeneous lipid bilayers (i.e independently of lipid phase separation). Condensates are also formed by the purified Src N-terminal regulatory element, including the myristoylated SH4 domain, the intrinsically disordered Unique domain and the globular SH3 domain. The isolated SH4 domain forms small protein-lipid clusters, but not micron-size condensates.

Our findings reveal lipid-mediated kinase self-association as an additional mechanism for Src regulation.

Significance Statement

Condensate formation, often associated to intrinsically disordered protein regions is emerging as a widespread regulatory mechanism. Protein phase separation has been linked to the regulation of kinases recruited to condensates formed by other proteins. Here we show i) that the N-terminal disordered region of Src kinase drives lipid-mediated self-association to form condensates on the cell surface, ii) a lysine cluster in the N-terminal SH4 domain is essential for this process, iii) mutation of these lysine residues to arginine increases self-association in vitro and in vivo, and iv) self-association of Src results in enhanced transforming capacity in human cells. Similar lysine clusters are present in juxtamembrane regions suggest a general mechanism for modulating protein-protein interactions by lipids.

The article shows the formation of condensates by Src on supported lipid membranes mediated by lipids, dependent of a conserved lysine cluster in its SH4 domain, and modulating Src’s transforming capacity.

Full length Src and truncated variants including its myristoylated SH4 domain self-associate on the surface of homogeneous lipid bilayers.

The interaction of a lysine cluster in SH4 domain with lipids modulates Src self-association

Atomic force microscopy shows the formation of micron-size condensates and smaller clusters on the surface of supported lipid bilayers, depending on the lipid composition or the presence of mutations in the lysine cluster

Src self-association is confirmed in human cells and the Src transforming function of Src in human cells is modulated by lipid-mediated self-association
Biological Boundary Conditions Regulate the Internalization ofAspergillus FumigatusConidia by Alveolar Cells
Authors: Schiefermeier-Mach Natalia , Polleux Julien , Heinrich Lea , Lechner Lukas , Vorona Olexandra , Perkhofer Susanne
Published: November 2024

Introduction

The lung environment is defined by unique biological boundary conditions, including complex alveolar geometry, extracellular matrix composition and mechanical forces generated during respiration. These factors were shown to regulate alveolar permeability, surfactant secretion, cell contractility and apoptosis, but their role in fungal infections remains unknown.Aspergillus fumigatusis a critical fungal pathogen that causes severe pulmonary infections in immunocompromised individuals. Our study addresses a knowledge gap by investigating how boundary conditions affectA. fumigatusconidia interactions with alveolar epithelial cells.

Methods

We applied micropatterned substrates to confine cells into defined shapes and densities, allowing precise control over geometric conditions and extracellular matrix composition. Using cell line stably expressing the phagolysosomal protein Lamp1-NeonGreen and multiplane fluorescent microscopy, we evaluatedA. fumigatus conidiabinding and internalization efficiency.

Results

We observed significantly faster and more efficientA. fumigatusconidia internalization in cells confined on micropatterns compared to previously reported studies using cell monolayers. Altering cell geometry, density, and extracellular matrix composition strongly affected conidia binding and localization to Lamp1+phagolysosomes. Cells on X-shaped or multicellular micropatterns showed higher internalization rates, particularly at the periphery, suggesting spatial heterogeneity in pathogen uptake. Additionally, changes in extracellular matrix composition influenced the intracellular trafficking ofA. fumigatusconidia.

Discussion

Our findings emphasize the essential role that local mechanical and biochemical cues play in shaping the interactions between fungal pathogens and alveolar cells. Understanding how lung boundary conditions change in disease states will provide important insights into fungal infection outcomes.
Complete genomes of DNA viruses in faecal samples from small terrestrial mammals in Spain
Authors: Buigues Jaime , Viñals Adrià , Martínez-Recio Raquel , Monrós Juan S. , Sanjuán Rafael , Cuevas José M.
Published: November 2024

Viromics studies are allowing us to understand not only the enormous diversity of the virosphere, but also the potential threat posed by emerging viruses. Regarding the latter, the main concern lies in monitoring the presence of RNA viruses, but the zoonotic potential of some DNA viruses, on which we have focused in the present study, should also be highlighted. For this purpose, we analysed 160 faecal samples from 14 species belonging to three orders of small terrestrial mammals (i.e.Rodentia, LagomorphaandEulypotyphla). This allowed us to identify a total of 25 complete or near-complete genomes belonging to the familiesPapillomaviridae, Polyomaviridae, Adenoviridae, CircoviridaeandGenomoviridae, 18 of which could be considered new species or types. Our results provide a significant increase in the number of complete genomes of DNA viruses of European origin with zoonotic potential in databases, which are at present clearly under-represented compared to RNA viruses.
Chromatin architecture mapping by multiplex proximity tagging
Authors: Delamarre Axel , Bailey Benton , Yavid Jennifer , Koche Richard , Mohibullah Neeman , Whitehouse Iestyn
Published: November 2024

