bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionary diversity of CXCL16-CXCR6: Convergent Substitutions and Recurrent Gene Loss in Sauropsids
Authors: Salve Buddhabhushan Girish , Sharma Sandhya , Vijay Nagarjun
Published: September 2024

The CXCL16-CXCR6 axis is crucial for regulating the persistence of CD8 tissue-resident memory T-cells (TRM). CXCR6 deficiency lowers TRMcell numbers in the lungs and depletes ILC3s in the lamina propria, impairing mucosal defence. This axis is linked to diseases like HIV/SIV, cancer, and COVID-19. Together, these highlight that the CXCL16-CXCR6 axis is pivotal in host immunity. Previous studies of the CXCL16-CXCR6 axis found genetic variation among species but were limited to primates and rodents. To understand the evolution and diversity of CXCL16-CXCR6 across vertebrates, we compared ∼400 1-to-1CXCR6orthologs spanning diverse vertebrates. The unique DRF motif ofCXCR6facilitates leukocyte adhesion by interacting with cell surface-expressedCXCL16and plays a key role in G-protein selectivity during receptor signalling; however, our findings show that this motif is not universal. The DRF motif is restricted to mammals, turtles, and frogs, while the DRY motif, typical in other CKRs, is found in snakes and lizards. Most birds exhibit the DRL motif. These substitutions at the DRF motif affect the receptor─Gi/oprotein interaction. We establish recurrentCXCR6gene loss in 10 out of 36 bird orders, including Galliformes and Passeriformes, Crocodilia, and Elapidae, attributed to segmental deletions and/or frame-disrupting changes. Notably, single-cell RNA sequencing of the lung shows a drop in TRMcells in species withCXCR6loss, suggesting a possible link. The concurrent loss ofITGAE, CXCL16andCXCR6in chickens may have altered CD8 TRMcell abundance, with implications for immunity against viral diseases and vaccines inducing CD8 TRMcells.
Brain inflammation and cognitive decline induced by spinal cord injury can be reversed by spinal cord cell transplants
Authors: Delarue Quentin , Robac Amandine , Duclos Célia , Pileyre Baptiste , Raimond Clémence , Neveu Pauline , Riou Gaëtan , Guérout Nicolas
Published: September 2024

Spinal cord injuries (SCIs) affect between 250,000 and 500,000 people worldwide each year, most commonly due to road accidents or falls. These injuries result in permanent disabilities, the severity and impact of which are directly related to the extent and location of the injury. Recent studies have also shown that SCIs can lead to cognitive disorders due to inflammation in the brain.

From a therapeutic perspective, numerous treatments have been explored, including cell therapy. It has been established that a common mechanism across various cellular transplant models is the modulation of inflammation at the injury site. However, it remains unclear whether the immunomodulatory effects observed in the spinal cord also extend to the brain.

To test this hypothesis, we induced SCI in wild-type mice and treated them with transplants of differentiated cells, specifically olfactory ensheathing cells, or stem cells, such as mesenchymal stem cells. Our results demonstrate that both types of transplants can reverse cognitive disorders induced by SCI. Additionally, we found that these cellular transplants modulate brain inflammation and increase neuronal density in the hippocampus.

To our knowledge, this is the first study to show that cells transplanted into the spinal cord can modulate the inflammatory response in the brain, thereby reversing the negative effects of injury on brain function following SCI. These findings underscore the complex interactions between the brain and spinal cord under both physiological and pathological conditions.
Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia
Authors: Hwang Hyejin , Berry Brandon J , St. Croix Claudette , Wojtovich Andrew P , Shiva Sruti P , Ghazi Arjumand
Published: September 2024

Reproductive status influences metabolism and health across lifespan in diverse ways and mitochondrial function playing a critical role in mediating this relationship. Using theCaenorhabditis elegansgermline ablation model, we investigated the impact of germline stem cell (GSC) loss on mitochondrial dynamics and respiratory function. Our results show that GSC loss reduces mitochondrial volume and respiratory function in young adulthood but preserves mitochondrial activity during aging and upon exposure to hypothermic stress, correlating with enhanced survival. We found that the transcription factor NHR-49/PPARα, but not DAF-16/FOXO3A, was essential for preserving mitochondrial function and hypothermia resistance in these long-lived mutants. Together, these findings reveal the impact of germline signals on somatic mitochondrial health and underscore the intricate relationship between reproductive fitness and organismal health.
Heart rate variability impairment during sleep in Veterans with REM sleep behavior disorder, traumatic brain injury, and posttraumatic stress disorder: An early potential window into autonomic dysfunction?
Authors: Cunningham Hannah A. , Dovek Laura , Recoder Natasha , Bryant-Ekstrand Mohini D. , Ligman Brittany R. , Piantino Juan , Lim Miranda M. , Elliott Jonathan E.
Published: September 2024

