bluuebunny/crossref_metadata_2025 huggingface dataset:
Humoral waning kinetics against SARS-CoV-2 is dictated by disease severity and vaccine platform
Authors: Tong Xin , Kellman Benjamin , Avendano Maria-Jose , Mendu Maanasa , Hsiao Jeff C. , Serrano Eileen , Garcia-Salum Tamara , Muena Nicolas , Pardo-Roa Catalina , Morales Mauricio , Levican Jorge , Salinas Erick , Cardenas-Cáceres Simone , Riquelme Arnoldo , Tischler Nicole D. , Lauffenburger Douglas A. , Alter Galit , McNamara Ryan P. , Medina Rafael A.
Published: October 2024

SARS-CoV-2 vaccine-acquired immunity provides robust cross-variant recognition, while infection-acquired immunity can be heterogenous, with disease severity often modulating post-recovery responses. We assessed antibody waning dynamics between infection- and vaccination-acquired immunity across variants of concern (VOC). mRNA vaccination induced potent, cross-VOC Spike recognition and functional responses, but waned more rapidly for Omicron Spike. Hospitalized individuals developed more durable functional responses with lower peaks compared to mRNA vaccination, while outpatients exhibited slower decay than inactivated vaccine recipients. Humoral decay for the receptor binding domain tracked with neutralizing antibody titers, while S2-directed responses tracked with antibody-dependent myeloid cellular phagocytosis. Boosting the recovered patients with mRNA or inactivated vaccines expanded humoral breadth, durability, and restored functional responses, eliminating the severity- and platform-associated decay differences. Therefore, post-recovery hybrid immunization compensates for this distinction and broadens humoral breadth, highlighting the value of boosting immunity in previously infected individuals.

One Sentence Summary

Infection- and vaccine-acquired immunity to COVID-19 exhibit different functional antibody profiles, each characterized by distinct kinetics of waning over time.
Transformers for rapid detection of airway stenosis and stridor
Authors: Anibal James , Doctor Rebecca , Boyer Micah , Newberry Karlee , De Santiago Iris , Awan Shaheen , Abdel-Aty Yassmeen , Dion Gregory , Daoud Veronica , Huth Hannah , Watts Stephanie , Wood Bradford J. , Clifton David , Gelbard Alexander , Powell Maria , Toghranegar Jamie , Bensoussan Yael ,   the Bridge2AI Voice Consortium
Published: October 2024

Upper airway stenosis is a potentially life-threatening condition involving the narrowing of the airway. In more severe cases, airway stenosis may be accompanied by stridor, a type of disordered breathing caused by turbulent airflow. Patients with airway stenosis have a higher risk of airway failure and additional precautions must be taken before medical interventions like intubation. However, stenosis and stridor are often misdiagnosed as other respiratory conditions like asthma/wheezing, worsening outcomes. This report presents a unified dataset containing recorded breathing tasks from patients with stridor and airway stenosis. Customized transformer-based models were also trained to perform stenosis and stridor detection tasks using low-cost data from multiple acoustic prompts recorded on common devices. These methods achieved AUC scores of 0.875 for stenosis detection and 0.864 for stridor detection, demonstrating potential to add value as screening tools in real-world clinical workflows, particularly in high-volume settings like emergency departments.
TREM2Risk Variants with Alzheimer’s Disease Differ in Rate of Cognitive Decline
Authors: Dijkstra Janna I.R. , Vermunt Lisa , Venkatraghavan Vikram , Ozgehov Georgii , Coomans Emma M. , Ossenkoppele Rik , van de Giessen Elsmarieke , Hulsman Marc , de Geus Christa M. , van der Flier Wiesje M. , Sikkes Sietske A.M. , Barkhof Frederik , Tijms Betty , Gouw Alida A. , de Haan Willem , Vijverberg Everard G.B. , Pijnenburg Yolande A.L. , Holstege Henne , Teunissen Charlotte E. , van der Lee Sven J.
Published: October 2024

Rare variants of the triggering receptor expressed on myeloid cell 2 (TREM2) gene are major risk factors for Alzheimer’s disease (AD), and drugs targeting the TREM2 protein are being developed. However, it is unknown whether carriers of aTREM2risk variant have a clinically distinct AD phenotype. Here we studied a full range of clinical measures in a large cohort ofTREM2variant carriers (n=123, 7.8%, i.e., R62Hn=66, R47Hn=26, T96Kn=16, otherTREM2variantsn=17) compared to confirmed non-carriers (n=1,459) with biomarker confirmed symptomatic AD from Amsterdam Dementia Cohort.

TREM2variant carriers (mean age at diagnosis 64.4 years (SD ±7.1), 54% female) did not show distinct clinical measures of AD at presentation compared to AD patients not carrying aTREM2variant (mean age at diagnosis 64.4 ±7.0, 52% female). Specifically, we observed no differences in MMSE, most neuropsychological domains (except visuospatial functioning), MRI scores, CSF biomarkers, and EEG. Also, in an exploratory analysis of neuroimaging measures, including structural MRI (41 ROIs) and Tau-PET scans of four carriers (R62H, R47H, G58A, D87N),TREM2variant carriers showed similar atrophy patterns and similar abnormal tracer binding compared to non-carriers. Despite not being different at baseline, carriers did show faster cognitive decline in follow-up. Carriers declined 0.63 ±0.25 points on the MMSE more per year compared to non-carriers, but there was no difference in the hazard rate of death after diagnosis.

