bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Chronotypes Using the Symbolic Aggregate apprXimation (SAX) on Actigraphy Data
Authors: Luo Wen , Androulakis Ioannis P.
Published: September 2024

In this study, we discuss an efficient approach to characterizing chronotypes using Symbolic Aggregate approXimation (SAX) on actigraphy data. Actigraphy, a non-invasive monitoring of human rest/activity cycles, provides valuable insights into sleep-wake behaviors and circadian rhythms. However, the high dimensionality of actigraphy data poses significant challenges in storage, processing, and analysis. To address these challenges, we applied the SAX algorithm to transform continuous time-series actigraphy data into a symbolic representation, enabling dimensionality reduction while preserving essential patterns. We analyzed actigraphy data from the National Health and Nutrition Examination Survey (NHANES) database, covering over 10,000 individuals, and used unsupervised clustering to identify distinct chronotype patterns. The SAX transformation facilitated the application of machine learning techniques, revealing five chronotype clusters characterized by differences in activity onset, resolution, and intensity. Age distribution analysis showed biases towards specific age groups within the clusters, highlighting the relationship between age and chronotype. Key findings include age-related Chronotype variations with younger individuals exhibiting delayed chronotypes with significant differences in sleep onset (SOT) and wake time (WT) compared to older adults, suggesting a phase delay in sleep patterns as age decreases and activity transition dynamics where clusters showed distinct patterns in winding up and winding down periods, providing insights into the dynamics of activity transitions. This study demonstrates the efficiency and effectiveness of SAX in processing large-scale actigraphy data, enabling robust chronotype characterization that can inform personalized healthcare and public health initiatives. Further exploration of SAX integration with other biometric measures could deepen our understanding of human circadian biology and its impact on health and behavior.
Metal sensing properties of the disordered loop from the Arabidopsis metal transceptor IRT1
Authors: Cointry Virginia , Ródenas Reyes , Morellet Nelly , Cotelle Valérie , Neveu Julie , Vert Grégory
Published: September 2024

The plant IRT1 iron transporter is a plasma membrane protein that takes up iron in root upon iron-limited conditions. Besides its primary metal substrate iron, IRT1 also transports other divalent metals that overaccumulate in plants when soil iron is low andIRT1is highly expressed. We previously reported that the intracellular regulatory loop between transmembrane helices TM4 and TM5, comprising IRT1 residues from 144 to 185, is involved in the post-translational regulation of IRT1 by its non-iron metal substrates. Upon excess of zinc, IRT1 (144-185) undergoes phosphorylation by the CIPK23 kinase followed by its ubiquitination by IDF1 to target IRT1 for vacuolar degradation. This zinc-dependent downregulation of IRT1 requires the presence of four histidine (H) residues in IRT1 loop, that directly bind zinc. However, how selective metal binding is achieved and how this allows downstream regulation to take place is largely unknown. Here, we characterized the metal binding properties and structure of IRT1 loop to better understand the molecular basis of non-iron metal sensing and signaling. Using a combination of circular dichroism and NMR, we demonstrate that zinc and manganese bind to IRT1 loop with nanomolar range affinity, and that metal binding does not trigger structuration of the loop. We prove that zinc and manganese binding is mediated by the four H residues and identify aspartic acid (D) residue D173 as helping in metal coordination and participating to metal sensing and metal-dependent degradation of IRT1 in plants. Altogether, our data provide further evidence of how the regulatory loop of IRT1 senses high cytosolic divalent metal concentrations to regulate metal uptake in plants.
Protein secondary structure and remote homology detection
Authors: Al-Fatlawi Ali , Hossen Md. Ballal , El-Hendi Ferras , Schroeder Michael
Published: September 2024

1

A protein can be represented by its primary, secondary, or tertiary structure. With recent advances in AI, there is now as much tertiary as primary structural data available. Fast and accurate search methods exist for both types of data, with searches over both representations being highly precise. However, primary structure data can sometimes be incomplete. As a result, tertiary structure has become the gold standard for remote homology detection.

How does secondary structure perform in remote homology detection? Secondary structure interprets proteins as a sequence using an alphabet representing helices, strands, or loops. It shares its sequential nature with primary structure while retaining topological information similar to tertiary structure.

To assess the effectiveness of secondary structure in remote homology detection, we devised a challenging classification task aimed at determining the superfamily membership of very distantly related protein domains. We used benchmarks from the CATH and SCOP databases and evaluated sequence and structure alignment algorithms on primary, secondary, and tertiary structures.

As expected, both basic and advanced sequence alignment algorithms applied to primary structure achieved high precision, but their overall area under the curve was lower compared to the gold standard of structural alignment using tertiary structure.

Surprisingly, a simple string comparison algorithm applied to secondary structure performed close to the gold standard. This result supports the hypothesis that key structural information is already encoded in secondary structure and suggests that secondary structure may be a promising representation to use when high-confidence structural data is unavailable, such as in cases involving protein flexibility and disorder.
Subtype-specific Patterns of Evolution and Clinically Relevant Genomic Instability in Wilms Tumour
Authors: Cresswell George D. , Chagtai Tasnim , Al-Saadi Reem , Treger Taryn D. , Madhan Gaganjit , Mifsud Borbala , Vujanic Gordan , Williams Richard D. , Luscombe Nicholas M. , Pritchard-Jones Kathy , Mifsud William
Published: September 2024

Background

Understanding cancer evolution is fundamental to predicting cancer progression. However, the evolution of paediatric cancers is still under-researched. Large cohorts of patients are required to determine consistent evolutionary trajectories that shed light on key steps in cancer development and reveal underlying biology, especially in rare cancers. Additionally, well annotated clinical data is necessary for determining if evolutionary biomarkers are predictive of patient outcome.