Individuals with comorbid REM sleep behavior disorder (RBD) and neurotrauma (defined by traumatic brain injury and post-traumatic stress disorder) have an earlier age of RBD symptom onset, increased RBD-related symptom severity and more neurological features indicative of prodromal synucleinopathy compared to RBD only. An early sign of neurodegenerative condition is autonomic dysfunction, which we sought to evaluate by examining heart rate variability during sleep. Participants with overnight polysomnography were recruited from the VA Portland Health Care System. Veterans without neurotrauma or RBD (controls; n=19), with RBD only (RBD, n=14), and with RBD and neurotrauma (RBD+NT, n=19) were evaluated. Eligible 5-minute NREM and REM epochs without apneas/hypopneas, microarousals, and ectopic beats were analyzed for frequency and time domain (e.g. low frequency power, LF; high frequency power, HF; root mean square of successive RR intervals, RMSSD; % of RR intervals that vary ≥50 ms, pNN50) heart rate variability outcomes. Heart rate did not significantly differ between groups in any sleep stage. Time domain and frequency domain variables (e.g., LF power, HF power, RMSSD, and pNN50) were significantly reduced in the RBD and RBD+NT groups compared to controls and RBD only during NREM sleep. There were no group differences detected during REM sleep. These data suggest significant reductions in heart rate variability during NREM sleep in RBD+NT participants, suggesting greater autonomic dysfunction compared to controls or RBD alone. Heart rate variability during sleep may be an early, promising biomarker, yielding mechanistic insight for diagnosis and prognosis of early neurodegeneration in this vulnerable population.

STATEMENT OF SIGNIFICANCE

Comorbid REM sleep behavior disorder (RBD) and neurotrauma (NT, traumatic brain injury + post-traumatic stress disorder; RBD+NT) is associated with increased neurodegenerative symptom burden and worsened health. Sleep and autonomic function are integrally and bidirectionally related to neurodegenerative processes. In the current study, we sought to determine if early signs of autonomic dysfunction, measured via heart rate variability (HRV), were present during sleep in comorbid RBD+NT compared to RBD only and controls. Our data show reduced time and frequency domain HRV during NREM sleep in RBD+NT Veterans compared to RBD only and controls. These data contribute evidence that participants with RBD and comorbid NT demonstrate significantly worse autonomic dysfunction compared to age/sex matched participants with RBD alone.
MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis
Authors: Sarkar Lucky , Liu GuanQun , Acharya Dhiraj , Zhu Junji , Sayyad Zuberwasim , Gack Michaela
Published: September 2024

The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like proteins is crucial for regulating antiviral host responses. The cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance of MDA5 ISGylation for antiviral immunity in an infected organism has been elusive. Here, we generated knock-in mice (MDA5K23R/K43R) in which the two major ISGylation sites, K23 and K43, in MDA5 were mutated. Primary cells derived from MDA5K23R/K43R mice exhibited abrogated endogenous MDA5 ISGylation and an impaired ability of MDA5 to form oligomeric assemblies leading to blunted cytokine responses to MDA5 RNA-agonist stimulation or infection with encephalomyocarditis virus (EMCV) or West Nile virus. Phenocopying MDA5−/− mice, the MDA5K23R/K43R mice infected with EMCV displayed increased mortality, elevated viral titers, and an ablated induction of cytokines and chemokines compared to WT mice. Molecular studies identified human HERC5 (and its functional murine homolog HERC6) as the primary E3 ligases responsible for MDA5 ISGylation and activation. Taken together, these findings establish the importance of CARD ISGylation for MDA5-mediated RNA virus restriction, promoting potential avenues for immunomodulatory drug design for antiviral or anti-inflammatory applications.
DrugTar Improves Druggability Prediction by Integrating Large Language Models and Gene Ontologies
Authors: Borhani Niloofar , Izadi Iman , Motahharynia Ali , Sheikholeslami Mahsa , Gheisari Yousof
Published: September 2024

Target discovery is crucial in drug development, especially for complex chronic diseases. Recent advances in high-throughput technologies and the explosion of biomedical data have highlighted the potential of computational druggability prediction methods. However, most current methods rely on sequence-based features with machine learning, which often face challenges related to hand-crafted features, reproducibility, and accessibility. Moreover, the potential of raw sequence and protein structure has not been fully investigated. Here, we leveraged both protein sequence and structure using deep learning techniques, revealing that protein sequence, especially pre- trained embeddings, is more informative than protein structure. Next, we developedDrugTar, a highl7lperformance deep learning algorithm integrating sequence embeddings from the ESM-2 pre-trained protein language model with protein ontologies to predict druggability. DrugTar achieved areas under the curve and precision-recall curve values above 0.90, outperforming state-of-the-art methods. In conclusion, DrugTar streamlines target discovery as a bottleneck in developing novel therapeutics.
Designing of thermostable proteins with a desired melting temperature
Authors: Tijare Purva , Kumar Nishant , Raghava Gajendra P. S.
Published: September 2024

1.

The stability of proteins at higher temperatures is crucial for its functionality that is measured by their melting temperature (Tm). The Tm is the temperature at which 50% of the protein loses its native structure and activity. Existing methods for predicting Tm have two major limitations: first, they are often trained on redundant proteins, and second, they do not allow users to design proteins with the desired Tm. To address these limitations, we developed a regression method for predicting the Tm value of proteins using 17,312 non-redundant proteins, where no two proteins are more than 40% similar. We used 80% of the data for training and testing; remaining 20% of the data for validation. Initially, we developed a machine learning model using standard features from protein sequences. Our best model, developed using Shannon entropy for all residues, achieved the highest Pearson correlation of 0.80 with an R² of 0.63 between the predicted and actual Tm of proteins on the validation dataset. Next, we fine-tuned large language models (e.g., ProtBert, ProtGPT2, ProtT5) on our training dataset and generated embeddings. These embeddings have been used for developing machine learning models. Our best model, developed using ProtBert embeddings, achieved a maximum correlation of 0.89 with an R² of 0.80 on the validation dataset. Finally, we developed an ensemble method that combines standard protein features and embeddings. One of the aims of the study is to assist the scientific community in the design of targeted melting temperatures. We created a user-friendly web server and a python package for predicting and designing thermostable proteins. Our standalone software can be used to screen thermostable proteins in genomes and metagenomes. We demonstrated the application of PPTstab in identifying thermostable proteins in different organisms from their genomes, the model and data is available at:https://webs.iiitd.edu.in/raghava/pptstab.