Finally, we explored whether specificTREM2variants are associated with distinct clinical measures compared to the reference group, i.e. non-carriers, within the same cohort. Notably, both R47H and T96K carriers exhibited faster cognitive decline, and R47H carriers even showed an increased rate of death after diagnosis. In contrast to the shared cognitive decline, these variants showed different results for other measures at baseline.

This study presents a detailed overview of the clinical measures in AD patients carrying aTREM2risk variant, and it shows that carriers ofTREM2risk variants cannot be distinguished based on clinical presentation at baseline. However, carriers exhibit a faster global cognitive decline compared to non-carriers. Variant-specific analyses suggest that especially R47H and T96K carriers drive the association ofTREM2variants with faster cognitive decline.
Predictive accuracy of diagnostic tests for excessive bleeding in cardiac surgery: the COPTIC-C study
Authors: Liao Weiqi , Grant Robert , Lai Florence Y , Aujla Hardeep , Wozniak Marcin , Patel Hasmukh R , Green Laura , Mumford Andrew , Murphy Gavin J
Published: October 2024

Purpose

We tested the hypothesis that addition of biomarkers of multimorbidity and biological ageing would improve the predictive accuracy of point-of-care viscoelastometry or laboratory tests of coagulation for clinically important bleeding following cardiac surgery.

Methods

The analyses included 2437 participants in the Coagulation and Platelet laboratory Testing in Cardiac surgery (COPTIC study) with complete clinical, TEG®5000 Thromboelastography, ROTEM®, Multiplate® aggregometry, full blood count, laboratory reference tests of coagulopathy, and biomarkers of biological ageing and multimorbidity. Models with different biomarkers to predict the composite primary outcome, Clinically Important Bleeding, was developed using logistic regression and internally validated using 10-fold cross-validation. Discrimination, calibration, and clinical utility of the models were assessed comprehensively.

Results

For the primary outcome, the AUROC for the best predictive model using TEG/ROTEM with other biomarkers was 0.694 (0.612–0.775). The best predictive model included laboratory reference tests of coagulation, full blood count results, and biomarkers of multimorbidity and ageing, AUROC=0.701 (0.620–0.781), although clinical utility was not superior to using laboratory reference tests alone. Discrimination was higher for components of the primary outcome; large volume (≥4 units) red cell transfusion 0.754 (0.602–0.903), and large volume procoagulant transfusion 0.723 (0.590–0.857), but not for excess loss in drains/re-sternotomy 0.701 (0.613–0.788). Calibration was generally good among the models.

Conclusion

Diagnostic tests for bleeding following cardiac surgery demonstrate moderate discrimination, although this was influenced by the definition of bleeding. Small improvements in discrimination with inclusion of additional disease biomarkers, with similar calibration and clinical utility.

Take-home message

1. Current diagnostic tests demonstrate moderate predictive accuracy for excessive bleeding following cardiac surgery. In this study, addition of biomarkers of multimorbidity and biological ageing improved discrimination but not clinical utility.

2. Existing clinical definitions of bleeding represent heterogeneous phenotypes, presenting a barrier to research investigating the disease processes.

Important abbreviations used in this paper:

CIB – Clinically Important Bleeding

CCB – Clinical Concern about Bleeding

AUROC – Area Under the Receiver Operating Characteristic Curve
Factors Influencing Health Insurance Enrollment and Its Impact on Outpatient Service Utilization in Saudi Arabia: Insights from the National Saudi Family Health Survey
Authors: Althabaiti Khaled Shaeel , Hunsberger Monica , Khan Jahangir , Ahmed Sayem
Published: October 2024

The Kingdom of Saudi Arabia (KSA) recently launched a reform plan for its health care system in 2021 driven by its Vision 2030 initiative. This vision aims to reduce dependence on government resources by transitioning to the national health insurance model and the Cooperative Health Insurance program, especially for the immigrant population. This reform may impact the utilization of health services by citizenship and insurance status. The current study aims to identify factors influencing health insurance enrollment and its impact on outpatient service utilization in the Kingdom of Saudi Arabia. This study used data from the 2018 Saudi Family Health Survey (FHS). The survey covers a nationally representative sample from KSA (n=8,274), which contains questions that obtain information about the health insurance enrollment, health care utilization, chronic disease condition, and health status of the respondents. We conducted a bivariate analysis using a chi-square test and an independent-sample t-test to examine the significance of differences between groups (by nationality and insurance status). We employed multiple binary logistic regression models to measure the association between health insurance enrollment and the demographic and socioeconomic characteristics of the respondents. Further, the multiple Poisson regression model was used to estimate the effect of health insurance status on the utilization of outpatient care. Most of the respondents were Saudis (76.8%), and the number of males (54.9%) respondents were higher than the females. Around 26.2% of the total respondents were insured and the proportion of insured was significantly higher among non-Saudis (72.8%) compared to Saudis (12.1%). The logistic regression showed that individuals with a high monthly income, non-Saudi, males, being married, high level of education, and perceived good health were associated with health insurance enrollment. We found health insurance enrollment was associated with lower utilization of outpatient services (co-efficient -0.107; P<0.001). Other factors increasing utilization of outpatient services were being female, having a high monthly income, being never married, having chronic diseases, and the perception of bad health. Significant determinants of health insurance enrollment were being non-Saudi, males, having a high income, higher education level, and perceived good health status. However, health insurance was associated with lower utilization of outpatient services. The results of the current study should be taken into consideration when planning for the implementation and monitoring reform of the health system in Saudi Arabia.
Deep Learning-Based Detection of Carotid Plaques Informs Cardiovascular Risk Prediction and Reveals Genetic Drivers of Atherosclerosis
Authors: Omarov Murad , Zhang Lanyue , Doroodgar Jorshery Saman , Malik Rainer , Das Barnali , Bellomo Tiffany R. , Mansmann Ulrich , Menten Martin J. , Natarajan Pradeep , Dichgans Martin , Raghu Vineet K. , Anderson Christopher D. , Georgakis Marios K.
Published: October 2024