Methods

We performed detailed evolutionary analysis of 64 paediatric kidney cancers, including 60 Wilms tumours (WT), using DNA microarrays and, in a subset of 30 patients, a WT-specific targeted sequencing assay, to detect copy number alterations (CNA) and mutations, respectively. By analysing multiple tissue samples in the majority of cases we could detect mutation heterogeneity in each tumour. We reconstructed clones across the cohort and described their phylogenetic histories, in addition to detecting mirrored subclonal allelic imbalance.

Results

Our results highlight pervasive evidence of parallel evolution in WTs affecting CNAs, andCTNNB1andTP53mutations. Furthermore, we demonstrate that stromal-type WTs often evolve from a consistent series of events (WT1mutation, 11p uniparental disomy andCTNNB1mutation) and we suggest that 19q uniparental disomy is an important ancestral event in both epithelial and diffuse anaplastic WTs. Finally, we propose the total number of evolutionary CNA events as a prognostic biomarker in WTs for event-free survival, particularly in high-risk WT.

Conclusions

Overall, this study sheds light on the evolution of the most common paediatric kidney cancer and links evolutionary analysis to fundamental clinical and biological questions in a large cohort of WTs. We conclude that histological subtypes of WT are often defined by consistent evolutionary sequences. We present evidence that a key marker of evolvability, namely CNA diversity measured phylogenetically across multiple tumour sites, is prognostic of patient outcome and should be considered for clinical use to detect the most aggressive blastemal and diffuse anaplastic type WTs.
A pontine-specific axonal niche supports de novo gliomagenesis
Authors: Xie Zhigang , Pathak Adrija , Bankaitis Vytas A.
Published: September 2024

Diffuse intrinsic pontine gliomas (DIPGs), a major type of pediatric high-grade gliomas located in the pons, are the leading cause of death in children with brain cancer. A subset (20-25%) of DIPGs harbor a lysine 27-to-methionine (K27M) mutation inHIST1H3B, which encodes histone H3.1, and an activatingACVR1mutation. The occurrence of this pair of mutations in DIPGs, but not in pediatric gliomas in other anatomical locations, suggests the existence of a pontine-specific niche that favors DIPG gliomagenesis. Unfortunately, the identity of the underlying pontine niche remains elusive as available mouse models fail to recapitulate the anatomic specificity that characterizes DIPGs. Herein we show that the trigeminal root entry zone (TREZ), a pontine structure where several major axon tracts intersect, is enriched with proliferating oligodendrocyte-lineage cells during brainstem development. Introducing bothH3.1K27Mand activatingAcvr1andPik3camutations (which co-occur frequently withH3.1K27Min human DIPGs) into the mouse brain leads to rapid gliomagenesis. This pathology recapitulates the pons specificity of DIPGs as glioma cells proliferate on axon tracts at the TREZ. We further show that a hyaluronan receptor important for cell stemness (HMMR) plays a key role in glioma cell proliferation at the TREZ. We propose thatH3.1K27Mand its co-occurring mutations drive pontine specific gliomagenesis by inducing a proliferative response of oligodendrocyte-lineage cells with enhanced stemness on large TREZ axon tracts.

One-Sentence Summary

The trigeminal root entry zone underlies pontine-specific gliomagenesis driven byH3.1K27Mand its co-occurring mutations.
CD4+Foxp3E2+regulatory T cell frequency predicts breast cancer prognosis and recurrence
Authors: Fusco Clorinda , Rella Francesca Di , Liotti Antonietta , Colamatteo Alessandra , Ferrara Anne Lise , Gigantino Vincenzo , Collina Francesca , Esposito Emanuela , Donzelli Ivana , Porcellini Antonio , Feola Antonia , Micillo Teresa , Perna Francesco , Garziano Federica , Maniscalco Giorgia Teresa , Varricchi Gilda , Mottola Maria , Zuccarelli Bruno , Simone Bruna De , Bonito Maurizio di , Matarese Giuseppe , Accurso Antonello , Pontillo Martina , Russo Daniela , Insabato Luigi , Spaziano Alessandra , Cantone Irene , Pezone Antonio , Rosa Veronica De
Published: September 2024

CD4+Foxp3+regulatory T cells (Tregs) are key to maintain peripheralself-tolerance and suppress immune responses to tumors. Their accumulation in the tumor microenvironment (TME) correlates with poor clinical outcome in several human cancers, including breast cancer (BC). However, the properties of intratumoral Tregs remain largely unknown. Here, we found that a functionally distinct subpopulation of tumor-infiltrating Tregs, which express the Foxp3 splicing variant retaining exon 2 (Foxp3E2), is prominent in the TME and peripheral blood of hormone receptor- positive (HR+) BC subjects with poor prognosis. Notably, a comprehensive examination of the Tumor Cell Genome Atlas (TCGA) validated Foxp3E2 as an independent prognostic marker in all other BC subtypes. We found that FOXP3E2 expression underlies BCs with highly immune suppressive landscape, defective mismatch repair and a stem-like signature thus highlighting pathways involved in tumor immune evasion. Finally, we confirmed the higher immunosuppressive capacity of BC patients-derived Foxp3E2+Tregs by functional assays. Our study suggests Foxp3E2+Tregs might be used as an independent biomarker to predict BC prognosis and recurrence, and to develop super-targeted depletion-based immunotherapies.