Highlights

Prediction of melting temperature (Tm) on non-redundant proteins

Machine learning models based on sequence composition and ProtBert embeddings

A Webserver for predicting Tm and designing thermostable proteins
Using disease symptomatology to guide treatment in patients with central centrifugal cicatricial alopecia: introduction of C-CAT scoring tool
Authors: Qadri Aasheen , Will Elizabeth , Aguh Crystal
Published: September 2024

Background

Central centrifugal cicatricial alopecia (CCCA) is a progressive scarring alopecia. No disease activity scale exists, making assessment of therapeutic intervention difficult.

Objective

This study introduces the CCCA Clinical Assessment Tool (C-CAT), a novel scale that quantifies symptom severity to facilitate tailored treatment and track disease progression. Methods: A retrospective review of patients with CCCA were assessed on degree of pruritus, erythema, pain, disease progression, and scalp resistance, each scored from 0-2, over the course of a minimum of six months of therapy.

Results

Eighty-two patients were included. The average initial C-CAT score was 3.4, consistent with mild to moderate disease activity. After six months of treatment, 88% of patients had improvement in score, with 48% of all patients achieving remission. Intralesional kenalog injections and topical clobetasol were the most commonly used therapies. Patients required an average of 3.6 different treatments to achieve therapeutic response.

Limitations

The subjective nature of some C-CAT components may lead to inter-rater variability.

Conclusion

The C-CAT provides a structured, quantitative method to assess CCCA severity, which facilitates tracking of disease improvement for the majority of patients with targeted therapy. This tool promotes personalized, symptom-based treatment and supports clinicians and patients in understanding this complex condition.

CAPSULE SUMMARY

A novel central centrifugal cicatricial alopecia scoring tool demonstrates that established treatments quantitatively improve symptoms in most patients with central centrifugal cicatricial alopecia over 6 months.

The novel disease activity scale guides clinicians in structuring treatment based on specific symptomatology and aids patients in understanding progress.
Amygdala subregional functional connectivity in Treatment-Resistant Depression
Authors: Foster Sheryl L. , Landin-Romero Ramon , Lewis Sarah , Barreiros Ana Rita , Matis Sophie , Harris Anthony , Korgaonkar Mayuresh S.
Published: September 2024

Background

Treatment resistance impacts almost 50% of depression patients, with amygdala dysfunction being widely implicated. The amygdala is a complex amalgamation of subnuclei with diverse functions but fMRI studies have typically focussed on identifying whole rather than subregional amygdala functional connectivity. This study used high resolution 3T fMRI data to investigate subregional alterations that may differentiate treatment-resistant cohorts from healthy individuals and depressed patients who respond to treatment.

Methods

Resting-state fMRI data were obtained in 35 participants diagnosed with Treatment-Resistant Depression (TRD), 38 healthy control participants (HC), and 35 treatment-sensitive participants (TSD). Seed-based functional connectivity analyses of the three main subregions bilaterally (laterobasal, centromedial and superficial), as well as the whole amygdala, were performed and comparisons made between groups.

Results

We foundconnectivity differences in the right laterobasal amygdala subregion in TRD compared to both groups. TRD patients displayed hypoconnectivity to the right fusiform gyrus relative to HC whereas hyperconnectivity to the left inferior frontal gyrus relative to TSD was identified. No connectivity differences were found for the whole amygdala or any of the other subregions bilaterally.

Limitations

Modest sample size and cross-sectional study design are limitations. A causal relationship between functional connectivity alterations and treatment resistance cannot be established.

Conclusion

Altered connectivity of the right laterobasal subregion is a distinguishing feature of TRD. These alterations may underlie severe impairments in emotion processing and social functioning that are characteristic of TRD. These results emphasise the need for further investigation of the functional role of the amygdala subregions in depression.
Navigating Memorability Landscapes: Hyperbolic Geometry Reveals Hierarchical Structures in Object Concept Memory
Authors: Lee Fiona M. , Berman Marc G. , Stier Andrew J. , Bainbridge Wilma A.
Published: September 2024