Atherosclerotic cardiovascular disease, the leading cause of global mortality, is driven by lipid accumulation and plaque formation within arterial walls. Carotid plaques, detectable via ultrasound, are a well-established marker of subclinical atherosclerosis. In this study, we trained a deep learning model to detect plaques in 177,757 carotid ultrasound images from 19,499 UK Biobank (UKB) participants (aged 47-83 years) to assess the prevalence, risk factors, prognostic significance, and genetic architecture of carotid atherosclerosis in a large population-based cohort. The model demonstrated high performance metrics with accuracy, sensitivity, specificity, and positive predictive value of 89.3%, 89.5%, 89.2%, and 82.9%, respectively, identifying carotid plaques in 45% of the population. Plaque presence and count were significantly associated with future cardiovascular events over a median follow-up period of up to 7 years, leading to improved risk reclassification beyond established clinical prediction models. A genome-wide association study (GWAS) meta-analysis of carotid plaques (29,790 cases, 36,847 controls) uncovered two novel genomic loci (p < 5×10−8) with downstream analyses implicating lipoprotein(a) and interleukin-6 signaling, both targets of investigational drugs in advanced clinical development. Observational and Mendelian randomization analyses showed associations between smoking, low-density-lipoprotein (LDL) cholesterol, and high blood pressure and the odds of carotid plaque presence. Our study underscores the potential of carotid plaque assessment for improving cardiovascular risk prediction, provides novel insights into the genetic basis of subclinical atherosclerosis, and offers a valuable resource for advancing atherosclerosis research at the population scale.
Expansion of clinical genetic testing since the completion of the human genome project
Authors: Bastarache Lisa , Tinker Rory J. , Schuler Bryce A. , Richter Lucas , Phillips John A. , Stead William W. , Hooker Gillian , Peterson Josh F. , Ruderfer Douglas M.
Published: October 2024

The sequencing of the first human genome led to expectations of the widespread use of genetics in medicine. However, assessing the true impact of genetic testing on clinical practice is challenging due to the lack of integration in the electronic health record (EHR). We extracted clinical genetic tests from the EHRs of over 1.8 million patients seen at Vanderbilt University Medical Center from 2002 to 2022, using both automated and manual methods. Using these data, we quantified the extent of clinical genetic testing in healthcare and described how testing patterns have changed over time, including utilization rate, test comprehensiveness, diagnoses made, and the number of variants of uncertain significance (VUS) returned.

We also assessed genetic testing rates across medical specialties and introduce a measure – the genetic attributed fraction (GAF) – to compute the proportion of observed phenotypes attributable to a genetic diagnosis. We identified 104,392 tests, 32% of which were only reported in unstructured text, and 19,032 molecularly confirmed diagnoses or risk factors. The proportion of patients genetic testing recorded in their EHRs from 1.0% in 2002 to 6.1% in 2022, and testing became more comprehensive with the growing use of multigene panels. This corresponded with a substantial increase in the variety of diseases diagnosed with genetic testing, from 51 unique diseases in 2002 to 509 in 2022, alongside a growing number of VUS.

The phenome-wide GAF for 6,505,620 diagnoses made in 2022 was 0.46%, with 74 phenotypes having a GAF greater than 5%, including pancreatic insufficiency (67%), chorea (64%), atrial septal defect (24%), Microcephaly (17%), paraganglioma (17%), and ovarian cancer (6.8%). Our study provides a comprehensive quantification of the increasing role of genetic testing at a major academic medical institution. These results demonstrate the now pervasive use of genetic testing across diverse medical contexts and its growing utility in explaining observed medical phenome.
Coupling Between Functionality and Trafficking to the Axon Initial Segment in KCNQ2/3 K+Channels
Authors: Yoshioka Daisuke , Okamura Yasushi
Published: October 2024

KCNQ2/3 are the predominant voltage-gated K+channels localized at the axon initial segment (AIS), the critical site for the initiation of action potentials and the plasticity of excitability. Both the functionality and spatial distribution of KCNQ2/3 provide the basis for the regulation of neuronal excitability and the pathogenesis of various neurological disorders, including epilepsy. However, less is known about how functionality is coupled with trafficking regulation in KCNQ2/3. Here, we study the AIS localization of KCNQ2/3 by performing both multiple- and single-molecule imaging analyses. We found that low-activity mutations in the KCNQ3 subunit affect all of the 3D dynamics composed of lateral diffusion and exo/endocytosis processes through disruption of interaction with ankyrin-G, consequently suppressing the AIS targeting of KCNQ2/3. Thus, the functionality of KCNQ2/3 is coupled with its trafficking regulation, enhancing our understanding of the mechanisms underlying physiological and pathophysiological changes in neuronal excitability.
A global effort to benchmark predictive models and reveal mechanistic diversity in long-term stroke outcomes
Authors: Matsulevits Anna , Alvez Pedro , Atzori Manfredo , Beyh Ahmad , Corbetta Maurizio , Pup Federico Del , Dulyan Lilit , Foulon Chris , Hope Thomas , Ioannucci Stefano , Jobard Gael , Lemaitre Hervé , Neville Douglas , Nozais Victor , Rorden Christopher , Saprikis Orionas-Vasilis , Sibon Igor , Sperber Christoph , Teghipco Alex , Thirion Bertrand , Tshimanga Louis Fabrice , Umarova Roza , Vaidelyte Ema Birute , den Hoven Emiel van , Rodriguez Esteban Villar , Zanola Andrea , Tourdias Thomas , de Schotten Michel Thiebaut
Published: October 2024