One-sentence summaries

Foxp3E2+Treg enrichment reflects an increased tumor-immune suppression and predicts prognosis and recurrence in breast cancer.
Interplay of ferroptotic and apoptotic cell death and its modulation by BH3-mimetics
Authors: Qiu Yun , Hüther Juliana A. , Wank Bianca , Rath Antonia , Tykwe René , Laschat Sabine , Conrad Marcus , Stöhr Daniela , Rehm Markus
Published: September 2024

Ferroptosis and apoptosis are widely considered to be independent cell death modalities. Ferroptotic cell death is a consequence of insufficient radical detoxification and progressive lipid peroxidation, which is counteracted by glutathione peroxidase 4 (GPX4). Apoptotic cell death can be triggered by a wide variety of stresses, including oxygen radicals, and can be suppressed by anti-apoptotic members of the BCL-2 protein family. Mitochondria are the main interaction site of BCL-2 family members and likewise a major source of oxygen radical stress. We therefore studied if ferroptosis and apoptosis might intersect and possibly interfere with one another. Indeed, cells dying from impaired GPX4 activity displayed hallmarks of both ferroptotic and apoptotic cell death, with the latter including (transient) membrane blebbing, submaximal cytochrome-c release and caspase activation. Targeting BCL-2, MCL-1 or BCL-XL with BH3-mimetics under conditions of moderate ferroptotic stress in many cases synergistically enhanced overall cell death and frequently skewed primarily ferroptotic into apoptotic outcomes. Surprisingly though, in other cases BH3-mimetics, most notably the BCL-XL inhibitor WEHI-539, counter-intuitively suppressed cell death and promoted cell survival following GPX4 inhibition. Further studies revealed that most BH3-mimetics possess previously undescribed antioxidant activities that counteract ferroptotic cell death at commonly employed concentration ranges. Our results therefore show that ferroptosis and apoptosis can intersect. We also show that combining ferroptotic stress with BH3-mimetics, context-dependently can either enhance and convert cell death outcomes between ferroptosis and apoptosis or can also suppress cell death by intrinsic antioxidant activities.
Invasive cancer and spontaneous regression two weeks after papillomavirus infection
Authors: Bilger Andrea , Ward-Shaw Ella T. , Lee Denis L. , King Renee E. , Newton Michael A. , Buehler Darya , Matkowskyj Kristina A. , Sundberg John P. , Hu Rong , Lambert Paul F.
Published: September 2024

Development of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans – the throat, anus, and skin – and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression.

Summary Graphic
Nanoparticle-Supported, Rapid, and Electronic Detection of SARS-CoV-2 Antibodies and Antigens at Attomolar Level
Authors: Choi Yeji , Mirjalili Seyedsina , Ikbal MD Ashif , McClure Sean , Clemens Scott , Solano Jose , Heggland John , Zuo Jiawei , Wang Chao
Published: September 2024

A gold nanoparticle (AuNP)-supported rapid, electronic detection (NasRED) platform is demonstrated with high specificity to differentiate SARS-CoV-2 from human coronaviruses while achieving high sensitivity. Uniquely, active fluidic force is exerted on AuNPs in a microcentrifuge tube, through engineered centrifugation and vortex agitation, to accelerate signal transduction from biochemical protein binding to physical AuNP aggregation and precipitation and finally to electronic signals in a customized, stabilized circuitry. The limits of detection are found <80 aM (12 fg/mL) and ∼700 aM (105 fg/mL) to detect antibodies in human pooled serum and 20% diluted whole blood, and <900 aM (45 fg/mL) and 4.1 fM (200 fg/mL) to detect nucleocapsid proteins in human saliva and nasal fluid, respectively. With a small test volume (6 µL), a rapid turnaround time (as fast as <15 min), low reagent cost (estimated ∼$2), and a small system footprint, this novel digital platform can be utilized for accurate diagnosis and screening of a wide range of infectious and chronic diseases.
A community-oriented, data-driven resource to improve protocol design for cardiac modelling from human pluripotent stem cells
Authors: Chow Chris Siu Yeung , Negi Sumedha , Bao Shaine Chenxin , Fang Chen , Hudson James E. , Shim Woo Jun , Cao Yuanzhao , Palpant Nathan J.
Published: September 2024

Protocols for culturing cardiac cells derived from human-induced pluripotent stem cells (hiPSCs) are critical for studying mechanisms of development and disease. This study provides analysis of a community-oriented database to assess parameters used in published cardiac differentiation protocols, including a web-accessible portal for user-guided customisation of protocols. Validation studies support context-dependent roles for media composition in deriving functional maturation of hiPSC-derived cardiomyocytes.
Quality of Life and Psychiatric Comorbidities Associated with Migraines in Medical Students: A Cross-Sectional Study
Authors: Hassan Nusaiba , Hassan Roaa , Mohammed Batoul , Elomeiri Leina
Published: September 2024

Objectives

This study aims to assess the health-related quality of life (HRQoL) and psychiatric comorbidities among medical students suffering from migraines at the University of Khartoum.

