bluuebunny/crossref_metadata_2025 huggingface dataset:
Dust enrichment in the circum-galactic medium
Authors: Otsuki Mau , Hirashita Hiroyuki
Published: February 2024

To understand the origin of dust in the circum-galactic medium (CGM), we develop a dust enrichment model. We describe each of the central galaxy and its CGM as a single zone, and consider the mass exchange between them through galactic inflows and outflows. We calculate the evolution of the gas, metal, and dust masses in the galaxy and the CGM. In the galaxy, we include stellar dust production and interstellar dust processing following our previous models. The dust in the galaxy is transported to the CGM via galactic outflows, and it is further processed by dust destruction (sputtering) in the CGM. We parametrize the time-scale or efficiency of each process and investigate the effect on the dust abundance in the CGM. We find that the resulting dust mass is sensitive to the dust destruction in the CGM, and the dust supply from galactic outflows, both of which directly regulate the dust abundance in the CGM. The inflow time-scale also affects the dust abundance in the CGM because it determines the gas mass evolution (thus, the star formation history) in the galaxy. The dust abundance in the CGM, however, is insensitive to stellar dust formation in the galaxy at later epochs because the dust production is dominated by dust growth in the interstellar medium. We also find that the resulting dust mass in the CGM is consistent with the value derived from a large sample of SDSS galaxies.
Effective viscosity, resistivity, and Reynolds number in weakly collisional plasma turbulence
Authors: Yang Yan , Matthaeus William H , Oughton Sean , Bandyopadhyay Riddhi , Pecora Francesco , Parashar Tulasi N , Roytershteyn Vadim , Chasapis Alexandros , Shay Michael A
Published: February 2024

We examine dissipation and energy conversion in weakly collisional plasma turbulence, employing in situ observations from the Magnetospheric Multiscale mission and kinetic particle-in-cell simulations of proton–electron plasma. A previous result indicated the presence of viscous-like and resistive-like scaling of average energy conversion rates – analogous to scalings characteristic of collisional systems. This allows for extraction of collisional-like coefficients of effective viscosity and resistivity, and thus also determination of effective Reynolds numbers based on these coefficients. The effective Reynolds number, as a measure of the available bandwidth for turbulence to populate various scales, links turbulence macroscale properties with kinetic plasma properties in a novel way.
Evaluation and significance of a digital assistant for patient history-taking and physical examination in telemedicine
Authors: Verma Neha , Buch Bimal , Pandya R S , Taralekar Radha , Masand Ishita , Rangparia Hardik , Katira J M , Acharya Soumyadipta
Published: February 2024

Introduction

Assisted history-taking systems can be used in provider-to-provider teleconsultations to task-shift the collection of evidence-based medical history and physical exam information to a frontline health worker. We developed such a task-shifting digital assistant, called ‘Ayu’, for nurses in rural India to collect clinical information from a patient and share it with a remote doctor to arrive at an accurate diagnosis and triage decision.

Materials & Methods

We evaluated the ability of the task-shifting digital assistant to collect a comprehensive patient history by using 190 standardized patient case studies and evaluating the information recall of the assistant by a skilled clinician. Following this, we tested the ability of nurses to use the system by training and evaluating the system’s accuracy when used by 19 nurses in rural Gujarat, India. We also measured the diagnostic and triage accuracy based on the generated history note. Finally, we evaluated the system’s acceptability by using the Technology Acceptance Model framework.

Results

Ayu could capture 65% of patient history information and 42% of physical exam information from patient case studies. When used by nurses, the mean accuracy of the generated clinical note was 7.71 ± 2.42. Using the information collected by a nurse using Ayu, a primary care physician could arrive at the correct diagnosis in 74% of cases, and correct triage decision in 88% of cases. Overall, we saw a high acceptability from nurses to use the system.

Conclusions

Ayu can capture an acceptable proportion of clinical information and can aid in collecting an evidence-based medical history by task-shifting some of the early investigational steps. Further development of Ayu to increase its information retrieval ability and ease of use by health workers is needed.
The primary geology of the Paleoproterozoic Mt Weld Carbonatite Complex, Western Australia
Authors: Chandler Ross , Bhat Ganesh , Mavrogenes John , Knell Brad , David Rhiannon , Leggo Thomas
Published: February 2024