Why are some object concepts (e.g., birds, cars, vegetables, etc.) more memorable than others? Prior studies have suggested that features (e.g., color, animacy, etc.) and typicality (e.g., robin vs. penguin) of object images influences the likelihood of being remembered. However, a complete understanding of object memorability remains elusive. In this study, we examine whether the geometric relationship between object concepts explains differences in their memorability. Specifically, we hypothesize that image concepts will be geometrically arranged in hierarchical structures and that memorability will be explained by a concept’s depth in these hierarchical trees. To test this hypothesis, we construct a Hyperbolic representation space of object concepts (N=1,854) from the THINGS database (Hebart et al., 2019), which consists of naturalistic images of concrete objects, and a space of 49 feature dimensions derived from data-driven models. Using ALBATROSS (Stier, A. J., Giusti, C., & Berman, M. G., In prep), a stochastic topological data analysis technique that detects underlying structures of data, we demonstrate that Hyperbolic geometry efficiently captures the hierarchical organization of object concepts above and beyond a traditional Euclidean geometry and that hierarchical organization is related to memorability. We find that concepts closer to the center of the representational space are more prototypical and also more memorable. Importantly, Hyperbolic distances are more predictive of memorability and prototypicality than Euclidean distances, suggesting that concept memorability and typicality are organized hierarchically. Taken together, our work presents a novel hierarchical representational structure of object concepts that explains memorability and typicality.
Steerable Tape-Spring Needle for Autonomous Sharp Turns Through Tissue
Authors: Abdoun Omar , Tjandra Davin , Yin Katie , Kurzan Pablo , Yin Jessica , Yim Mark
Published: September 2024

Steerable needles offer a minimally invasive method to deliver treatment to hard-to-reach tissue regions. We introduce a new class oftape-springsteerable needles capable of sharp turns ranging from 15 to 150 degrees with a turn radius as low as 3mm, which minimizes surrounding tissue damage. In this work, we derive and experimentally validate a geometric model for our steerable needle design. We evaluate both manual and robotic steering of the needle along a Dubins path in 7 kPa and 13 kPa tissue phantoms, simulating our target clinical application in healthy and unhealthy liver tissue. We conduct experiments to measure needle robustness to stiffness transitions between non-homogeneous tissues. We demonstrate progress towards clinical use with needle tip tracking via ultrasound imaging, navigation around anatomical obstacles, and integration with a robotic autonomous steering system.
Framework for Martini-based Coarse-grained Model of Enzymes: Model Development and Experimental Validation
Authors: Hooten Mason , Murthy Sanjeeva , Pal Nityananda , Khare Sagar D. , Gormley Adam J. , Dutt Meenakshi
Published: September 2024

Recent experiments have shown that enzyme activity can preserved in harsh environments by complexing enzyme with polymer into a Protein-Polymer Hybrid (PPH). In a successful PPH, heteropolymer strands bind to the enzyme surface and restrain the folded protein without adversely affecting the binding and active sites. It is believed that hybridization is driven by non-covalent interactions at the enzyme surface including hydrophobicity and electrostatics. Molecular modeling of these interactions is not practical at the all-atom scale due to the long timescales and large particle counts needed to characterize binding. Protein structure at the scale of amino acid residues is parsimoniously represented by a coarse-grained model in which one particle represents several atoms, significantly reducing the cost of simulation. In this study we present two coarse-grained enzyme models – lipase and dehalogenase – prepared using a top-down modeling strategy. We simulate each enzyme in aqueous solution and calculate statistics of protein surface features and shape descriptors. The values from the coarse-grained data are compared with the same calculations performed on all-atom reference systems, revealing key similarities of surface chemistry at the two scales. Structural measures are calculated from the all-atom reference systems and compared with estimates from small-angle X-ray scattering (SAXS) experiments, with good agreement between the two. The described procedures of modeling and analysis comprise a framework for the development of coarse-grained models of protein surfaces with validation to experiment.
Identification and study of Prolyl Oligopeptidases and related sequences in bacterial lineages
Authors: Nayak Soumya , Sowdhamini Ramanathan
Published: September 2024

Proteases are enzymes that break down proteins, and serine proteases are an important subset of these enzymes. Prolyl oligopeptidase (POP) is a family of serine proteases (S9 family) that has the ability to cleave peptide bonds involving proline residues and it is unique for its ability to cleave various small oligopeptides shorter than 30 amino acids. The S9 family from the MEROPS database, is classified into four subfamilies based on active site motifs. These S9 subfamilies assume a crucial position owing to their diverse biological roles and potential therapeutic applications in various diseases. In this study, we have examined ∼32000 completely annotated bacterial genomes from the NCBI RefSeq Assembly database to identify annotated S9 family proteins. This results in the discovery of ∼53,000 bacterial S9 family proteins (referred to as POP homologues). These sequences are classified into distinct subfamilies through various machine-learning approaches and comprehensive analysis of their distribution across various phyla and species and domain architecture analysis are also conducted. Distinct subclusters and class-specific motifs of POPs were identified, suggesting differences in substrate specificity in POP homologues. This study can enable future research of these gene families that are involved in many important biological processes.
Distinct Longitudinal Clinical-Neuroanatomical Trajectories in Parkinson’s Disease Clinical Subtypes: Insight Towards Precision Medicine
Authors: Fereshtehnejad Seyed-Mohammad , Moqadam Roqaie , Azizi Houman , Postuma Ronald B. , Dadar Mahsa , Lang Anthony E. , Marras Connie , Zeighami Yashar
Published: September 2024

Background

Parkinson’s disease (PD) varies widely across individuals in clinical manifestations and course of progression. Identification and characterization of distinct biological subtypes could help explain this heterogeneity, identify the underlying pathophysiology, and predict disease progression across the subgroups of PD.