Materials and Methods

A descriptive observational cross-sectional study was conducted on 78 medical students diagnosed with migraines. Participants completed a self-reported questionnaire that included the SF-12 Health Survey to assess HRQoL and the Hopkins Symptom Checklist (HSCL-25) to evaluate psychiatric symptoms.

Results

42.3% of students reported poor quality of life, particularly in the mental component (MCS) compared to the physical component (PCS). Psychiatric symptoms, including anxiety and depression, were prevalent in 70.5% of the participants. Gender was the only sociodemographic factor significantly affecting both HRQoL and psychiatric comorbidity, with females reporting poorer physical health and higher rates of psychiatric symptoms than males, consistent with findings from other studies.

Conclusion

Quality of life in regard to the mental aspect is significantly impaired in medical students suffering from migraine. Psychiatric comorbidities, namely depression and anxiety, are common in these patients. Universities should keep reports of students who are diagnosed with migraine and provide support programs and follow-up regarding medical treatment and psychiatric evaluation.
Erythrocyte Osmotic Fragility as A Diagnostic Marker in Glaucoma: A Comprehensive Analysis Using LASSO Regression
Authors: Yang Jialiang , Yang Fang , Gu Junming , Cheng Yilian , Luo Qian , Hao Fang , Gong Bo , Zhang Houbin
Published: September 2024

Objective

This study investigates the potential of blood biomarkers in the early diagnosis of glaucoma, focusing on erythrocyte osmotic fragility (EOF) as a novel indicator. We used Least Absolute Shrinkage and Selection Operator (LASSO) regression to evaluate EOF’s predictive utility for glaucoma diagnosis.

Methods

We included 195 confirmed glaucoma patients and an equal number of age- and sex-matched healthy controls. Blood samples were analyzed for various parameters, including white blood cell count, neutrophil count, red blood cell (RBC) count, and EOF. Key differential markers were identified, and a predictive model was constructed using LASSO regression models.

Results

LASSO regression analysis identified HCT, NEUT, LYMPH, MCV, MCHC, and EOF as critical blood biomarkers discriminating glaucoma patients from healthy controls. Incorporating EOF into the model significantly enhanced its predictive performance, with EOF showing a positive correlation with the likelihood of glaucoma.

Conclusions

EOF is a promising predictive biomarker for glaucoma. Combining EOF with other blood biomarkers significantly improves the accuracy of glaucoma diagnosis.
Dynamic Graph Transformer for Brain Disorder Diagnosis
Authors: Shehzad Ahsan , Zhang Dongyu , Yu Shuo , Abid Shagufta , Xia Feng
Published: September 2024

Dynamic brain networks are crucial for diagnosing brain disorders, as they reveal changes in brain activity and connectivity over time. Previous methods exploit the sliding window approach on fMRI data to construct these networks. However, this approach encounters two major issues: fixed temporal length, which inadequately captures the temporal dynamics of brain activity, and global spatial scope, which introduces noise and reduces sensitivity to localized dysfunctions when applied across the entire brain. These issues can lead to inaccurate brain network representations, potentially resulting in misdiagnosis. To overcome these challenges, we propose BrainDGT, a dynamic Graph Transformer model that adaptively captures and analyzes modular brain activities for improved diagnosis of brain disorders. BrainDGT addresses the fixed temporal length issue by estimating adaptive brain states through deconvolution of the Hemodynamic Response Function (HRF), avoiding the constraints of fixed-size windows. It also addresses the global spatial scope issue by segmenting fMRI scans into functional modules based on established brain networks for detailed, module-specific analysis. The model employs a dual attention mechanism: graph-attention extracts structural features from dynamic brain network snapshots, while self-attention identifies significant temporal dependencies. These spatio-temporal features are adaptively fused into a unified representation for disorder classification. BrainDGT's effectiveness is validated through classification experiments on three real fMRI datasets ADNI, PPMI, and ABIDE demonstrating superior performance compared to state-of-the-art methods. BrainDGT improves brain disorder diagnosis by offering adaptive, localized analysis of dynamic brain networks, advancing neuroimaging and enabling more precise treatments in biomedical research.
Biomedical engineers density indicator per hospital beds.
Authors: Ayala Luis G.
Published: September 2024

A biomedical engineers density indicator per hospital beds (𝝆IBcc) is presented. It calculates the ratio between the number of biomedical engineers providing professional services within the hospital setting, either as internal staff or mixed staff as reported by the World Health Organization, and the available hospital beds in a health system for a specific year. This is an alternative proposal that relates the biomedical engineer to their professional intervention object (medical devices), as opposed to the current measure published by the World Health Organization, which is the density of biomedical engineers per 10,000 inhabitants. Data on the number of biomedical engineers and hospital beds can be obtained from reports of various state, national, and regional health systems over different time periods. For the methodological development of the indicator, the text 'Health Indicators' from PAHO/WHO has been used as a reference.
Large language models outperform traditional natural language processing methods in extracting patient-reported outcomes in IBD
Authors: Patel Perseus V. , Davis Conner , Ralbovsky Amariel , Tinoco Daniel , Williams Christopher Y.K. , Slatter Shadera , Naderalvojoud Behzad , Rosen Michael J. , Hernandez-Boussard Tina , Rudrapatna Vivek
Published: September 2024

Background and Aims

Patient-reported outcomes (PROs) are vital in assessing disease activity and treatment outcomes in inflammatory bowel disease (IBD). However, manual extraction of these PROs from the free-text of clinical notes is burdensome. We aimed to improve data curation from free-text information in the electronic health record, making it more available for research and quality improvement. This study aimed to compare traditional natural language processing (tNLP) and large language models (LLMs) in extracting three IBD PROs (abdominal pain, diarrhea, fecal blood) from clinical notes across two institutions.