The paleoregolith overlying the c. 2.06 Ga Mt Weld carbonatite (eastern Yilgarn Craton, Western Australia) hosts one of the largest Rare Earth Element (REE) deposits globally. Historic exploration and research has focussed on this weathered material, with a lack of unweathered samples preventing a thorough investigation into the nature of the underlying carbonatite. Recent deep drilling has allowed this first in-depth study into the primary geology, mineralogy and geochemistry of the carbonatite complex. Mt Weld shares a similar lithological architecture to other global carbonatite complexes, such as Ngualla (Tanzania, Bonga (Angola), Chilwa Island (Malawi) and Mirima Hill (Malawi), displaying a central (~600 m diameter) unit of magnesio- to ferrocarbonatite is surrounded by a broad (~1.2 km) annulus of calciocarbonatite, itself surrounded by a fenitic halo. Primary REE mineralisation occurs within the central magnesio- to ferrocarbonatites (~2% Total Rare Earth Oxides in bulk rock) and is dominated by fine-grained monazite hosted within fractures and voids, as well as late magmatic synchysite/bastnäsite. Both high and low phosphourous ferrocarbonatites occur within this central magnesio- to ferrocarbonatite unit that display (respectively) monazite or synchysite/bastnäsite mineralisation with textural evidence for these REE-bearing carbonates occasionally forming as polycrystalline pseudomorphs of earlier burbankite group minerals. Magnesio- to ferrocarbonatite dykes with zhonghuacerite/olekminskite/ancylite assemblages occur throughout the otherwise REE-poor calciocarbonatites (~0.2% Total Rare Earth Oxides in bulk rock). Late hydrothermal events strongly influenced the modern-day mineral assemblages with much of the existing ore mineral textures interpreted as hydrothermal reworkings of pre-existing REE-bearing minerals. A comparison of the fresh carbonatite and the paleoregolith geochemistry suggests minimal horizontal migration of ore elements during paleoregolith formation, with the overlying paleoregolith material broadly reflecting the underlying carbonatite trace and minor element signatures. This allows the inference of an approximately 5× upgrade in REE (and Nb) concentrations from the primary carbonatite to the overlying paleoregolith. Mt Weld shows distinct geological, mineralogical and isotopic differences to other currently mined carbonatite-associated REE deposits, such as Bayan Obo (China), Mountain Pass (USA) and the Mianning-Dechang belt (China), which suggests that fundamentally different carbonatite mantle sources and evolutionary paths can form world-class REE ore bodies.
Fluid-Induced Metamorphism and Deformation at the Eastern Boundary of the Sveconorwegian Province
Authors: Urueña C L , Möller C
Published: February 2024

The Sveconorwegian orogen in Scandinavia and the Grenville orogen in Canada are both remnants of large and hot orogens that formed part of the supercontinent Rodinia around 1 billion years ago. Formerly deeply buried portions of crust in these orogens are exposed and offer insights into the tectonic dynamics of the basement within large orogens. The Eastern Segment of the Sveconorwegian Province hosts a ~ 30 000 km2 crustal portion that was buried to c. 40 km depth at a late stage of the orogeny, 980–960 Ma ago, and is bound towards the foreland in the east by a ~ 25 km wide zone of step anastomosing deformation, the Frontal wedge. This zone represents the outermost ductile deformation that developed within the crystalline basement in the orogen. We investigated a heterogeneously deformed and recrystallised syenodiorite with the aim to understand the character of the deformation-related metamorphism within the Frontal wedge. Field relations, microtextures, and mineral reactions show that the metamorphic recrystallisation was governed by hydrous fluid infiltration along the ductile deformation zones. Equilibrium was attained on a millimetre scale only and metamorphic recrystallisation was dependent on the introduction of hydrous fluid. The metamorphism reached high-pressure epidote-amphibolite-facies; geothermobarometric estimates suggest 540°C to 600°C and 9 to 12 kbar. Metamorphic zircon formed during the breakdown of Zr-bearing igneous phases, primarily baddeleyite. SIMS U–Pb analyses of igneous zircon and baddeleyite date the igneous crystallisation of the syenodiorite at 1230 ± 6 Ma. Metamorphic zircon grains are <20 μm and too small for precise dating, but yielded ages around 1 Ga. Collectively, the metamorphic data indicate that subvertical movements along steep planes within the Frontal wedge allowed for the regional-scale tectonic burial to ~40 km depth of the Eastern Segment to the west. Some of the same steep deformation structures were re-utilised as discrete movement planes during later exhumation.
Comment on ‘The Generation of Eocene Mafic Dike Swarms During the Exhumation of a Core Complex, Biarjmand Area, NE Iran’ by Azizi et al. (2023), Journal of Petrology, 64, 1–18
Authors: Malekpour-Alamdari Ahmadreza
Published: February 2024

Azizi, H., Daneshvar, N., Asahara, Y., Minami, M. & Anma, R. (2023). The generation of Eocene mafic dike swarms during the exhumation of a Core complex, Biarjmand area, NE Iran. Journal of Petrology64, 1–18 have attributed the E–W-oriented mafic dike swarm in the Biarjmand metamorphic core complex to an Eocene extensional event which is much younger than a previously suggested Late Jurassic–Early Cretaceous age. They proposed that the emplacement of these dikes occurred in a rapid extensional regime coeval with the exhumation of the core complex after gravitational instability in the Central Iran/Eurasia collision zone. I appreciate the opportunity this article provides to shed light on specific aspects of the Late Mesozoic–Early Cenozoic continental extension within the Eurasian sector of the Neotethys subduction system. However, I here bring to attention certain discrepancies within Azizi et al.'s publication. Specifically, the assignment of an Eocene age to the emplacement of the E–W-oriented dike swarm, even though purportedly supported by U–Pb zircon dating, appears to be at odds with field observations and previously published geochronological data. Furthermore, the article contains internal contradictions in its presentation of the core complex model for the study area. It is important to note that Malekpour-Alamdari, A., Axen, G. J., Heizler, M. T. & Hassanzadeh, J. (2017). Large-magnitude continental extension in the northeastern Iranian plateau: insight from K-feldspar 40Ar/39Ar thermochronology from the Shotor Kuh-Biarjmand metamorphic core complex. Geosphere13, 1207–1233 previously documented the geochronological-based metamorphic core complex model of the area. Regrettably, despite its direct relevance, these earlier works have not been acknowledged in Azizi et al.'s paper. In this comment, I outline the problems with the structural and regional geology, the zircon U–Pb age of the dike samples, the age of the dike swarm, and the geodynamic interpretations in Azizi et al.'s work.
Price for waiting: the adverse outcomes of boarding critically ill elderly medical patients in the emergency department
Authors: Huang Kuang-Wen , Yin Chun-Hao , Chang Renin , Chen Jin-Shuen , Chen Yao-Shen
Published: February 2024

Purpose

Boarding, the period in which a patient spends in the emergency department (ED) before admission, may be hazardous to critically ill patients, particularly the elderly. This study investigated the associations of boarding with hospital course, prognosis, and medical expenditure in older patients.