Stroke remains a leading cause of mortality and long-term disability worldwide, with variable recovery trajectories posing substantial challenges in anticipating post-event care and rehabilitation planning. To address these challenges, we established the NeuralCup consortium to benchmark predictive models of stroke outcome through a collaborative, data-driven approach. This study presents findings from 15 international teams who used a comprehensive dataset including clinical and imaging data, to identify and compare predictors of motor, cognitive, and emotional outcomes one year post-stroke. Our analyses integrated traditional statistical approaches and novel machine learning algorithms to uncover ’optimal recipes’ for predicting each domain. The differences in these ‘optimal recipes’ reflect distinct brain mechanisms in response to different tasks. Key predictors across all domains included infarct characteristics, T1-weighted MRI sequences, and demographic factors. Additionally, integrating FLAIR imaging and white matter tract analysis significantly improved the prediction of cognitive and motor outcomes, respectively. These findings support a multifaceted approach to stroke outcome prediction, underscoring the potential of collaborative data science to develop personalized care strategies that enhance recovery and quality of life for stroke survivors. To encourage further model development and validation, we provide access to the training dataset athttp://neuralcup.bcblab.com
Molecular mechanism of thyroxine transport by monocarboxylate transporters
Authors: Tassinari Matteo , Tanzi Giorgia , Maggiore Francesco , Groeneweg Stefan , van Geest Ferdy S. , Freund Matthijs , Stavast Christiaan J. , Boniardi Irene , Pasqualato Sebastiano , Visser W. Edward , Coscia Francesca
Published: October 2024

Thyroid hormones (the common name for prohormone thyroxine and the bioactive form triiodothyronine) control major developmental and metabolic processes. Release of thyroid hormones from the thyroid gland into the bloodstream and their transport into target cells is facilitated by plasma membrane transporters, of which monocarboxylate transporter (MCT)8 and the highly homologous MCT10 are most important. Patients with MCT8 mutations suffer from a severe neurodevelopmental and metabolic disorder, however, the molecular mechanism underlying thyroid hormone transport is unknown. Using cryogenic-sample electron microscopy (cryo-EM), we determined the ligand-free and thyroxine-bound human MCT8 structures in the outward-open state and the thyroxine-bound human MCT10 in the inward-facing state. Our structural analysis revealed a network of conserved gate residues involved in conformational changes upon thyroxine binding, triggering ligand release on the opposite compartment. We then determined the structure of a folded, but inactive patient-derived MCT8 mutant, indicating a subtle conformational change which explains its reduced transport activity. In addition, we determined the structure of MCT8 bound to its inhibitor silychristin, revealing an interaction with residues essential to drive transition to the inward-facing state, thereby locking the protein in the outward-facing state. This study provides molecular and structural insights into normal and disordered thyroid hormone transport.
B cell expression of the enzyme PexRAP, an intermediary in ether lipid biosynthesis, promotes antibody responses and germinal center size
Authors: Cho Sung Hoon , Jones Marissa A. , Meyer Kaylor , Anderson David M. , Chetyrkin Sergei , Calcutt M. Wade , Caprioli Richard M. , Semenkovich Clay F. , Boothby Mark R.
Published: October 2024

The qualities of antibody (Ab) responses provided by B lymphocytes and their plasma cell (PC) descendants are crucial facets of responses to vaccines and microbes. Metabolic processes and products regulate aspects of B cell proliferation and differentiation into germinal center (GC) and PC states as well as Ab diversification. However, there is little information about lymphoid cell-intrinsic functions of enzymes that mediate ether lipid biosynthesis, including a major class of membrane phospholipids. Imaging mass spectrometry (IMS) results had indicated that concentrations of a number of these phospholipids were substantially enhanced in GC compared to the background average in spleens. However, it was not clear if biosynthesis in B cells was a basis for this finding, or whether such cell-intrinsic biosynthesis contributes to B cell physiology or Ab responses. Ether lipid biosynthesis can involve the enzyme PexRAP, the product of theDhrs7bgene. Using combinations of IMS and immunization experiments in mouse models with inducibleDhrs7bloss-of-function, we now show that B lineage-intrinsic expression of PexRAP promotes the magnitude and affinity maturation of a serological response. Moreover, the data revealed aDhrs7b-dependent increase in ether phospholipids in primary follicles with a more prominent increase in GC. Mechanistically, PexRAP impacted B cell proliferation via enhanced survival associated with controlling levels of ROS and membrane peroxidation. These findings reveal a vital role of this peroxisomal enzyme in B cell homeostasis and the physiology of humoral immunity.
Microbially Produced Bile Acids are Associated with High Levels of IgG Autoantibodies and Worse Mental Well-being in Fibromyalgia Subjects
Authors: Jakobsson Jenny E. , Carlsson Henrik , Erngren Ida , Menezes Joana , Krock Emerson , Hunt Matthew A. , Sohlin Jeanette Tour , Al-Grety Asma , Sandor Katalin , Kosek Eva , Svensson Camilla I. , Kultima Kim
Published: October 2024

Fibromyalgia (FM) is a disease primarily associated with chronic widespread pain, but other common symptoms are anxiety and depression. We previously proposed that autoimmunity contributes to FM based on findings of increased immunoglobulin G binding to satellite glial cells (anti-SGC IgG) in FM subjects compared to healthy controls (HC). Emerging research suggests that an altered gut microbiota composition is connected to psychological symptoms in FM rather than pain. Gut microbiota can produce or alter bile acids (BAs) and short-chain fatty acids (SCFAs), which have immune and inflammatory functions. Here, we investigate alterations in BA and SCFA concentrations in FM subjects compared to healthy controls (HC) and potential associations with FM symptoms and anti-SGC IgG levels.