Methods

Clinic notes were annotated for each PRO using preset protocols. Models were developed and internally tested at the University of California San Francisco (UCSF), and then externally validated at Stanford University. We compared tNLP and LLM-based models on accuracy, sensitivity, specificity, positive and negative predictive value. Additionally, we conducted fairness and error assessments.

Results

Inter-rater reliability between annotators was >90%. On the UCSF test set (n=50), the top-performing tNLP models showcased accuracies of 92% (abdominal pain), 82% (diarrhea) and 80% (fecal blood), comparable to GPT-4, which was 96%, 88%, and 90% accurate, respectively. On external validation at Stanford (n=250), tNLP models failed to generalize (61-62% accuracy) while GPT-4 maintained accuracies >90%. PaLM-2 and GPT-4 showed similar performance. No biases were detected based on demographics or diagnosis.

Conclusions

LLMs are accurate and generalizable methods for extracting PROs. They maintain excellent accuracy across institutions, despite heterogeneity in note templates and authors. Widespread adoption of such tools has the potential to enhance IBD research and patient care.
Planar cell polarity coordination in a cnidarian embryo provides clues to animal body axis evolution
Authors: Uveira Julie , Donati Antoine , Léria Marvin , Lechable Marion , Lahaye François , Vesque Christine , Houliston Evelyn , Momose Tsuyoshi
Published: September 2024

Body axis specification is a crucial event in animal embryogenesis and was an essential evolutionary innovation for founding the animal kingdom. It involves two distinct components that coordinate to establish the spatial organisation of the embryo: initiation of cascades of regionalised gene expression and orientation of morphogenetic processes such as body elongation. Intense interest in the first component has revealed Wnt/β-catenin signalling as ancestrally responsible for initiating regional gene expression, but the evolutionary origin of oriented morphogenesis has received little attention. Here, by addressing the cell and morphological basis of body axis development in embryos of the cnidarianClytia hemisphaerica,we have uncovered a simple and likely ancestral coordination mechanism between Wnt/β-catenin signalling and directed morphogenesis. We show that the ligand Wnt3, known to initiate oral gene expression via localised Wnt/β-catenin pathway activation, also has a key β-catenin-independent role in globally orienting planar cell polarity (PCP) to direct morphogenesis along the oral-aboral axis. This PCP orientation occurs in two distinct steps: local orientation by Wnt3 and global propagation by conserved core PCP protein interactions along the body axis. From these findings we propose novel scenarios for PCP-driven symmetry-breaking underlying the emergence of the animal body plan.
Next generation APOBEC3 inhibitors: Optimally designed for potency and nuclease stability
Authors: Hedger Adam K. , Myint Wazo , Lee Jeong Min , Suchenski-Loustaunau Diego , Balachandran Vanivilasini , Shaqra Ala M. , Kurt-Yilmaz Nese , Watts Jonathan K. , Matsuo Hiroshi , Schiffer Celia A.
Published: September 2024

APOBEC3 (or A3) enzymes have emerged as potential therapeutic targets due to their role in introducing heterogeneity in viruses and cancer, often leading to drug resistance. Inhibiting these enzymes has remained elusive as initial phosphodiester (PO) linked DNA based inhibitors lack stability and potency. We have enhanced both potency and nuclease stability, of 2′-deoxy-zebularine (dZ), substrate-based oligonucleotide inhibitors for two critical A3’s: A3A and A3G. While replacing the phosphate backbone with phosphorothioate (PS) linkages increased nuclease stability, fully PS-modified inhibitors lost potency (1.4-3.7 fold) due to the structural constraints of the active site. For both enzymes, mixed PO/PS backbones enhanced potency (2.3-9.2 fold), while also vastly improving nuclease resistance. We also strategically introduced 2′-fluoro sugar modifications, creating the first nanomolar inhibitor of A3G-CTD2. With hairpin-structured inhibitors containing optimized PS patterns and LNA sugar modifications, we characterize the first single-digit nanomolar inhibitor targeting A3A. These extremely potent A3A inhibitors, were highly resistant to nuclease degradation in serum stability assays. Overall, our optimally designed A3 oligonucleotide inhibitors show improved potency and stability, compared to previous attempts to inhibit these critical enzymes, opening the door to realize the therapeutic potential of A3 inhibition.
Data Release: High-Resolution Imaging and Segmentation of P7 Mouse Tissue Microarchitecture Using FIB-SEM and Machine Learning
Authors: Ackerman David , Avetissian Emma , Bleck Christopher K. E. , Bogovic John A. , Innerberger Michael , Korff Wyatt , Li Wei-Ping , Lu Zhiyuan , Petruncio Alyson , Preibisch Stephan , Qiu Wei , Rhoades Jeff , Saalfeld Stephan , Silva Malan , Trautman Eric T. , Vorimo Rebecca , Weigel Aubrey , Yu Zhiheng , Zubov Yurii ,   CellMap Project Team
Published: September 2024