Methods

From January 2019 to December 2021, the medical records of older patients (age ≥ 65) visiting the ED of a tertiary referral hospital who were admitted to the medical intensive care unit (ICU) were retrospectively reviewed. Eligible patients were categorized into two groups according to boarding time with a cutoff set at 6 h. Primary outcomes were in-hospital mortality, ICU/hospital length of stay, and total/average hospitalization cost. Subgroup analyses considered age and disease type.

Results

Among 1318 ICU admissions from the ED, 36% were subjected to boarding for over 6 h. Prolonged boarding had a longer ICU (8.9 ± 8.8 vs. 11.2 ± 12.2 days, P < .001) and hospital (17.8 ± 20.1 vs. 22.8 ± 23.0 days, P < .001) stay, higher treatment cost (10.4 ± 13.9 vs. 13.2 ± 16.5 thousands of USD, P = .001), and hospital mortality (19% vs. 25% P = .020). Multivariate regression analysis showed a longer ICU stay in patients aged 65–79 (8.3 ± 8.4 vs. 11.8 ± 14.2 days, P < .001) and cardiology patients (6.9 ± 8.4 vs. 8.8 ± 9.7 days, P = .001). Besides, the treatment cost was also higher for both groups (10.4 ± 14.6 vs. 13.7 ± 17.7 thousands of USD, P = .004 and 8.4 ± 14.0 vs. 11.7 ± 16.6 thousands of USD, P < .001, respectively).

Conclusion

Extended ED boarding for critically ill medical patients over 65 years old was associated with negative outcomes, including longer ICU/hospital stays, higher treatment costs, and hospital mortality.
A patient-enriched MEIS1 coding variant causes a restless legs syndrome-like phenotype in mice
Authors: Leu Chia-Luen , Lam Daniel D , Salminen Aaro V , Wefers Benedikt , Becker Lore , Garrett Lillian , Rozman Jan , Wurst Wolfgang , Hrabě de Angelis Martin , Hölter Sabine M , Winkelmann Juliane , Williams Rhîannan H
Published: February 2024

Restless legs syndrome (RLS) is a neurological disorder characterized by uncomfortable or unpleasant sensations in the legs during rest periods. To relieve these sensations, patients move their legs, causing sleep disruption. While the pathogenesis of RLS has yet to be resolved, there is a strong genetic association with the MEIS1 gene. A missense variant in MEIS1 is enriched sevenfold in people with RLS compared to non-affected individuals. We generated a mouse line carrying this mutation (p.Arg272His/c.815G>A), referred to herein as Meis1R272H/R272H (Meis1 point mutation), to determine whether it would phenotypically resemble RLS. As women are more prone to RLS, driven partly by an increased risk of developing RLS during pregnancy, we focused on female homozygous mice. We evaluated RLS-related outcomes, particularly sensorimotor behavior and sleep, in young and aged mice. Compared to noncarrier littermates, homozygous mice displayed very few differences. Significant hyperactivity occurred before the lights-on (rest) period in aged female mice, reflecting the age-dependent incidence of RLS. Sensory experiments involving tactile feedback (rotarod, wheel running, and hotplate) were only marginally different. Overall, RLS-like phenomena were not recapitulated except for the increased wake activity prior to rest. This is likely due to the focus on young mice. Nevertheless, the Meis1R272H mouse line is a potentially useful RLS model, carrying a clinically relevant variant and showing an age-dependent phenotype.
Plant-based fat supply is associated with reduced ADHD disease burden
Authors: Ni Duan , Senior Alistair , Raubenheimer David , Simpson Stephen J. , Nanan Ralph
Published: February 2024

Objectives

Attention-Deficit/Hyperactivity Disorder (ADHD) is emerging as a major neurodevelopmental disorder on a global scale, affecting both children and increasingly adult population. Its aetiology is unclear but seems to involve genetic and environmental factors, particularly diets and nutrients. However, most studies so far only focused on specific nutrients or dietary patterns, lacking systematic perspectives of their potential interactions, and also neglecting other confounding factors like socioeconomic status. Thus, we aim to systematically interrogate the association between nutrient supply, reflecting the food exposure and environment, socioeconomic status and ADHD disease burden at a global level over time.

Methods

ADHD disease burden, macronutrient supply and gross domestic product (GDP) were collated from more than 150 countries from 1990 to 2018 and analyzed with nutritional geometry generalized additive mixed models (GAMMs).

Results

Modelling results suggested the interactive effects of nutrients and socioeconomic status on ADHD. Fat, especially plant-based fat supply, is associated with decreased ADHD disease burden. These associations were conserved across sexes and ages and were not confounded by the total energy supply.