Objective

We aimed to compare long-term trajectories of various motor and non-motor clinical features, as well as patterns of brain atrophy between PD subtypes, using longitudinally acquired brain MRIs.

Methods

Data on 421 individuals with early-stage PD was retrieved from the Parkinson’s Progression Markers Initiative (PPMI), with an average follow-up time of 8.2 years until February 2024. Participants were classified into three clinical subtypes at thede novostage using a previously validated subtyping criteria based on major motor and non-motor classifiers (early cognitive impairment, REM sleep behavior disorder (RBD), dysautonomia): ‘mild-motor predominant’ (n=223), ‘intermediate’ (n=146), and diffuse-malignant (n=52). To investigate the pattern of brain atrophy, we used T1-weighted MRIs from a subset of the PPMI population with at least two MRIs obtained, which consisted of 134 PD individuals and 60 healthy controls. Deformation-based morphometry (DBM) maps were calculated and mixed effect models were used to examine the interaction between PD subtypes and rate of atrophy across brain regions, controlling for sex and age at baseline.

Results

Compared to the ‘mild motor-predominant’ subtype, participants who were categorized as diffuse-malignant PD at baseline experienced greater worsening in motor severity (p=0.007), cognition (p<0.0001) and activities of daily living (ADL) (p<0.0001) after 8 years. Individuals with diffuse-malignant PD showed a significantly higher rate of atrophy across multiple brain regions, including precuneus, paracentral lobule, inferior temporal gyrus, fusiform gyrus, and lateral hemisphere of the cerebellum (correctedp<0.05).

Conclusion

Our study revealed a distinct pattern of long-term progression in various motor and non-motor clinical outcomes between different subtypes of idiopathic PD. Furthermore, we demonstrated an accelerated atrophy pattern within several brain regions in the diffuse-malignant PD subtype. These findings suggest a more widespread and aggressive neurodegenerative process in a subgroup of people with PD, favoring the existence of diverse underlying pathophysiology with clinical relevance for future precision medicine in PD.
Personal protective beliefs and behaviors during the COVID-19 pandemic at a large, multi-campus, public university in Pennsylvania: a cross-sectional survey
Authors: Stachowski Jill , Murphy Ryan , Pomerantz Lauren , Kuruppumullage Don Prabhani , Long Bradley
Published: September 2024

Introduction

The COVID-19 pandemic impacted many higher education institutions. Understanding the personal protective beliefs and behaviors surrounding public health measures such as face masking, social distancing, and handwashing helps to inform public health outreach measures.

Objective

This study evaluates the beliefs and occurrences of face masking, social distancing, and handwashing behaviors among people at a multi-campus, public university in Pennsylvania.

Methods

From October 5-November 30, 2021, a 10-minute REDCap survey was available to students, faculty, and staff 18 years of age and older at the Pennsylvania State University (PSU). Recruitment included targeted email, social media, digital advertisements, and university newspapers. 4,231 responses were received. Simple percentage associations between the selected factors and face masking behaviors as well as beliefs on the origin of the COVID-19 virus were made with IBM SPSS Statistics, version 29.0.2.0 (20).

Results

Of 3,662 completed surveys, 65.2% of respondents were positive that facemasks prevented the transmission of airborne disease, 49.9% of the respondents stated that they wore facemasks always (27.9%), almost always (26.9%), or often (11.1%). 65.3% believed social distancing prevented transmission of COVID-19, 57.5% reported social distancing while on-campus or out in public (always: 18.8%, almost always: 20.3%, often: 18.4%). The response rate for some level of conscientiously washing hands for the 20 second duration was 87.5% (always: 26.0%, almost always: 31.9%, sometimes: 19.9%, only after being out in public: 4.9%, and only when convenient: 4.8%).

Conclusions

Beliefs in public health and safety measures during the COVID-19 pandemic did not always match the behaviors of individuals surveyed. Understanding barriers to performing behaviors or public health safety may help inform future areas for targeted intervention.
Bridging Language Gaps in Neurology Patient Education Through Large Language Models: a Comparative Analysis of ChatGPT, Gemini, and Claude
Authors: Haq Mahdi , Ur Rehman Muhammad Mushhood , Derhab Mohamed , Saeed Reeda , Kalia Junaid
Published: September 2024

This study evaluates the capability to translate neurology patient education material using three Large Language Models (LLMs) - ChatGPT-4 Omni, Gemini 1.5 Pro, and Claude 3.5 Sonnet. Five neurological conditions (Bell’s palsy, multiple sclerosis, stroke, migraine, and epilepsy) were translated from English into Spanish, Urdu, and Arabic. The translations were assessed by physicians using four metrics: accuracy, clarity, comprehensiveness, and readability at a 6th grade level. Results showed that Claude outperformed both ChatGPT and Gemini overall, particularly excelling in Spanish and Urdu translations, while Gemini led in Arabic. All LLMs demonstrated superior performance in Spanish compared to Urdu and Arabic. This study highlights the potential of LLMs in enhancing patient education across languages, while also identifying areas for improvement in translation accuracy and readability.
An integrative modelling approach to the mitochondrial cristae
Authors: Brown Chelsea M. , Westendorp Marieke S. S. , Zarmiento-Garcia Rubi , Stevens Jan A. , Rouse Sarah L. , Marrink Siewert J. , Wassenaar Tsjerk A.
Published: September 2024