This report presents a comprehensive data release exploring the tissue microarchitecture of P7 aged mice using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) combined with machine learning-based segmentations of nuclei. The study includes high-resolution 3D volumes and nucleus segmentations for seven vital tissues—pancreas, liver, kidney, heart, thymus, hippocampus, and skin—from a single mouse. The detailed datasets are openly accessible onOpenOrganelle.org, providing a valuable resource for the scientific community to support further research and collaboration.
Paramyxovirus matrix proteins modulate host cell translation via exon-junction complex interactions in the cytoplasm
Authors: Hung Chuan-Tien , Haas Griffin D , Watkinson Ruth E , Chiu Hsin-Ping , Kowdle Shreyas , Stevens Christian S , Park Arnold , Wohlschlegel James A , Thibault Patricia A , Lee Benhur
Published: September 2024

Viruses have evolved myriad strategies to exploit the translation machinery of host cells to potentiate their replication. However, how paramyxovirus (PMVs) modulate cellular translation for their own benefit has not been systematically examined. Utilizing puromycylation labeling, overexpression of individual viral genes, and infection with wild-type virus versus its gene-deleted counterpart, we found that PMVs significantly inhibit host cells’ nascent peptide synthesis during infection, with the viral matrix being the primary contributor to this effect. Using the rNiV-NPL replicon system, we discovered that the viral matrix enhances viral protein translation without affecting viral mRNA transcription and suppresses host protein expression at the translational level. Polysome profile analysis revealed that the HPIV3 matrix promotes the association of viral mRNAs with ribosomes, thereby enhancing their translation efficiency during infection. Intriguingly, our NiV-Matrix interactome identified the core exon-junction complex (cEJC), critical for mRNA biogenesis, as a significant component that interacts with the paramyxoviral matrix predominantly in the cytoplasm. siRNA knockdown of eIF4AIII simulated the restriction of cellular functions by the viral matrix, leading to enhanced viral gene translation and a reduction in host protein synthesis. Moreover, siRNA depletion of cEJC resulted in a 2-3 log enhancement in infectious virus titer for various PMVs but not SARS-CoV-2, enterovirus D68, or influenza virus. Our findings characterize a host translational interference mechanism mediated by viral matrix and host cEJC interactions. We propose that the PMV matrix redirects ribosomes to translate viral mRNAs at the expense of host cell transcripts, enhancing viral replication, and thereby enhancing viral replication. These insights provide a deeper understanding of the molecular interactions between paramyxoviruses and host cells, highlighting potential targets for antiviral strategies.
Calpains Orchestrate Secretion of Annexin-containing Microvesicles during Membrane Repair
Authors: Williams Justin Krish , Ngo Jordan Matthew , Murugupandiyan Abinayaa , Croall Dorothy E. , Hartzell H Criss , Schekman Randy
Published: September 2024

Microvesicles (MVs) are membrane-enclosed, plasma membrane-derived particles released by cells from all branches of life. MVs have utility as disease biomarkers and may participate in intercellular communication; however, physiological processes that induce their secretion are not known. Here, we isolate and characterize annexin-containing MVs and show that these vesicles are secreted in response to the calcium influx caused by membrane damage. The annexins in these vesicles are cleaved by calpains. After plasma membrane injury, cytoplasmic calcium-bound annexins are rapidly recruited to the plasma membrane and form a scab-like structure at the lesion. In a second phase, recruited annexins are cleaved by calpains-1/2, disabling membrane scabbing. Cleavage promotes annexin secretion within MVs. Our data supports a new model of plasma membrane repair, where calpains relax annexin-membrane aggregates in the lesion repair scab, allowing secretion of damaged membrane and annexins as MVs. We anticipate that cells experiencing plasma membrane damage, including muscle and metastatic cancer cells, secrete these MVs at elevated levels.
Sex-Specific Cytokine, Chemokine, and Growth Factor Signatures in T1D Patients and Progressors
Authors: Girdhar Khyati , Mine Keiichiro , DaCosta Jeffrey M. , Atkinson Mark A. , Ludvigsson Johnny , Altindis Emrah
Published: September 2024

While studies have reported altered levels of cytokines in type 1 diabetes (T1D) patients, the results are inconsistent, likely because of variable factors. This study tests the hypothesis that there are sex-based differences in cytokine levels in T1D, prior to and after disease onset. We analyzed 48 blood cytokine, chemokine, and growth factor levels using a multiplex assay. We found only two cytokines, M-CSF and IL-6, with significant differences between T1D patients (n=25) versus controls overall (n=25). However, we identified notable alterations when comparing sex-age-matched controls and T1D samples. Inflammatory cytokines (TNF-α, IL-6, IL-1a), Th2 cytokines (IL-4, IL-13), and chemokines (MIP-1α, RANTES, MIP-3) were lower in female T1D patients compared to female controls, but not in males. IL-22 was lower in female T1D patients compared to female controls, while it was higher in male T1D patients compared to male controls. In contrast, growth factors (EGF, PDGF-AB/BB) were higher in male T1D patients compared to male controls. In T1D progressors (children who developed the disease years after the sample collection, n=16-21), GROa was lower compared to controls in both sexes. Our findings underscore the importance of understanding sex-specific differences in T1D pathogenesis and their implications for developing personalized treatments.
PI3K/AKT Signaling Mediates Stress-Inducible Amyloid Aggregation Through c-myc
Authors: Lacroix Emma , Momchilova Evgenia A. , Chandhok Sahil , Padavu Mythili , Zapf Richard , Audas Timothy E.
Published: September 2024