Conclusions

Globally, far, particularly plant-based fat supply seemed to drive the reduction of ADHD disease burden, which is supported by previous reports about the amelioration of ADHD by ketogenic diets. Further in-depth studies are needed to elucidate the underlying mechanistic and may inform future targeted dietary interventions for ADHD prevention and/or treatment.
RAMDS: Retrieval Augmented Medical Diagnosis System for Explainable Breast Cancer Classification from Ultrasound Images
Authors: Johnson Ethan Thomas , Bande Jathin K , Thomas Johnson
Published: February 2024

Breast cancer, a leading cause of cancer-related deaths in women, presents a growing challenge in medical diagnostics. Despite the effectiveness of mammography and ultrasound, the ambiguity in non-invasive scans often necessitates invasive procedures. Our primary goal was to create an AI model that could predict breast cancer with high negative predictive value and reduce unnecessary procedures. This study introduces the Retrieval-Augmented Medical Diagnosis System (RAMDS) for breast cancer, a novel approach combining an AI model with a retrieval-augmented mechanism to enhance diagnostic accuracy and explainability. The RAMDS employs a pretrained ResNet 34 model, fine-tuned on breast ultrasound image datasets from four countries. It integrates a similarity-based weighted adjustment mechanism to compare new cases with historical diagnoses. It’s like having an experienced doctor who remembers every case they’ve ever seen and uses that knowledge to make better decisions. RAMDS improved sensitivity by 11%, and negative predictive value by 9% when compared to the base model. Notably, the RAMDS improves explainability by linking AI predictions to similar historical cases, aligning with the medical community’s interest in transparent and understandable AI decisions.

A unique feature of this system is its adaptability to varied imaging contexts without retraining, addressing the challenge of dataset variability across medical institutions. In conclusion, the RAMDS offers a significant advancement in breast cancer diagnosis, combining enhanced accuracy, explainability, and adaptability. It holds promise for clinical application, though further research is needed to optimize its performance and integrate multi-modal data.
Multistability and predominant double-positive states in a four node mutually repressive network: a case study of Th1/Th2/Th17/T-reg differentiation
Authors: Duddu Atchuta Srinivas , Andreas Elizabeth , Harshavardhan BV , Grover Kaushal , Singh Vivek Raj , Hari Kishore , Jhunjhunwala Siddharth , Cummins Breschine , Gedeon Tomas , Jolly Mohit Kumar
Published: February 2024

Elucidating the emergent dynamics of complex regulatory networks enabling cellular differentiation is crucial to understand embryonic development and suggest strategies for synthetic circuit design. A well-studied network motif often driving cellular decisions is a toggle switch - a set of two mutually inhibitory lineage-specific transcription factors A and B. A toggle switch often enables two possible mutually exclusive states - (high A, low B) and (low A, high B) - from a common progenitor cell. However, the dynamics of networks enabling differentiation of more than two cell types from a progenitor cell is not well-studied. Here, we investigate the dynamics of four master regulators A, B, C and D inhibiting each other, thus forming a toggle tetrahedron. Our simulations show that a toggle tetrahedron predominantly allows for co-existence of six ‘double positive’ or hybrid states where two of the nodes are expressed relatively high as compared to the remaining two - (high A, high B, low C, low D), (high A, low B, high C, low D), (high A, low B, low C, high D), (low A, high B, high C, low D), (low A, low B, high C, high D) and (low A, high B, low C, high D). Stochastic simulations showed state-switching among these phenotypes, indicating phenotypic plasticity. Finally, we apply our results to understand the differentiation of naive CD4+T cells into Th1, Th2, Th17 and Treg subsets, suggesting Th1/Th2/Th17/Treg decision-making to be a two-step process. Our results reveal multistable dynamics and establish the stable co-existence of hybrid cell-states, offering a potential explanation for simultaneous differentiation of multipotent naïve CD4+ T cells.
Renal-Derived Human sPRR Does Not Increase Blood Pressure in High Fat Diet Mice
Authors: Arthur Gertrude , Biel Katherine , Osborn Jeffrey L , Hinds Terry D. , Gong Ming , Loria Analia S.
Published: February 2024

Obesity is a risk factor for hypertension. Obesity-related hypertension has been associated with elevated plasma soluble prorenin receptor (sPRR) particularly in men. Additionally, renal PRR and sPRR protein expression is upregulated during obesity and diabetes. However, whether renal-derived human sPRR (HsPRR) may influence the intrarenal RAS status to regulate blood pressure and kidney function during obesity has not been investigated. Therefore, we studied the role of collecting duct (CD) derived-HsPRR on blood pressure and kidney function in male and female mice during obesity. Eight-week-old male and female CD-HsPRR mice were placed on a high fat diet for 25 weeks. HsPRR increased renal sPRR concentration but did not change its circulating levels in male and female littermates compared to CTL mice. GFR, water intake and urine flow were not influenced by the CD-HsPRR expression in either sex. Moreover, after 21 weeks of HFD, blood pressure was similar between groups, while only male CD-HsPRR mice showed an impaired pressor response to losartan. In the renal cortex, male CD-HsPRR mice showed increased renin and AT1R mRNA expression associated with increased AQP2, and ENaC subunits protein expression. These data indicate that renal-derived HsPRR induces local upregulation in renin, AT1R and sodium/water transporters in male mice without altering renal hemodynamics or blood pressure. In obese females, CD-HsPRR expression did not affect blood pressure or renal function, which suggests that females may be protected from obesity induced renal function impairment and hypertension.
Loss of TIM4-Dependent Efferocytosis in Kupffer Cells Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis
Authors: Shi Hongxue , Wang Xiaobo , Gerlach Brennan , Yurdagul Arif , Moore Mary P. , Mirshahi Faridoddin , Ronzoni Luisa , Sanyal Arun J. , Valenti Luca , Lin Chyuan-Sheng , Tabas Ira
Published: February 2024

Background and aims

Hepatocyte apoptosis is a key feature of non-alcoholic steatohepatitis (NASH), but the fate of apoptotic hepatocytes in NASH is poorly understood. Herein we explore the hypothesis that impaired TIM4-mediated clearance of dead hepatocytes by liver macrophages (efferocytosis) is impaired in NASH and drives the progression to liver fibrosis.