Mitochondria are implicated in many cellular functions such as energy production and apoptosis but also disease pathogenesis. To effectively perform these roles, the mitochondrial inner membrane has invaginations known as cristae that dramatically increase the surface area. This works to provide more space for membrane proteins that are essential to the roles of mitochondria. While separate components of this have been studied computationally, it remains a challenge to combine elements into an overall model. Here we present a workflow to create a comprehensive model of a crista junction from a human mitochondrion. Our coarse-grained representation of a crista shows how various experimentally determined features of organelles can be combined with molecular modelling to give insights into the interactions and dynamics of complicated biological systems. This work is presented as an initial ‘living’ model for this system, intended to be built upon and improved as our understanding, methodology and resources develop.
SGLT2 inhibitors protect against diabetic cardiomyopathy and atrial fibrillation through a CaMKII independent mechanism
Authors: Severino Alex , Reyes-Gaido Oscar E , Nguyen Pauline , Elkarim Ahmed , Luczak Elizabeth D , Mesubi Olurotimi O.
Published: September 2024

Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been implicated as an important mediator of the increasingly evident cardioprotective benefits exerted by sodium– glucose transport protein 2 channel inhibitors (SGLT2i). However, the exact nature of the relationship between CaMKII and SGLT2i remains unclear. Here, we find that empagliflozin but not dapagliflozin attenuated susceptibility to atrial fibrillation (AF) in a type 2 diabetic (T2D) mouse model. However, both empagliflozin and dapagliflozin protected from diabetic cardiomyopathy in T2D mice. We then used real-time microscopy of neonatal rat ventricular cardiomyocytes (NRVMs) with the CaMKII biosensor - CaMKAR to demonstrate that direct inhibition of CaMKII is not essential for the effects of SGLT2i in these cells. Therefore, we conclude that the benefits of SGLT2i in heart disease likely occur through indirect modulation of CaMKII activity, or possibly through an alternative pathway altogether.
Hepatic aldose reductase drives a Warburg effect-like metabolic reprogramming to promote insulin resistance, fatty liver and obesity
Authors: Song Dan , Yang Dianqiang , Wen Longping , Zheng Feng , Yang James Y.
Published: September 2024

Background & Aims

Emerging evidence suggest that abnormal activation of aldose reductase/the polyol pathway (Ar/PP) is associated with the pathogenesis or development of fatty liver, obesity and metabolic syndrome. However, the underlying mechanisms were unclear. In this study, we investigated the metabolic reprogramming following activation or inhibition of Ar, the first and the rate-limiting enzyme of PP. We also investigated the long-term effects of Ar/PP-mediated metabolic shiftin vivo.

Methods

Metabolomic analyses were performed with the AB-SCIE QTRAP-5500 LC-MS/MS System for control mouse hepatocytes and hepatocytes stably overexpressing Ar and exposed to 25 mM glucose. Glycolysis stress tests and mitochondrial stress tests were performed using the Seahorse Bioscience Extracellular Flux Analyzer. Thein vivolong-term effects of Ar overexpression and inhibition were evaluated in either transgenic mice overexpressing AR or a line of double transgenic mice carrying an Ar-null mutation and an Agouti-yellowAymutation.

Results

Abnormal activation of Ar in hepatocytes was found to trigger and drive a drastic Warburg effect-like metabolic reprogramming, inducede novolipogenesis, and alter insulin and AMP-activated protein kinase signaling. In glucose-fedAR-overexpressing transgenic mice, AR activation causes systemic alterations in physiological parameters and the development of overt phenotypes of insulin resistance, fatty liver, obesity. In the yellow obese syndrome mice,Ardeficiency greatly improvesAgouti Aymutation-induced abnormalities.

Conclusions

Collectively, the results highlight the important contribution of Ar/PP or the putative pseudo-glycolysis in hepatic metabolic homeostasis and the development of metabolic diseases. These findings have profound implications for the development of therapeutic strategies or drugs against metabolic diseases and cancer.

GRAPHICAL ABSTRACT

Highlights

Activation of aldose reductase triggers and drives a Warburg effect-like metabolic eprogramming in hepatocytes.

Liver-specific activation of the polyol pathway leads to insulin resistance, fatty liver and obesity.

Inhibition of aldose reductase greatly amelioratesAgouti Ay-induced metabolic abnormalities.

Impact and implications

This study reveals that abnormal activation of Ar/PP will trigger and drive a Warburg effect-like metabolic reprogramming in hepatocytes. In normal subjects, Ar/PP mediated metabolic reprogramming tends to promote lipogenesis, insulin resistance, fatty liver and obesity. In cancer cells, Ar/PP mediated metabolic reprogramming will be part of the Warburg effect to support the growth and proliferation of cancer cells. These findings imply that Ar and its down-stream metabolic enzymes are important therapeutic targets for cancers and metabolic diseases.
The exopolysaccharide Poly-N-Acetyl-Glucosamine (PNAG) coatsKlebsiella pneumoniae in vivo
Authors: Bradshaw Jonathan , Sanchez-Garrido Julia , Berkachy Rita , Rattle Jaie , Preston Connor , Pizza Mariagrazia , Ros Immaculada Margarit , Romano Maria Rosaria , Wong Joshua L.C. , Frankel Gad
Published: September 2024