In response to environmental stress, eukaryotic cells reversibly form functional amyloid aggregates, called amyloid bodies (A-bodies). While these solid-like biomolecular condensates share many biophysical characteristics with pathological amyloids, A-body are non-toxic, and induce a protective state of cellular dormancy. As a recently identified structure, the modulators of A-body biogenesis remain uncharacterized, with the seeding noncoding RNA being the only known regulatory factor. Here, we use an image-based high-throughput screen to identify candidate pathways regulating A-body biogenesis. Our data demonstrates that the PI3K signaling axis meditates A-body formation during heat shock, by activating AKT and repressing GSK3-mediated degradation of c-myc. This enhances c-myc binding to regulatory elements of the seeding noncoding RNA, upregulating the transcripts that nucleate A-body formation. Identifying a link between PI3K signaling, c-myc, and physiological amyloid aggregates, extends the range of activity for these well-established regulators, while providing insight into cellular components whose dysregulation could underly amyloidogenic disorders.
A comprehensive comparative analysis of bacterial communities within cryoconite holes of Arctic and Antarctic glaciers as a response to global warming changes
Authors: Sasin-Kurowska Joanna , Golan Maciej , Piłsyk Sebastian , Sochacka-Piętal Marta
Published: September 2024

Cryoconite holes, water-filled ponds with sediment at the bottom, play a crucial role for glacial microbiological ecosystems. While they have been widely studied in various regions of the world (e.g., the Arctic, Antarctic, Alps, Himalayas, Central Andes), the novelty of the analyses presented here lies in their deeper exploration of metagenomic data. This study provides a comparative analysis of environmental factors influencing microbial biodiversity, with an additional focus on explaining the effects of pollution on bacterial communities.
The Parenting and Family Adjustment Scales (PAFAS) questionnaire: psychometric qualities of the parenting scale in two large Brazilian birth cohorts
Authors: Martins Rafaela Costa , Gomes Hugo S. , Bauer Andreas , Hoffmann Maurício Scopel , de Mola Christian Loret , Altafim Elisa Rachel Pisani , Domingues Marlos Rodrigues , Murray Joseph
Published: September 2024

Objective

Analyse the psychometric properties of the Portuguese version of the PAFAS (Parenting and Family Adjustment Scales) parenting scale, using data from two large Brazilian birth cohorts.

Methods

The original PAFAS parenting scale, which consists of 18 items (parental inconsistency 5 items, coercive parenting 5 items, positive encouragement 3 items, and parent-child relationship 5 items) was applied in two Brazilian birth cohorts in Pelotas (ages 4 [n = 4010] and 6-7 [n = 3867]) and Rio Grande (age 3 [n = 992]). Confirmatory factor analysis was conducted, and internal consistency assessed, as well as construct validity in relation to maternal depression measured on the Edinburgh Postnatal Depression Scale.

Results

The model with a structure of 4 subscales showed that the global scale of parenting on the PAFAS had a good fit, but certain items did not fit well on sub-scales and were removed (2 items from parental inconsistency, 1 from coercive parenting, and 1 from positive encouragement). The original form of the parent-child relationship sub-scale was maintained. Considering the total PAFAS parenting score, we found that mothers with maternal depression had a higher likelihood of more problematic parental practices than mothers without depression.

Conclusions

A revised 14-item PAFAS parenting scale has good psychometric properties and we encourage its use in Brazilian populations.
Leveraging Machine Learning & Mobile Application Technology for Vitiligo Management: A Proof-of-Concept
Authors: Abdolahnejad Mahla , Jeong Hyerin , Lin Victoria , Ng Tiffany , Altaki Emad , Mo Anthea , Yildiz Burak , Chan Hannah O. , Hong Collin , Joshi Rakesh
Published: September 2024

Vitiligo, a dermatological condition characterized by depigmented patches on the skin, affects up to 2% of the global population. Its management is complex, often hindered by delayed diagnosis due to limited access to dermatologists and/ digital tools. Recent advancements in machine learning (ML) offer a potential solution by providing digital tools for early detection and management. This proof-of-concept study describes the development of a machine learning pipeline integrated into a mobile application for vitiligo assessment.

Using a dataset of 1,309 images, including segmental and generalized vitiligo, the CNN was trained for binary classification with an accuracy of 95%. The model segments depigmented patches and conducts colorimetric analysis for precise evaluation. We compared traditional Wood’s lamp imaging with CNN-generated maps, showing comparable or superior results in detecting faint depigmentation.

Developed using Flutter for cross-platform compatibility, the app enables patients to upload images for analysis and track disease progression. A Golang-based backend ensures robust data management, while a PostgreSQL database supports secure storage of patient information. The integration of Azure Active Directory enhances security and user authentication.