Methods

Kupffer cell (KC)-TIM4 expression and efferocytosis were assayed in normal and NASH liver from humans and diet-induced NASH mice. The engulfment of human and mouse apoptotic hepatocytes by primary human and mouse liver KCs was assayedex vivo. Causation was assessed in NASH mice using anti-TIM4 antibodies, KC-TIM4-knockout, or inducible KC-TIM4 expression, with analyses focused on efferocytosis of apoptotic hepatocytes by liver macrophages and liver fibrosis.

Results

In human and mouse NASH liver, apoptotic hepatocytes accumulated and was associated with the loss of the KC efferocytosis receptor TIM4. Anti-TIM4 inhibited the engulfment of apoptotic hepatocytes by primary human and mouse liver KCsex vivo, and anti-TIM4 administration to early NASH mice worsened liver macrophage efferocytosis and accelerated the progression to fibrotic NASH. A similar result was obtained by genetically deleting TIM4 in KCs in NASH mice. Most importantly, genetic restoration of macrophage TIM4 in NASH mice enhanced the clearance of apoptotic hepatocytes by liver macrophages and decreased liver fibrosis.

Conclusions

The loss of macrophage TIM4 that occurs during NASH progression impairs the clearance of apoptotic hepatocytes by liver macrophages, which subsequently promotes the progression to fibrotic NASH. This pathogenic sequence of events can be prevented by restoring macrophage TIM4, suggesting that future therapeutic approaches designed to boost TIM4 expression in liver macrophages could represent a novel strategy to prevent fibrotic NASH progression.

Lay summary

Nonalcoholic steatohepatitis (NASH) is emerging as the leading cause of liver disease, but the processes leading to liver fibrosis in NASH, which determines clinical outcome, are incompletely understood. Our study provides evidence impaired clearance of dead liver cells by liver macrophages in NASH, which is due to loss of a macrophage receptor called TIM4, contributes to liver fibrosis. Knowledge of this process may suggest new ways to bolster the clearance of dead liver cells in NASH and thereby prevent the progression to liver fibrosis and subsequent liver disease.
RNA3DB: A structurally-dissimilar dataset split for training and benchmarking deep learning models for RNA structure prediction
Authors: Szikszai Marcell , Magnus Marcin , Sanghi Siddhant , Kadyan Sachin , Bouatta Nazim , Rivas Elena
Published: February 2024

With advances in protein structure prediction thanks to deep learning models like AlphaFold, RNA structure prediction has recently received increased attention from deep learning researchers. RNAs introduce substantial challenges due to the sparser availability and lower structural diversity of the experimentally resolved RNA structures in comparison to protein structures. These challenges are often poorly addressed by the existing literature, many of which report inflated performance due to using training and testing sets with significant structural overlap. Further, the most recent Critical Assessment of Structure Prediction (CASP15) has shown that deep learning models for RNA structure are currently outperformed by traditional methods.

In this paper we present RNA3DB, a dataset of structured RNAs, derived from the Protein Data Bank (PDB), that is designed for training and benchmarking deep learning models. The RNA3DB method arranges the RNA 3D chains into distinct groups (Components) that are non-redundant both with regard to sequence as well as structure, providing a robust way of dividing training, validation, and testing sets. Any split of these structurally-dissimilar Components are guaranteed to produce test and validations sets that are distinct by sequence and structure from those in the training set. We provide the RNA3DB dataset, a particular train/test split of the RNA3DB Components (in an approximate 70/30 ratio) that will be updated periodically. We also provide the RNA3DB methodology along with the source-code, with the goal of creating a reproducible and customizable tool for producing structurally-dissimilar dataset splits for structural RNAs.

Graphical Abstract

Highlights

While there is a recent surge in applying deep learning to RNA structure prediction, domain experts have raised concerns about generalization and current trends in benchmarking.

Many of the concerns primarily relate to how novel RNA families–i.e. families unseen in the training set–are benchmarked, and whether the models are effective at handling such cases. Performance on bench-marks reflective of real-world applications, such as CASP15 and RNA-Puzzles, is poor for RNA deep learning models.

We present a dataset–RNA3DB–that is designed for training and bench-marking deep learning models for RNA structure prediction. RNA3DB provides coverage of all RNA chains found in the Protein Data Bank (PDB).