Bile acids and SCFAs were quantified using liquid chromatography coupled with high-resolution mass spectrometry and anti-SGC IgG levels were assessed with immunocytochemistry. The correlations between FM symptoms, anti-SGC IgG levels, and serum concentrations of 24 BAs and 11 SCFAs in 35 FM subjects and 32 matched HC were examined.

Fibromyalgia subjects had significantly higher levels of microbially produced BAs than HC. Strikingly, 11 out of 24 BAs were significantly elevated in FM subjects with high, compared to those with low, anti-SGC IgG levels. Concentrations of specific BAs were associated with increased disease severity and worse mental well-being.

These results revealed increased levels of secondary BAs in FM subjects compared to HC. The strong association between BAs, anti-SGC IgG levels, and mental well-being may help elucidate the importance of BAs in the psychological symptoms of FM.

Significance statement

Fibromyalgia (FM) is a chronic pain syndrome that significantly impacts an individual’s quality of life. In addition to persistent pain, people with FM often experience depression, anxiety, and irritable bowel syndrome. Previously, we identified autoantibodies that bind to satellite glial cells in the dorsal root ganglia associated with more severe FM symptoms. Our current results demonstrate a novel association between these autoantibodies in FM and bile acids (BAs). Bile acids are essential for lipid metabolism but also act as signaling molecules. We show that patients with elevated levels of autoantibodies also exhibit increased levels of BAs. Furthermore, the BAs strongly correlate with worse FM symptom severity, particularly affecting mental well-being. Our study suggests that lowering BA levels could alleviate the psychological symptoms associated with FM.
An ensemble method for predicting and designing of druggable proteins
Authors: Jain Shipra , Gupta Srijanee , Raghava Gajendra P. S.
Published: October 2024

In the past, numerous proteins/peptides have been discovered, which have a wide range of therapeutic properties like anticancer, antimicrobial, antihypertensive. Only few hundreds of proteins are druggable (approved by US FDA), most of the proteins fails in clinical trials. In this study, an attempt had been made to understand properties of FDA approved proteins to develop models for predicting druggable proteins. Our main dataset 356 FDA approved proteins as positive dataset and equal number of randomly selected proteins as negative dataset. We used 80% data for training and 20% for independent validation, no protein in validation dataset have more than 40% similarity with any protein in training dataset. We deployed machine learning based models using a five-fold cross-validation and test on validation dataset. Our random forest-based model developed using SVC-L1 selected features obtained maximum performance AUC of 0.80 with MCC 0.61 on validation data. In addition to this, we performed MERCI-based motif analysis to find motifs in druggable proteins. Finally, we developed an ensemble-based method combining best performing machine learning model with motifs and achieved AUC 0.92 with MCC 0.83 on independent validation dataset. We developed a web server and standalone package ThPPred to facilitate scientific community in predicting and designing druggable proteins (https://webs.iiitd.edu.in/raghava/thppred/).

Highlights

Analysis of FDA approved or druggable proteins

Discrimination of druggable and non-druggable proteins

Machine learning based models for predicting druggable molecules

Identification of motifs in druggable proteins

A web server for providing service to community
MLL/WDR5 complex recruits KIF2C to midbody to ensure MT depolymerization and furrow compaction during cytokinesis
Authors: Kataria Avishek , Hemalatha Neeraja , Chinchole Akash , Tyagi Shweta
Published: October 2024

Mixed-lineage leukemia (MLL) protein is a well characterized epigenetic regulator whose non-canonical activities remain under appreciated. Here we show that MLL and its associated protein WDR5, localize to the midbody. Loss of MLL/WDR5 results in defective midbody formation, which displays a wide midzone-like microtubule structure, along with chromosome bridges, resulting in binucleated cells. We show that MLL and WDR5 interact with kinesin 13 motor—KIF2C, and targets it to the midbody. The depolymerase activity of KIF2C promotes correct localization of centralspindlin complex, compaction of midzone MTs and finally furrow completion. By characterizing the previously undiscovered role of MLL and KIF2C in the regulation of cytokinesis, our work underscores the importance of these proteins at the interface of actin and microtubule cytoskeleton regulation, pathways that are frequently altered in oncogenesis.
Exposure to complex mixtures of urban sediments containing Tyre and Road Wear Particles (TRWPs) increases the germ-line mutation rate inChironomus riparius
Authors: Rigano Lorenzo , Schmitz Markus , Linnemann Volker , Krauss Martin , Hollert Henner , Pfenninger Markus
Published: October 2024