Chromatin plays a pivotal role in genome expression, maintenance, and replication. To better understand chromatin organization, we developed a novel proximity-tagging method which assigns unique DNA barcodes to molecules that associate in 3D space. Using this method – Proximity Copy Paste (PCP) – we mapped the connectivity of individual nucleosomes in Saccharomyces cerevisiae. By analyzing nucleosome positions and spacing on single molecule fibers, we show that chromatin is predominantly organized into regularly spaced nucleosome arrays that can be positioned or delocalized. Basic features of nucleosome arrays are generally explained by gene size and transcription. PCP can also map long-range, multi-way interactions and we provide the first direct evidence supporting a model that metaphase chromosomes are compacted by cohesin loop clustering. Analyzing single-molecule nuclease footprinting data we define distinct chromatin states within a mixed population to show that non-canonical nucleosomes, notably Overlapping-Di-Nucleosomes (OLDN) are a stable feature of chromatin. PCP is a versatile method allowing the detection of the connectivity of individual molecules locally and over large distance to be mapped at high-resolution in a single experiment.
Proteomic characterization ofMycobacterium tuberculosissubjected to carbon starvation
Authors: Devlin Kaylyn L. , Leach Damon T. , Stratton Kelly G. , Lamichhane Gyanu , Lin Vivian S. , Beatty Kimberly E.
Published: November 2024

Mycobacterium tuberculosis(Mtb) is the causative agent of tuberculosis (TB), the leading cause of infectious-disease related deaths worldwide. TB infections present as a spectrum from active to latent disease. In the human host,Mtbfaces hostile environments, such as nutrient deprivation, hypoxia, and low pH. Under these conditions,Mtbcan enter a dormant, but viable, state characterized by a lack of cell replication and increased resistance to antibiotics. These dormantMtbpose a major challenge to curing infections and eradicating TB globally. In the current study, we subjectedMtbto carbon starvation (CS), a culture condition that induces growth stasis and mimics nutrient-starved conditions associated with dormancyin vivo. We provide a detailed analysis of the proteome in CS compared to replicating samples. We observed extensive proteomic reprogramming, with 36% of identified proteins significantly altered in CS. Many enzymes involved in oxidative phosphorylation and lipid metabolism were retained or upregulated in CS. The cell wall biosynthetic machinery was present in CS, although numerous changes in the abundance of peptidoglycan, arabinogalactan, and mycolic acid biosynthetic enzymes likely result in pronounced remodeling of the cell wall. Many clinically approved anti-TB drugs target cell wall biosynthesis, and we found that these enzymes were largely retained in CS. Lastly, we compared our results to those of other dormancy models and propose that CS produces a physiologically-distinct state of stasis compared to hypoxia inMtb.
Molecular determinants of protein pathogenicity at the single-aggregate level
Authors: Urbanek Agnieszka , Garland Emma F. , Prescott Emily E. , King Marianne C. , Olerinyova Anna , Wareing Hollie E. , Georgieva Nia , Bradshaw Ellie L. , Tzokov Svetomir B. , Knight Alexander , Tartakovskii Alexander I. , Malm Tarja , Highley J Robin , De Suman
Published: November 2024

Determining the structure-function relationships of protein aggregates is a fundamental challenge in biology. These aggregates, whether formedin vitro, within cells, or in living organisms, present significant heterogeneity in their molecular features such as size, structure, and composition, making it difficult to determine how their structure influences their functions. Interpreting how these molecular features translate into functional roles is crucial for understanding cellular homeostasis and the pathogenesis of various debilitating diseases like Alzheimer’s and Parkinson’s. In this study, we introduce a bottom-up approach to explore how variations in protein aggregates’ size, composition, post-translational modifications and point mutations profoundly influence their biological functions. Applying this method to Alzheimer’s and Parkinson’s associated proteins, we uncover the mechanism of novel disease-relevant pathways and demonstrate how subtle alterations in composition and morphology can shift the balance between healthy and pathological states. Our findings establish a broadly applicable framework for investigating protein dysfunctions in various proteinopathies.
Respi-Radar – a tool to monitor respiratory infections in Belgium during the winter season 2023- 2024
Authors: De Muylder Géraldine , Couvreur Simon , Stefani Giulietta , Brugerolles Claire , Dockx Yinthe , Callies Milena , Janssens Raphaël , De Mot Laurane , Bossuyt Nathalie , Stassijns Jorgen
Published: November 2024

Following the experience gathered during the COVID-19 crisis, the Respi-Radar was developed by the Belgian Risk Assessment Group (RAG) in the summer of 2023, with the aim of assessing the epidemiological situation of respiratory infections and informing public health preparedness and response in Belgium.