RNA3DB is clustered into groups that are both sequentially and structurally non-redundant, providing a robust way of creating training, validation, and testing sets for deep learning models. Along with the dataset, we also provide a transparent methodology as well as the source-code, making our tool both reproducible and customizable.
Synthesis of 5-Benzylamino and 5-Alkylamino-substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity
Authors: Asressu Kesatebrhan Haile , Smith Jeffery L. , Dickmander Rebekah J. , Moorman Nathaniel J. , Wellnitz James , Popov Konstantin I. , Axtman Alison D. , Willson Timothy M.
Published: February 2024

A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous solubility. Among the range of analogs, those bearing electron-withdrawing (4cand4g) or donating (4f) substituents on the benzyl ring as well as introduction of non-aromatic groups such as the cyclohexylmethyl (4t) were shown to maintain CSNK2A activity. The CSNK2A activity was also retained withN-methylation of SGC-CK2-2, but α-methyl substitution of the benzyl substituent led to a 10-fold reduction in potency. CSNK2A inhibition potency was restored with indene-based compound4af, with activity residing in the S-enantiomer (4ag). Analogs with the highest CSNK2A potency showed good activity for inhibition of Mouse Hepatitis Virus (MHV) replication. Conformational analysis indicated that analogs with the best CSNK2A inhibition (4t, 4ac, and4af) exhibited smaller differences between their ground state conformation and their predicted binding pose. Analogs with reduced activity (4ad, 4ae, and4ai) required more substantial conformational changes from their ground state within the CSNK2A protein pocket.
GNN4DM: A Graph Neural Network-based method to identify overlapping functional disease modules
Authors: Gézsi András , Antal Péter
Published: February 2024

Motivation

Identifying disease modules within molecular interaction networks is an essential exploratory step in computational biology, offering insights into disease mechanisms and potential therapeutic targets. Traditional methods often struggle with the inherent complexity and overlapping nature of biological networks, and they are limited in effectively leveraging the vast amount of available genomic data and biological knowledge. This limitation underscores the need for more effective, automated approaches to integrate these rich data sources.

Results

In this work, we propose GNN4DM, a novel graph neural network-based structured model that automates the discovery of overlapping functional disease modules. GNN4DM effectively integrates network topology with genomic data to learn the representations of the genes corresponding to functional modules and align these with known biological pathways for enhanced interpretability. Following the DREAM benchmark evaluation setting and extending with three independent data sources (GWAS Atlas, FinnGen, and DisGeNET), we show that GNN4DM performs better than several state-of-the-art methods in detecting biologically meaningful modules. Furthermore, we highlight the method’s applicability through its discovery of two novel multimorbidity-modules significantly enriched in a wide array of apparently unrelated diseases.

Availability and Implementation

Source code, all training data, and all identified disease modules are freely available for download athttps://github.com/gezsi/gnn4dm. GNN4DM was implemented in Python.

Contact

gezsi.andras@vik.bme.hu
Transcriptional responses to priority effects in nectar yeast
Authors: Chappell Callie R. , Goddard Pagé C. , Golden Lexi-Ann , Hernandez Jonathan , Chavez Daniela Ortiz , Hossine Marziiah , Paredes Sur Herrera , Fukami Tadashi , Dhami Manpreet K.
Published: February 2024

Priority effects, where the order and timing of species arrival influence the assembly of ecological communities, have been observed in a variety of taxa and habitats. However, the genetic and molecular basis of priority effects remains unclear in most cases, hindering the mechanistic understanding of priority effects. We sought to gain such understanding for the common nectar yeast Metschnikowiareukaufii, which engages in strong priority effects with other species of nectar yeast, includingM. rancensis, another species commonly found in the nectar of our study plant, the hummingbird-pollinatedDiplacus(Mimulus)aurantiacus. After inoculation into two contrasting types of synthetic nectar simulating early arrival ofM. rancensis, we conducted whole-transcriptome sequencing of 108 genetically diverse strains ofM. reukaufii. We found that several genes were differentially expressed inM. reukaufiistrains when the nectar had been conditioned by growth ofM. rancensis. Many of these genes were associated with amino acid metabolism, consistent with our previous finding that early-arriving species limit late-arriving species’ growth by reducing amino acid availability. Furthermore, investigation of expression quantitative trait loci (eQTLs) revealed that genes involved in amino acid transport and resistance to antifungal compounds were enriched in genetic variants, with differing effects on gene expression based on priority effects ofM. rancensis. These results demonstrate that intraspecific variation in the ability of nectar yeasts to respond to nutrient limitation and direct fungal competition may underpin the molecular mechanisms of priority effects.
A natural language processing system for the efficient extraction of cell markers
Authors: Cheng Peng , Peng Yan , Zhang Xiao-Ling , Chen Sheng , Fang Bin-Bin , Li Yan-Ze , Sun Yi-Min
Published: February 2024

1.

Background

In the last few years, single-cell RNA sequencing (scRNA-seq) has been widely used in various species and tissues. The construction of the cellular landscape for a given species or tissue requires precise annotation of cell types, which relies on the quality and completeness of existing empirical knowledge or manually curated cell marker databases. The natural language processing (NLP) technique is a potent tool in text mining that enables the rapid extraction of entities of interest and relationships between them by parsing the syntax structure.