This approach aims to bridge the gap in dermatological care by providing an accessible, ML-driven solution for vitiligo management. Future iterations will expand the applications’ capability to screen for other depigmentation disorders, incorporate automated scoring systems for more personalized patient management, and communication services.
Cardiac Cross-Reactivity of NaV Autoantibodies in Metastatic Breast Cancer: A Possible Trigger for Sudden Cardiac Death
Authors: Pappone Carlo , Tarantino Adriana , Melgari Dario , Piccoli Marco , Ciconte Giuseppe , Frosio Anthony , Micaglio Emanuele , Calamaio Serena , Vantellino Chiara , Cirillo Federica , Creo Pasquale , Castoldi Valerio , Prevostini Rachele , De Toma Alessandro , Boccellino Antonio , Negro Gabriele , Giannelli Luigi , Ćalović Žarko , Leocani Letizia , Santinelli Vincenzo , Toma Domenico De , Rivolta Ilaria , Anastasia Luigi
Published: September 2024

Background and Aims

Patients with metastatic breast cancer have an increased risk of sudden cardiac death (SCD) that cannot be fully explained by cardiotoxic treatments. Recent evidence shows that autoantibodies targeting the cardiac NaV1.5 sodium channel in Brugada syndrome (BrS) can trigger arrhythmias and elevate SCD risk. Similarly, autoantibodies against the neonatal NaV1.5 isoform have been found in metastatic breast cancer patients. Given the high homology between these NaV1.5 isoforms, we investigated whether these autoantibodies cross-react with the cardiac isoform, potentially contributing to SCD in this population.

Methods

Plasma from twenty metastatic breast cancer patients was analyzed for anti-NaV1.5 autoantibodies using HEK293A cells expressing the NaV1.5 protein, followed by Western blotting. The effects of these autoantibodies on sodium current density were assessed in cellular models and wild-type mice, with electrocardiographic monitoring after plasma infusion.

Results

Fifteen plasma samples from metastatic breast cancer patients tested positive for anti-NaV1.5 autoantibodies, significantly reducing sodium current density in vitro. Mice injected with these plasma samples developed severe arrhythmias and a Brugada syndrome-like ECG pattern. In contrast, plasma samples either without the autoantibodies or with IgG depletion showed no such effects, underscoring the role of IgG in sodium current reduction and confirming the pathogenicity of the autoantibodies.

Conclusions

This study demonstrates that anti-NaV1.5 autoantibodies in metastatic breast cancer patients can cross-react with the cardiac NaV1.5 isoform, potentially leading to fatal arrhythmias. These findings highlight a novel mechanism for the high SCD rate in this population and suggest that therapies involving sodium blockers should be used with caution to avoid exacerbating this risk. Reliable diagnostic tests and targeted therapies are urgently needed to mitigate SCD risk in affected patients.
A Psychometric Examination of the Dimensional Obsessive Compulsive Scale in a Treatment-Seeking Youth Sample
Authors: Farrell Nicholas R. , MacDonald Catherine W. , Nuñez Mia , Rhode Andreas , Lume Nicholas , McGrath Patrick B. , Baskova Marina , Wilson Eli , Abramowitz Jonathan S. , Feusner Jamie D.
Published: September 2024

The Dimensional Obsessive Compulsive Scale (DOCS) was developed to address several limitations of existing self-report measures of obsessive compulsive disorder (OCD) symptoms, and has been found to be a psychometrically sound method of assessing OCD symptoms in adults. However, to date, the psychometric performance of the DOCS has not been studied in a youth sample. The present study addressed this gap in the literature by examining the psychometric properties of the DOCS in a large sample (n=182) of treatment-seeking youth diagnosed with OCD. Results indicated that the DOCS showed good convergent validity with a youth OCD assessment scale, as well as similar sensitivity to the effects of treatment-related change in symptom severity. The DOCS also maintained its original four-factor structure in the youth sample, similar to findings in adults, supporting the consistency of the four subscales included. Overall, the DOCS appears to represent a promising method for assessing OCD symptom severity and response to treatment of OCD in youth.
Modeling the Risk of Airborne Transmission of Respiratory Viruses in Microgravity
Authors: Sararat Chayanin , Jiravejchakul Natnicha , Nawattanapaiboon Kawin , Modchang Charin
Published: September 2024

Airborne transmission is the most efficient and widespread route of viral spread, posing a significant challenge in controlling major infectious diseases such as COVID-19 and influenza. In microgravity environment, such as the International Space Station (ISS), this mode of transmission requires heightened vigilance and preventive measures due to the prolonged suspension of virus-laden particles, which increases the risk of infection. Using the COVID Airborne Risk Assessment (CARA) tool, we assess the risk of airborne transmission of respiratory viruses in microgravity by simulating the emission, dispersion, and inhalation of virus-laden particles. Our findings show that the unique conditions of microgravity allow these particles to remain airborne for significantly longer periods compared to Earth, leading to a 286-fold increase in virus concentration in the air, resulting in nearly twice the probability of infection for a susceptible host. We also evaluated the effectiveness of preventive measures, and found that facemasks can reduce the risk by up to 23% while continuous HEPA filtration at five air changes per hour proves crucial for managing air quality and minimizing infection risks by reducing airborne virus concentration at 99.79%. However, when simulated the infection risk by accounting the spaceflight-induced immune suppression, we found that the infection probability increased by 12% in the condition that viral load in infected host increase for 8-fold and absence of protective measures. Although facemasks and air filtration help mitigate the risk, their effectiveness diminishes when the viral load carrying by host is high. Enhancing host immunity through vaccination or other interventions is vital, potentially reducing infection probability by up to 14.17% when combined with HEPA filtration. These findings highlight the need for robust mitigation strategies to safeguard the health of astronauts against airborne pathogens during future space missions.