The Respi-Radar consisted of four levels (green, yellow, orange and red) which indicated the extent of viral circulation and/or pressure on the healthcare system. Depending on the level, specific measures would apply to reverse the trend. The Respi-Radar used six indicators, from the Influenza-Like Illness and Severe Acute Respiratory Infection sentinel surveillances in nursing homes, primary and secondary care, as well as from the wastewater surveillance. Additional information, such as data from the national reference laboratories, also contributed to assessing the situation.

Based on the Respi-Radar tool, the RAG regularly evaluated the epidemiological situation of respiratory infections between September 2023 and March 2024.

The Respi-Radar tool appeared useful for following trends and effectively communicating on the epidemiological situation of respiratory infections. Applying specific measures depending on a level was less straightforward. The experience gained using the Respi-Radar tool was key to determine the best approach to assess and manage the epidemiological situation for future respiratory seasons.
Multiple paralogues and recombination mechanisms contribute to the high incidence of 22q11.2 Deletion Syndrome
Authors: Vervoort Lisanne , Dierckxsens Nicolas , Sousa Santos Marta , Meynants Senne , Souche Erika , Cools Ruben , Heung Tracy , Devriendt Koen , Peeters Hilde , McDonald-McGinn Donna , Swillen Ann , Breckpot Jeroen , Emanuel Beverly S. , Van Esch Hilde , Bassett Anne S. , Vermeesch Joris R.
Published: November 2024

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by nonallelic homologous recombination between the low copy repeats on Chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.
Inverse Cherenkov dielectric laser accelerator with alternating phase focusing for subrelativistic particles
Authors: Zhang Liwen , Xu Hongliang , Liu Weihao
Published: November 2024

In this paper, we propose a dielectric laser acceleration scheme based on the inverse Cherenkov effect, which uses the principle of alternating phase focusing to accelerate, confine, and bunch the subrelativistic electron beam over an extended distance. In this scheme, the reference electron is always synchronized with the acceleration wave and is thus continuously accelerated. Electrons around it are alternately subjected to focusing and defocusing forces by alternately jumping its phase. Optimizing the focusing period can achieve stable beam confinement. Simulations show that a 100 keV electron bunch can be coherently accelerated with the average acceleration gradient of 220.8  MV/m, and it can travel nearly 200  μm without loss in a channel only 500 nm wide. This approach is scalable, potentially enabling the development of millimeter-scale MeV particle accelerators for ground-breaking use in medical, scientific, and materials research.

Published by the American Physical Society
2024
New operation analysis method for vacuum tube driving a tuned cavity
Authors: Wu Jian , Zhang Chunlin , Wu Bin , Liu Hanyang , Li Xiang , Liu Yang , Long Wei , Li Xiao
Published: November 2024

The rf system of China Spallation Neutron Source (CSNS) Rapid Cycling Synchrotron (RCS) utilizes vacuum tubes to drive the ferrite-loaded cavities. Ensuring stable tube operation in the rf system is crucial for the acceleration of high-intensity beams, as any instability may impede further increases in beam power. Therefore, the operation of the vacuum tube under heavy beam loading has attracted significant attention, particularly in the case of CSNS-II RCS, where the circulating beam current is expected to reach up to 15.25 A, imposing a substantial burden on the vacuum tube for beam loading compensation. Thus, a comprehensive analysis of tube operation is imperative. However, current methods for the tube operation analysis are developed based on wideband rf cavities, which are inadequate when the load of the tube is a narrowband ferrite-loaded cavity equipped with a tuning system. The presence of a tuning system renders the modeling method for wideband rf cavities inapplicable for ferrite-loaded cavities. Therefore, the development of a new method is necessary. This paper introduces a novel method for analyzing operation of vacuum tube driving a tuned cavity. The effectiveness of the method is validated by comparing the analysis results with measurements under beam loading conditions. Furthermore, an estimation of tube operation under 500 kW beam loading for CSNS-II is provided.