Methods and results

We developed MarkerGeneBERT, an NLP-based system designed to automatically extract information about species, tissues, cell types and cell marker genes by parsing the full texts of the literature from single-cell sequencing studies. As a result, 8873 cell markers of 1733 cell types in 435 human tissues/subtissues and 9064 cell markers of 1832 cell types in 492 mouse tissues/subtissues were collected from 3987 single-cell sequencing-related studies. By comparison with the marker genes of existing manual curated cell marker databases, our method achieved 76% completeness and 75% accuracy. Furthermore, within the same literature, we found 89 cell types and 183 marker genes for which the cell marker database was not available. Finally, we annotated brain tissue single-cell sequencing data directly using the compiled list of brain tissue marker genes from our software, and the results were consistent with those of the original studies. Taken together, the results of this study illustrate for the first time how systematic application of NLP-based methods could expedite and enhance the annotation and interpretation of scRNA-seq data.
Relative contribution of COVID-19 vaccination and SARS-CoV-2 infection to population-level seroprevalence of SARS-CoV-2 spike antibodies in a large integrated health system
Authors: Chervo Tyler C. , Elkin Eric P. , Nugent Joshua R. , Valice Emily , Amsden Laura B. , Ergas Isaac J. , Munneke Julie R. , Flores Monica , Saelee Gina N. , Hsiao Crystal A. , Schapiro Jeffery M. , Quesenberry Charles P. , Corley Douglas A. , Habel Laurel A. , Kushi Lawrence H. , Skarbinski Jacek
Published: February 2024

Background

Understanding the relative contributions of SARS-CoV-2 infection-induced and vaccine- induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions.

Methods

Using a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population- level SARS-CoV-2 seroprevalence. EHR and survey data were incorporated to determine spike antibody positivity due to SARS-CoV-2 infection and COVID-19 vaccination. We used sampling and non-response weighting to create population-level estimates.

Results

We enrolled 4,319 persons over six recruitment waves. SARS-CoV-2 spike antibody seroprevalence increased from 83.3% (CI 77.0-88.9) in May 2021 to 93.5% (CI 89.5-97.5) in April 2022. By April 2022, 68.5% (CI 61.9-74.3) of the population was seropositive from COVID-19 vaccination only, 13.9% (10.7-17.9) from COVID-19 vaccination and prior diagnosed SARS-CoV-2 infection, 8.2% (CI 4.5- 14.5) from prior diagnosed SARS-CoV-2 infection only and 2.9% (CI 1.1-7.6) from prior undiagnosed SARS-CoV-2 infection only. We found high agreement (≥97%) between EHR and survey data for ascertaining COVID-19 vaccination and SARS-CoV-2 infection status.

Conclusions

By April 2022, 93.5% of persons had detectable SARS-CoV-2 spike antibody, predominantly from COVID-19 vaccination. In this highly vaccinated population and over 18 months into the pandemic, SARS-CoV-2 infection without COVID-19 vaccination was a small contributor to overall population-level seroprevalence.

Article summary

By April 2022, >93% of people had antibodies to SARS-CoV-2 with COVID-19 vaccination as the main driver of overall population-level seroprevalence in our healthcare system. SARS-CoV-2 infection without vaccination made a small contribution to population-level seroprevalence in our healthcare system.
Examining the indirect effects of life satisfaction and perceived social support on selection optimization compensation and PTSD among the senior citizens of Ekiti State: A moderated mediation approach
Authors: Yarseah Dogbahgen Alphonso , Ogunsanmi Ololade Omolayo , Ogunsanmi Joyce Olufunke , Adesola Alade Foladade , Akinilabi Falana Bernard , Ibimiluyi Olu Francis , Cheeseman Viola H.
Published: February 2024

This study addresses the escalating concern of Posttraumatic Stress Disorder (PTSD) among the elderly population in Ekiti State, Nigeria. As the country experiences a growing number of older individuals, understanding and mitigating PTSD in this demographic is of paramount importance. Despite this urgency, there is a significant gap in the literature pertaining to PTSD among older Nigerians. To fill this void, our research investigates the impact of Selection, Optimization, and Compensation (SOC) strategies on perceived social support (PSS), life satisfaction (LS), and PTSD in the elderly.

Our study explores the relationships between PSS and LS, considering their potential roles in alleviating the psychological impact of trauma-related disorders. We also examine how age groups moderate the relationship between SOC and PTSD. Additionally, we explore the indirect effects of PSS and LS on the SOC-PTSD relationship.

Conducting a cross-sectional study, we collected data from 321 individuals aged 65 and above (260 males, 61 females) across four Local Government Areas. Our data collection instruments included socio-demographic variables, the SOC instrument, the PTSD scale, the Multidimensional scale of PSS, and the LS index-z.

Utilizing the Hayes Model 5 macro process for Structural Equation Modeling (SEM) analysis, our results highlight the significant moderating effect of age groups on the SOC-PTSD relationship. Furthermore, we find that PSS and LS partially mediate the relationships between SOC and PTSD, with SOC directly influencing both PTSD and PSS. These findings carry substantial practical implications and provide avenues for future research. In light of our study, we offer recommendations for addressing the mental health needs of Ekiti State’s elderly population, emphasizing the importance of further studies in the critical field of geropsychology.
The Impact of Digital Adherence Technologies on Health Outcomes in Tuberculosis: A Systematic Review and Meta-Analysis
Authors: Mohamed Mona S. , Zary Miranda , Kafie Cedric , Chilala Chimweta I. , Bahukudumbi Shruti , Foster Nicola , Gore Genevieve , Fielding Katherine , Subbaraman Ramnath , Schwartzman Kevin
Published: February 2024

Background

Suboptimal tuberculosis (TB) treatment adherence may lead to unsuccessful treatment and relapse. Digital adherence technologies (DATs) may allow more person-centric approaches for supporting treatment. We conducted a systematic review (PROSPERO-CRD42022313166) to evaluate the impact of DATs on health outcomes in TB.

Methods

We searched MEDLINE, Embase, CENTRAL, CINAHL, Web of Science and preprints from medRxiv, Europe PMC, andclinicaltrials.govfor relevant literature from January 2000 to April 2023. We considered experimental or cohort studies reporting quantitative comparisons of clinical outcomes between a DAT and the standard of care in each setting.