The conserved bacterial polysaccharide Poly-N-Acetyl-Glucosamine (PNAG) is a potential broad-spectrum vaccine candidate. While the immunogenicity of PNAG-based vaccine candidates has been established, characterisation of PNAG production across clinically relevant bacteria remains largely unknown. In particular, PNAG production in the Gram-negative pathogenKlebsiella pneumoniae(KP) is not well understood. Here, we demonstrate that PNAG production is prevalent in clinical KP isolates, where it is secreted as extracellular networks during adherent growth conditions. However, during severe KP pulmonary infection, KP PNAG production undergoes a switch to a cell-associated phenotype, coating the bacterial cell surface. By screening a panel of isogenic KP mutants in prominent cell surface components (ΔwcaJ,ΔrmpADC,Δrfb,ΔompAandΔompk36), we identified KP capsular polysaccharide as a key determinant underpinning the phenotype. Deleting genes involved in capsule synthesis (ΔwcaJ) and regulation (ΔrmpADC) resulted in cell-associated PNAG during adherent growth and infection of alveolar epithelial cellsin vitro. Taken together, we describe a novel interaction between KP surface polysaccharides and detect for the first time, cell-associated PNAG in KP during lung infection, highlighting PNAG as an attractive KP vaccine antigen.

Author summary

The Gram-negative pathogenKlebsiella pneumoniae(KP) is a leading cause of hospital-associated lung and bloodstream infections worldwide. As KP exhibits resistance to most frontline antibiotics, there is a growing demand for immune-based strategies to treat KP infections. Poly-N-Acetyl-Glucosamine (PNAG) is a surface sugar produced by most clinically relevant bacteria, including KP. However, relatively little is known about PNAG production in KP. Therefore, we set out to characterise PNAG production in KP during in vitro growth and following lung infection in a pulmonary mouse model. Duringin vitrogrowth, KP produces extracellular PNAG networks. In contrast, during anin vivosevere lung infection, PNAG is found cell-associated, coating the bacterial surface. We propose that the visible change in KP PNAG betweenin vitroandin vivoenvironments is due to crosstalk with capsule, another polysaccharide on the KP surface. Together, this supports PNAG as an attractive KP antigen.
AI-Augmented R-Group Exploration in Medicinal Chemistry
Authors: Zhao Hongtao , Kwapień Karolina , Nittinger Eva , Tyrchan Christian , Nilsson Magnus , Berglund Susanne , Czechtizky Werngard
Published: September 2024

Efficient R-group exploration in the vast chemical space, enabled by increasingly available building blocks or generative AI, remains an open challenge. Here, we developed an enhanced Free-Wilson QSAR model embedding R-groups by atom-centric pharmacophoric features. Regioisomers of R-groups can be distinguished by explicitly accounting for the atomic positions. Good predictivity is observed consistently across 12 public datasets. Integrated into an open-source program, we showcase its application in performing classic Free-Wilson analysis as well as R-group exploration in uncharted chemical space.
Dense but not alpha granules of platelets are required for insulin secretion from pancreatic β cells
Authors: Kolczyńska-Matysiak Katarzyna , Karwen Till , Loeffler Mona , Hawro Izabela , Kassouf Toufic , Stegner David , Sumara Grzegorz
Published: September 2024

Objectives

Platelets, originally described for their role in blood coagulation, are now also recognized as key players in modulating inflammation, tissue regeneration, angiogenesis, and carcinogenesis. Recent evidence suggests that platelets also influence insulin secretion from pancreatic β cells. The multifaceted functions of platelets are mediated by the factors stored in their alpha granules (AGs) and dense granules (DGs). AGs primarily contain proteins, while DGs are rich in small molecules, and both types of granules are released during blood coagulation. Specific components stored in AGs and DGs are implicated in various inflammatory, regenerative, and tumorigenic processes. However, the relative contributions of AGs and DGs to the regulation of pancreatic β cell function have not been previously explored.

Methods

In this study, we utilized mouse models deficient in AG content (neurobeachin-like 2 (Nbeal2) -deficient mice) and models with defective DG release (Unc13d-deficiency in bone marrow-derived cells) to investigate the impact of platelet granules on insulin secretion from pancreatic β cells.

Results

Our findings indicate that AG deficiency has little to no effect on pancreatic β cell function and glucose homeostasis. Conversely, mice with defective DG release exhibited glucose intolerance and reduced insulin secretion. Furthermore,Unc13d-deficiency in hematopoietic stem cells led to a reduction in adipose tissue gain in obese mice.