Published by the American Physical Society
2024
Optimized detection modality for radio-frequency sensing with a double-resonance alignment magnetometer
Authors: Akbar A. , Koźbiał M. , Elson L. , Meraki A. , Kołodyński J. , Jensen K.
Published: November 2024

In this work, we present a comprehensive and comparative analysis of two detection modalities, i.e., polarization rotation and absorption measurement of light, for a double-resonance alignment magnetometer (DRAM). We derive algebraic expressions for magnetometry signals based on the description of multipole moments. Experiments are carried out using a room-temperature paraffin-coated cesium-vapor cell and measuring either the polarization rotation or absorption of the transmitted laser light. A detailed experimental analysis of the resonance spectra is performed to validate the theoretical findings for various input parameters. The results signify the use of a single isotropic relaxation rate, thus simplifying the data analysis for optimization of the DRAM. The sensitivity measurements are performed and reveal that the polarization-rotation detection mode yields larger signals and better sensitivity than absorption measurement of light.

Published by the American Physical Society
2024
Engineering exchange bias at the interface of self-polarized ultrathin ferroelectric
BaTiO3
and ferromagnetic
La0.67Sr0.33MnO3
Authors: Maity Tuhin , Bansal Manisha , Strkalj Nives , Dolui Kapildeb , Zhang Di , He Zihao , Nataf Guillaume F. , Lovett Adam , Ghidini Massimo , Dhesi Sarnjeet S. , Lu Ping , Wang Haiyan , Li Weiwei , MacManus-Driscoll Judith L.
Published: November 2024

We investigate the emergence and optimization of conventional exchange bias (EB) in ultrathin (<10 nm) ferroelectric (FE) BaTiO3 (BTO)/ferromagnetic (FM) La0.67Sr0.33MnO3 (LSMO) epitaxial bilayers without an antiferromagnetic (AFM) material. The EB originates from the electronic orbital reconstruction at the FE-FM interface due to the ferroelectric polarization. We achieve maximum EB of approximately 42 Oe with single-domain polarization in nine-unit-cell-thick BTO, setting the BTO thickness above the critical threshold for ferroelectricity yet below the thickness of strain relaxation and multidomain breakdown. Furthermore, the LSMO layer needs to be thick enough to sustain both the FM layer and polarization-induced AFM spin configuration at the LSMO/BTO interface, yet as thin as possible to enable the EB loop shift. The temperature, training, field, and thickness dependence of the EB confirm that the LSMO/BTO interface exhibits conventional EB despite its unconventional origin. Using x-ray magnetic circular dichroism, scanning transmission electron microscopy, and density-functional-theory calculations, we confirm that the macroscopic EB effect originates from the interfacial AFM spin configuration in LSMO driven by FE-induced -orbital modifications in interfacial Mn ions. Thus, we engineer strong interfacial EB coupling in artificial multiferroics without a conventional AFM material by controlling FE polarization, highlighting the potential for advanced spintronic applications.

Published by the American Physical Society
2024
Inclusion of statistical matter in the nonrelativistic limit of NS-NS supergravity
Authors: Lescano Eric
Published: November 2024

We combine techniques from kinetic theory and string dualities to couple statistical matter to a nonrelativistic supergravity background, enabling the theory to be formulated in a T-duality invariant form. Similarly to the relativistic case, we explicitly demonstrate that, in the nonrelativistic limit, the many-strings system necessitates a viscous fluid description for describing the statistical matter. This is achieved coupling a generalized energy-momentum tensor in the framework of double field theory, which it is covariant under T-duality transformations.

Published by the American Physical Society
2024
Dry polymer model for a string of pushers: Nontrivial scaling of tumbling time with shear rate
Authors: Saju Siji S. , Manna Raj Kumar , Kumar P. B. Sunil
Published: November 2024

Understanding the dynamics of active polymers is an important component for modeling the dynamic response of biological cells and microorganisms when subjected to external forces. A minimal computational model of active filaments that captures all the essential features of activity-induced filament motion is required to study large systems of dense suspensions. In this paper we present a model of a dry active polymer, compare its steady-state static and dynamic properties with those of a polymer consisting of extensile stresslets, and show that the two models give very similar results. When subjected to shear flow, both models show two distinct regimes in the tumbling interval as a function of shear rate, with a diffuse crossover regime in between. At high shear rate, the active and passive polymers follow the same power law for the tumbling interval. However, the tumbling interval is smaller than that of the passive polymer for low shear rates and larger for the high shear rate. We show that activity-induced large bends increase the coupling of the polymer with the shear gradient in the low-shear-rate regime, leading to a decrease in the tumbling interval. However, in the high-shear-rate regime, the active forces on the folds at the end of the stretched polymer prevent it from tumbling, leading to a larger tumbling interval. We show that the critical shear rate, at which the tumbling interval versus the shear-rate curve of the active polymer crosses that of the passive polymer, is determined by the balance of bending and shear forces and increases with κ/N3, where κ is the bending coefficient and N is the length of the polymer.

Published by the American Physical Society
2024