Results

Seventy studies (total 58,950 participants) met inclusion criteria. They reported SMS-based interventions (k=18 studies), feature phone-based interventions (k=7), medication sleeves with phone calls (branded as “99DOTS,” k=5), video-observed therapy (VOT; k=17), smartphone-based interventions (k=5), digital pillboxes (k=18), ingestible sensors (k=1), and interventions combining 2 DATs (k=1). Overall, the use of DATs was associated with more frequent treatment success in TB disease (OR = 1.18 [1.06, 1.33]; I2= 66%, k = 46), a decrease in loss to follow up (OR = 0.71 [0.53, 0.94]; I2= 80%, k = 36) and an increase in adverse event reporting (OR = 1.53 [1.26, 1.86]; I2= 0%, k = 9). VOT was associated with an increased likelihood of treatment success in TB disease (OR 1.54 [1.09; 2.19]; I2= 0%, k = 8) and treatment completion in TB infection (OR 4.69 [2.08; 10.55]; I2= 0%, k = 2) as well as an increased frequency of adverse event reporting (OR = 1.79 [1.27; 2.52]; I2= 34%, k = 4). Other interventions involving smartphone technologies were associated with increased treatment success in TB disease (OR 1.98 [1.07; 3.65]; I2=56%, k = 5) and a decreased frequency of loss to follow up (OR = 0.31 [0.13; 0.77]; I2= 36%, k = 5). Digital pillboxes were also associated with an improvement in treatment success (OR = 1.32 [1.00; 1.73]; I2= 71%, k = 11). However, improved treatment success was only seen in high- and upper middle-income countries. SMS-based interventions, feature-phone interventions and 99DOTS were not associated with improvements in short-term clinical outcomes.

Conclusion

Certain DATs--notably VOT and smartphone-based interventions, in higher income settings and sometimes combined with other supportive measures—may be associated with improvements in treatment success and losses to follow-up, compared to standard care. However, evidence remains highly variable, and generalizability limited. Higher quality data are needed.
Metabolic priming of GD2TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence
Authors: Cappabianca Dan , Pham Dan , Forsberg Matthew H. , Bugel Madison , Tommasi Anna , Lauer Anthony , Vidugiriene Jolanta , Hrdlicka Brookelyn , McHale Alexandria , Sodji Quaovi , Skala Melissa C. , Capitini Christian M. , Saha Krishanu
Published: February 2024

Manufacturing Chimeric Antigen Receptor (CAR) T cell therapies is complex, with limited understanding of how media composition impact T-cell phenotypes. CRISPR/Cas9 ribonucleoproteins can precisely insert a CAR sequence while disrupting the endogenous T cell receptor alpha constant (TRAC) gene resulting inTRAC-CAR T cells with an enriched stem cell memory T-cell population, a process that could be further optimized through modifications to the media composition. In this study we generated anti-GD2TRAC-CAR T cells using “metabolic priming” (MP), where the cells were activated in glucose/glutamine low media and then expanded in glucose/glutamine high media. T cell products were evaluated using spectral flow cytometry, metabolic assays, cytokine production, cytotoxicity assaysin vitroand potency against human GD2+ xenograft neuroblastoma modelsin vivo. Compared to standardTRAC-CAR T cells, MPTRAC-CAR T cells showed less glycolysis, higher CCR7/CD62L expression, more bound NAD(P)H activity and reduced IFN-γ, IL-2, IP-10, IL-1β, IL-17, and TGFβ production at the end of manufacturingex vivo, with increased central memory CAR T cells and better persistence observedin vivo. Metabolic priming with media during CAR T cell biomanufacturing can minimize glycolysis and enrich memory phenotypesex vivo, which could lead to better responses against solid tumorsin vivo.
Somite-independent regeneration of the axolotl primary body axis
Authors: Masselink Wouter , Gerber Tobias , Falcon Francisco , Deshayes Tom , Papadopoulos Sofia-Christina , Pende Marko , Jamwal Vijayishwer Singh , Taniguchi-Sugiura Yuka , Lin Tzi-Yang , Kurth Thomas , Wang Jingkui , Arendt Detlev , Fei Ji-Feng , Treutlein Barbara , Tanaka Elly M. , Murawala Prayag
Published: February 2024

Primary body axis development is a highly conserved process that proceeds through somitogenesis and further subdivision into dermatome, myotome, and sclerotome. Defects in somitic-clock genes such asHes7lead to vertebral segmentation defects in mice and fish. Here we show that in the axolotl,Hes7is also necessary for proper embryonic vertebral segmentation but is, surprisingly, dispensable during axolotl tail regeneration. Using genetic barcoding and fate mapping we found that during regeneration, the somitic derivatives (muscle, cartilage, tendon, fibroblasts) arose from tendon-like,Lfng+multi-potent stem cells residing at the myotendonal junction that we term “asomitic stem cells”. Throughout homeostasis and regeneration these stem cells display a distinct gene regulatory state compared to developmental progenitors with comparable lineage potential. These observations contrast to axolotl limb regeneration that proceeds via fibroblast dedifferentiation and the subsequent recapitulation of a limb developmental program. Taken together our research shows that divergent strategies are deployed between limb and tail regeneration, and that regeneration of complex body parts does not necessarily involve the complete redeployment of developmental programs.