Tyre and road wear particles (TRWPs) are a significant yet often underestimated source of environmental pollution, contributing to the accumulation of microplastics and a complex mixture of contaminants in both terrestrial and aquatic ecosystems. Despite their prevalence, the long-term evolutionary effects of TRWPs, beyond their immediate toxicity, remain largely unknown. In this study, we assessed mutagenicity in the non-biting midgeChironomus riparius, upon exposure to urban sediment collected from a runoff sedimentation basin. To assess the extent of mutagenic effects over multiple generations, we combined the urban sediment exposure model with short-term mutation accumulation lines (MALs) and subsequent whole genome sequencing (WGS). Our results reveal that the exposure to urban sediment significantly increases mutation rates compared to control groups by 50%, independent of concentration (0.5% and 10%). To infer potential causal processes, we conducted a comparative analysis with known mutational spectra from experiments with other studies. This comparison showed that the mutation profiles induced by urban sediment clearly clustered with those caused by Benzo[a]Pyrene (BaP), a known polycyclic aromatic hydrocarbon (PAH). A comprehensive chemical characterization of the sediment confirmed a considerable impact of road runoff and traffic-related contamination, including PAHs of primarily petrogenic origin. This suggests that PAH-like compounds present in urban sediments may play a significant role in the observed mutagenic effects. Our study shows that urban sediments influence mutation rates and alter mutational spectra in exposed organisms, potentially compromising genomic stability and shaping evolutionary trajectories. Additionally, we show that comparatively analysing mutational spectra may provide valuable insights into mutational processes. These genetic changes may have profound long-term effects on population dynamics and ecosystem health, underscoring the importance of understanding the evolutionary consequences of environmental pollution.
Differential expression of GABARAPs in GBM renders temozolomide sensitivity in a p53-dependent manner
Authors: Chaudhary Megha , Soni Naveen , Dongre Shweta , Tiwari Ashwani , Malik Nargis , Chosdol Kunzang , Bissa Bhawana
Published: October 2024

Glioblastoma (GBM) is one of the most debilitating and extremely aggressive tumors, with a median survival of less than a year. GBMs have high metastatic potential and frequently acquire chemoresistance. The current multimodal treatment approaches for GBM include surgical tumor resurrection, radiotherapy, and chemotherapy but these approaches leave the patient with long-term disabilities such as depletion of cognitive abilities, leukoencephalopathy, and recurrence in 6-8 months. Glioma cells are highly dependent on autophagy to survive and proliferate. Autophagy inhibition has proven to be a beneficial strategy for restricting glioma growth. However, the autophagy pathway cannot be efficiently targeted due to the lack of specific autophagy inhibitors. Understanding the vulnerabilities in autophagy gene expression can help to design better autophagy inhibitors. This study demonstrates the differential expression of GABARAP family members in low-grade glioma and GBM. Our study highlights the differential expression of GABARAP family members in response to autophagy inhibition and induction. Moreover, the knockdown of specific GABARAP family members enhanced proliferation and reduced temozolomide (TMZ) sensitivity of glial cells by decreasing the p53 expression. The selective expression pattern of GABARAP genes in Glioblastoma can be utilized to screen for patients who might respond better to temozolomide treatment. The differential expression of GABARAP family members highlights the subtle regulation of the autophagy pathway in response to environmental cues.
Octahedral small virus-like particles of dengue virus type 2
Authors: Johnson Adam , Traian Martín Dodes , Walsh Richard M. , Jenni Simon , Harrison Stephen C.
Published: October 2024

Flavivirus envelope (E) and precursor M (prM) proteins, when ectopically expressed, assemble into empty, virus-like particles (VLPs). Cleavage of prM to M and loss of the pr fragment converts the VLPs from immature to mature particles, mimicking a similar maturation of authentic virions. Most of the VLPs obtained by prM-E expression are smaller than virions; early, low-resolution cryo-EM studies suggested a simple, 60-subunit, icosahedral organization. We describe here the cryo-EM structure of immature, small VLPs from dengue virus type 2 and show that they have octahedral rather than icosahedral symmetry. The asymmetric unit of the octahedral particle is an asymmetric trimer of prM-E heterodimers, just as it is on icosahedral immature virions; the full, octahedrally symmetric particle thus has 24 such asymmetric trimers, or 72 prM-E heterodimers in all. Cleavage of prM and release of pr generates ovoid, somewhat irregular, mature particles. Previous work has shown that mature smVLPs have fusion properties identical to those of virions, consistent with local, virion-like clustering of 36 E dimers on their surface. The cryo-EM structure and the properties of these VLPs described here relate directly to on-going efforts to use them as vaccine immunogens.

IMPORTANCE

Ectopic expression of flavivirus envelope (E) and precursor M (prM) proteins leads to formation and secretion of empty, virus-like particles (VLPs), which are candidate, non-infectious, virion-like components of flavivirus vaccines. We show that the immature particles of a major class of VLPs -- “small VLPs” (smVLPs), which have smaller diameter than those of virion size, -- are octahedrally (rather than icosahedrally) symmetric, with the same clustering of prM and E, as asymmetric trimers of prM-E heterodimers, found on immature virions. Cleavage of prM and formation of mature, smVLPs yields somewhat irregular, ovoid particles. Design and characterization of VLPs as vaccine components will need to take these properties into account.
Trim7 does not have a role in the restriction of murine norovirus infection in vivo
Authors: Annaswamy Srinivas Mridula , Pierce Linley R. , Olson Mikayla C. , Roberston Shelly J. , Sturdevant Gail L. , Best Sonja M. , Orchard Robert C.
Published: October 2024