Conclusions

Obtained data suggest that DGs, but not AGs, mediate the influence of platelets on pancreatic β cells, thereby modulating glucose metabolism.
Production of the sesquiterpene bisabolene from one-carbon compounds in an engineeredMethanosarcina acetivorans
Authors: Mentrup Andrea , Scheitz Luca V. , Wallenfang Theo , Rother Michael
Published: September 2024

The isoprenoid bisabolene, one of the simplest monocyclic sesquiterpenes, is a natural plant product that, in addition to its biological function, serves as a precursor for many industrial products. Due to the low concentration of bisabolene and the long harvest cycle, industrial production of this isoprenoid in plants is economically challenging. Chemical synthesis of bisabolene also suffers from significant disadvantages, such as low yields, toxic side products and high costs. Archaea appear suitable producers of isoprenoids, as their membrane lipids consist of isoprenoid ethers, which are synthesized via a variant of the mevalonate pathway. Archaeal model species have versatile metabolic capacities, which makes them suitable candidates for biotechnological applications. Here, we engineeredMethanosarcina acetivoransfor production of α-bisabolene from one-carbon substrates by introducing a bisabolene synthase fromAbies grandis. Expression of a codon-optimized bisabolene synthase gene in aM. acetivoranswild-type strain resulted in 10.6 mg bisabolene/ liter of culture. Overexpressing genes of the mevalonate pathway only slightly increased bisabolene yields, which, however, were reached much earlier during incubations than in the corresponding wild-type strain. The data presented argue for the suitability ofM. acetivoransfor the biotechnical production of certain isoprenoids.
CHAMP1 complex directs heterochromatin assembly and promotes homology-directed DNA repair
Authors: Li Feng , Zhang Tianpeng , Syed Aleem , Elbakry Amira , Holmer Noella , Nguyen Huy , Mukkavalli Sirisha , Greenberg Roger A. , D’Andrea Alan D.
Published: September 2024

The CHAMP1 complex, a little-known but highly conserved protein complex consisting of CHAMP1, POGZ, and HP1α, is enriched in heterochromatin though its cellular function in these regions of the genome remain unknown. Here we show that the CHAMP complex promotes heterochromatin assembly at multiple chromosomal sites, including centromeres and telomeres, and promotes homology-directed repair (HDR) of DNA double strand breaks (DSBs) in these regions. The CHAMP1 complex is also required for heterochromatin assembly and DSB repair in highly-specialized chromosomal regions, such as the highly-compacted telomeres of ALT (Alternative Lengthening of Telomeres) positive tumor cells. Moreover, the CHAMP1 complex binds and recruits the writer methyltransferase SETDB1 to heterochromatin regions of the genome and is required for efficient DSB repair at these sites. Importantly, peripheral blood lymphocytes from individuals with CHAMP1 syndrome, an inherited neurologic disorder resulting from heterozygous mutations inCHAMP1, also exhibit defective heterochromatin clustering and defective repair of local DSBs, suggesting that a defect in DNA repair underlies this syndrome. Taken together, the CHAMP1 complex has a novel role in heterochromatin assembly and the enhancement of HDR in heterochromatin.
Insights into Health Data Science Education: A Qualitative Content Analysis
Authors: Rohani Narjes , Gallagher Michael , Gal Kobi , Manataki Areti
Published: September 2024

Background

Early career researchers in Health Data Science (HDS) struggle to effectively manage their learning process due to the novel and interdisciplinary nature of this field. To date, there is limited understanding about learning strategies in health data science. Therefore, we aim to uncover learning strategies that early career researchers employ to address their educational challenges, as well as shed light on their preferences regarding HDS teaching approach and course design.

Method

In this study, we conducted a qualitative content analysis through semistructured interviews with ten early career researchers, including individuals pursuing master’s, PhD, and postdoctoral research programmes in HDS, across two higher education institutions in the United Kingdom. Interviews were carried out in person from June 2023 to August 2023. Data were analysed qualitatively using NVivo software. Descriptive statistics were employed for quantitative analysis.

Results

Regarding learning strategies, we identified ten main categories with 22 codes, including collaboration, information seeking, active learning, focus granularity, elaboration, organisation, order granularity, goal orientation, reviewing, and deep learning strategies. Regarding course design and teaching, we discovered four categories with 14 codes, including course materials, duration and complexity, online discussion, and teaching approaches.

Conclusions

Early career researchers used a range of learning strategies aligned with well-established learning theories, such as peer learning, information seeking, and active learning. It is also evident that learners in HDS favour interactive courses that provide them with hands-on experience and interactive discussion. The insights derived from our findings can enhance the quality of education in HDS.
Auditory decision-making deficits after permanent noise-induced hearing loss
Authors: Berns Madeline P. , Nunez Genesis M. , Zhang Xingeng , Chavan Anindita , Zemlianova Klavdia , Mowery Todd M. , Yao Justin D.
Published: September 2024

Loud noise exposure is one of the leading causes of permanent hearing loss. Individuals with noise-induced hearing loss (NIHL) suffer from speech comprehension deficits and experience impairments to cognitive functions such as attention and decision-making. Here, we tested whether a specific sensory deficit, NIHL, can directly impair auditory cognitive function. Gerbils were trained to perform an auditory decision-making task that involves discriminating between slow and fast presentation rates of amplitude-modulated (AM) noise. Decision-making task performance was assessed across pre-versus post-NIHL sessions within the same gerbils. A single exposure session (2 hours) to loud broadband noise (120 dB SPL) produced permanent NIHL with elevated threshold shifts in auditory brainstem responses (ABRs). Following NIHL, decision-making task performance was tested at sensation levels comparable to those prior to noise exposure in all animals. Our findings demonstrate NIHL diminished perceptual acuity, reduced attentional focus, altered choice bias, and slowed down evidence accumulation speed. Finally, video-tracking analysis of motor behavior during task performance demonstrates that NIHL can impact sensory-guided decision-based motor execution. Together, these results suggest that NIHL impairs the sensory, cognitive, and motor factors that support auditory decision-making.