Trim7 is an E3 ubiquitin ligase that was recently identified as a central regulator of host- viral interactions with both pro-viral and anti-viral activity in cell culture. As an inhibitor, Trim7 overexpression ubiquitinates viral proteins by recognizing C-terminal glutamines that are hallmarks of 3C-like protease cleavage events. Here we sought to determine the physiological impact of Trim7 in resolving murine norovirus (MNV) infection of mice as MNV is potently inhibited by Trim7 in vitro. Utilizing two independently derived Trim7 deficient mouse lines we found no changes in the viral burden or tissue distribution of MNV in both an acute and persistent model of infection. Additionally, no changes in cytokine responses were observed after acute MNV infection of Trim7-deficient mice. Furthermore, removal of potentially confounding innate immune responses such as STING and STAT1 did not reveal any role for Trim7 in regulating MNV replication. Taken together, our data fails to find a physiological role for Trim7 in regulating MNV infection outcomes in mice and serves as a caution for defining Trim7 as a broad acting antiviral.

Importance

Intrinsic antiviral molecules that restrict viral replication are important drivers of viral evolution and viral tropism. Recently, Trim7 was shown to provide cell intrinsic protection against RNA viruses, including murine norovirus. Biochemically, Trim7 recognizes the cleavage product of viral proteases, suggesting a novel and broad mechanism to restrict viral replication. Here, we tested whether Trim7 had a physiological role in restricting murine norovirus replication in mice. Unexpectedly, we found no impact of viral replication or innate immune responses during murine norovirus infection. Our findings urge caution in defining Trim7 as a broad antiviral factor in the absence of in vivo evidence.
Early-life antibiotic exposure leads to gut microbial dysbiosis associated with neurodevelopment and neuroregeneration
Authors: Zhao Qing , Fan Pianpian , Gu Qie , Mo Xiaoyu , Tan Xuemei , Zhou Xinying , Yang Fan , Zhou Xiang , Li Qingchu
Published: October 2024

Early-life is a critical period for neurodevelopment and establishment of gut microbiota, which are highly susceptible to antibiotic exposure. Here, we aimed to investigate association between gut microbiota and metabolites with neurodevelopment and neuroregeneration in early-life after antibiotic exposure. To induce microbial dysbiosis in offspring, a broad-spectrum antibiotic cocktail was administered to mice dams. The prefrontal lobe, spinal cord tissues and gut sample of offspring were collected at different time with or without spinal cord crush injury. 16S rRNA sequencing and metabolomics were performed to analyze the gut microbiota and metabolites. NG2 glia were cultured and treated by mitochondrial fusion and fission compounds and metabolites. Maternal antibiotic exposure significantly affected neuronal maturation, NG2 glia proliferation, prefrontal cortex myelination and injured spinal cord neuroregeneration of offspring. Mice in antibiotic exposure group exhibited disruption of gut microbiota and metabolites, along with lower Ace, Chao and Shannon indexes, higher relative abundance ofEnterobacterandEscherichia_Shigella,lowerlactobacillusandStreptococcusgenus, and downregulated Cyclo(Arg-Gly-Asp-D-Phe-Val), Ampicilloyl, DG(8:0/i-19:0/0:0), Petasinine and 6-Hydroxymelatonin glucuronide. These metabolites were enriched in alpha-Linolenic acid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, linoleic acid metabolism. 6-Hydroxymelatonin glucuronide, PC(20:3/0:0), PC(20:2/0:0), Ameltolide, DG(8:0/i-19:0/0:0), Inproquone, and Chorismate were the cores of networks between gut microbiota and metabolites and negatively associated with neurodevelopment and neuroregeneration. Additionally, gut microbiota metabolites promoted NG2 glia differentiation, partly through reversing the effects of mitochondrial fusion/fission compounds. Totally, antibiotic exposure in early-life changed the composition, abundance, and metabolites of gut microbiota in offspring, which was associated with neurodevelopment and neuroregeneration.
Initiation of ERAD by the bifunctional complex of Mnl1 mannosidase and protein disulfide isomerase
Authors: Zhao Dan , Wu Xudong , Rapoport Tom A.
Published: October 2024

Misfolded glycoproteins in the endoplasmic reticulum (ER) lumen are translocated into the cytosol and degraded by the proteasome, a conserved process called ER-associated protein degradation (ERAD). InS. cerevisiae, the glycan of these proteins is trimmed by the luminal mannosidase Mnl1 (Htm1) to generate a signal that triggers degradation. Curiously, Mnl1 is permanently associated with protein disulfide isomerase (Pdi1). Here, we have used cryo- electron microscopy, biochemical, andin vivoexperiments to clarify how this complex initiates ERAD. The Mnl1-Pdi1 complex first de-mannosylates misfolded, globular proteins that are recognized through a C-terminal domain (CTD) of Mnl1; Pdi1 causes the CTD to ignore completely unfolded polypeptides. The disulfides of these globular proteins are then reduced by the Pdi1 component of the complex, generating unfolded polypeptides that can be translocated across the membrane. Mnl1 blocks the canonical oxidative function of Pdi1, but allows it to function as the elusive disulfide reductase in ERAD.
A limbal stem cell deficiency murine model with residual limbal stem cells
Authors: Someya Hideaki , Shirahama Shintaro , Karg Margarete M. , Gregory-Ksander Meredith S. , Dana Reza , Ksander Bruce R.
Published: October 2024

Bilateral limbal stem cell deficiency (LSCD) is a significant cause of corneal blindness and is more difficult to treat, as compared with unilateral LSCD because no source of autologous limbal stem cells (LSCs) remains in these patients. Thus, bilateral patients could be candidates for treatment with allogeneic LSC transplants that require long-term systemic immunosuppression therapy. Thus, if possible, for the correct candidates, using autologous LSCs could be a preferred treatment. Recentin vivolaser confocal microscopic examination of the ocular surfacein situ, combined with impression cytology, has indicated that some patients diagnosed with a complete bilateral LSCD possess residual LSCs. However, it remains unknown whether these residual LSCs still have stem cell potential due to the lack of animal models that mimic this pathology. The goal of the current study is to make a complete LSCD model that possesses evidence of residual LSCs. We induced complete LSCD in mice using two methods: (1) removed the corneal epithelium and the epithelial basement membrane using a rotating burr, and (2) removed the corneal epithelium using 20% ethanol but retained an intact epithelial basement membrane. A complete LSCD was defined by a lack of CK12-positive corneal epithelial cells and the presence of infiltrating CK19-positive conjunctival epithelial cells. Corneas were examined for wound closure, corneal opacity, LSC exhaustion, and inflammation. We observed that complete LSCD mice without an intact epithelial basement membrane resulted in few residual LSCs. By contrast, complete LSCD mice that retained the epithelial basement membrane were accompanied by a reduced inflammatory response plus a significant number of residual LSCs. This model will allow future studies to determine the function of residual LSCs in complete LSCD.
A ZO-2 scaffolding mechanism regulates the Hippo signalling pathway
Authors: Liu Olivia Xuan , Lin Lester Bocheng , Bunk Soumya , Chew Tiweng , Wu Selwin K. , Motegi Fumio , Low Boon Chuan
Published: October 2024

Inhibition of proliferation upon contact is a critical cell density control mechanism governed by the Hippo signalling pathway. The biochemical signalling underlying cell density-dependent cues regulating Hippo signalling and its downstream effectors, YAP, remains poorly understood. Here, we reveal that the tight junction protein ZO-2 is required for the contact-mediated inhibition of proliferation. We additionally determined that the well-established molecular players of contact inhibition of proliferation, namely Hippo kinase LATS1 and YAP, are regulated by ZO-2, and that the scaffolding function of ZO-2 promotes the interaction with and phosphorylation of YAP by LATS1. Mechanistically, YAP is phosphorylated when ZO-2 brings LATS1 and YAP together via its SH3 and PDZ domains, respectively, subsequently leading to the cytoplasmic retention and inactivation of YAP. In conclusion, we demonstrate that ZO-2 maintains Hippo signalling pathway activation by promoting the stability of LATS1 to inactivate YAP.
Characterizing the diffuse continuum excitations in the classical spin liquid
h−YMnO3
Authors: Lass Jakob , Lenander Emma Y. , Krighaar Kristine M. L. , Tošić Tara N. , Prabhakaran Dharmalingam , Deen Pascale P. , Holm-Janas Sofie , Lefmann Kim
Published: October 2024

We extend previous inelastic neutron scattering results on the geometrically frustrated antiferromagnet hexagonal-YMnO3, which has been suggested to belong to the class of classical spin liquids. We expand the energy transfer range of the diffuse signal up to 6.9 meV within a wide temperature range around the ordering temperature, TN. The two distinct diffuse signals in the a−b plane, the signal localized at Γ′ and the scattering intensity connecting Γ′ points over the M′, are shown to be only weakly energy dependent. In addition, an external magnetic field of up to 10.5 T applied along c is shown to have no effect on the diffuse signal. In the orthogonal scattering plane, the signals are shown to be dependent on l only through the magnetic form factor, showing that the correlations are purely two-dimensional, and supporting the origin of this to be the frustrated Mn3+ triangles. This result is corroborated by atomistic spin dynamics simulations showing similar scattering vector and temperature behaviors. Lastly, data for the spin wave scattering in the (h,0,l) plane allow for a discussion of the magnetic ground state where better agreement is found between the data and an ordered structure of the Γ1 or Γ3 symmetry, albeit crystal electric field arguments dismiss the Γ1 as a possibility.

Published by the American Physical Society
2024
Magnetic polarizability of octet baryons via lattice QCD
Authors: Kabelitz Thomas , Bignell Ryan , Kamleh Waseem , Leinweber Derek
Published: October 2024

Drawing on recent advances in lattice QCD background-field techniques, the magnetic polarizability of octet baryons is calculated from the first principles of QCD. The results are presented in the context of new constituent quark model calculations providing a framework for understanding the lattice results and a direct comparison with simulation results at unphysical quark masses. Using smeared quark sources, low-lying Laplacian eigenmode projection and final-state Landau-mode projection, considerable attention is devoted to ensuring single-state isolation in the lattice correlation functions. We also introduce new weighting methods to reduce the sensitivity to correlation-function fits, averaging over many fits based on merit drawn from the full correlated χ2 of the fits. The techniques are implemented on the 323×64, 2+1-flavor dynamical-fermion lattices provided by the PACS-CS Collaboration following the introduction of uniform magnetic fields quantized to the lowest nontrivial values available. After some scaling of the constituent quark model parameters, we find the model captures the patterns observed in the lattice QCD results very well, providing important insights into the physics underpinning the magnetic polarizabilities. Finally, comparison with the most recent results from experiment proceeds through an effective field theory formalism which incorporates estimates of finite-volume corrections and small electroquenching corrections as the results are brought to the physical point. We find excellent agreement with experiment where available, including the proton and neutron polarizabilities.

Published by the American Physical Society
2024