bluuebunny/crossref_metadata_2025 huggingface dataset:
Human resources for health, service coverage and maternal and perinatal outcomes in Benin, Malawi, Tanzania and Uganda
Authors: Moller Ann-Beth , Welsh Joanne , Petzold Max , Siyam Amani
Published: July 2024

A well-performing and competent health workforce (HWF) is at the core of health systems yet many countries are facing a human resources for health (HRH) crisis. A prerequisite for achieving universal health coverage, including fulfilling the Sustainable Development Goals related to women and newborns, is an adequate supply of health workers able to provide quality of care at all levels of the health system. Thus, we evaluated how HRH policies and strategies influenced trends of maternal and newborn workforce densities and assessed the association between HWF densities, service coverage and health outcomes in Benin, Malawi, Tanzania and Uganda. We applied the READ framework (Ready your materials; Extract data; Analyse data and Distil findings) for our HRH policy and strategy document analysis and conducted a comparative analysis including three HWF densities (medical doctors, nursing and midwifery personnel) two health services, and five health outcome variables. Twenty HRH policies and strategies were included in the analysis published from 2010 to 2021. The scope of the HRH policies and strategies were described in four dimensions; availability, accessibility, acceptability and quality. We found that all policies and strategies addressed aspects related to availability and accessibility as well as the need for HRH quality improvements whereas acceptability was poorly represented. The comparative analysis revealed that service coverage and health outcomes appear to be insensitive to the fluctuations in HWF densities and related HRH policies as very little or no reduction was seen in outcomes from 2010 to 2020. There is a need to tackle the availability, accessibility, acceptability and quality of the HWF. Evidence needs to be translated into policy and practice otherwise the HWF in these countries will continue to struggle, affecting progress and realizing womens’ and newborn’s human rights to health.
Exploring Socio-demographic and Geographical Variation of Adults Hypertension in Bangladesh: Spatial Hotspot Analysis
Authors: Tabashsum Anika , Mahdee Chowdhury Mashrur , Asha Most. Jannatul Ferdous , Khan Md. Ashraful Islam , Rahman Md. Aminur
Published: July 2024

Hypertension is a chronic medical condition where blood pressure is too high. In Bangladesh, the overall incidence of hypertension is rising, like in other developing countries. Recent studies show hypertension can cause other non-communicable diseases such as cardiovascular diseases, strokes, etc. Utilizing information from the Bangladesh Demographic and Health Survey (BDHS) 2017–18, a cross-sectional and spatial analysis was done to determine the prevalence of hypertension. The existence of spatial autocorrelation is evaluated by using Moran’s I statistic, hotspot analysis, cold spot analysis, and influential observation analysis. The study was conducted on the basis of different factors such as gender, place of residence, age, BMI, etc. Among 12,926 people (43.19% men, 56.81% women), the women had a higher total prevalence of hypertension (41.18% (95% CI, 41.35–45.67) compared to the men’s 58.82% (95% CI, 57.16–60.45). Out of the total number of observations, 27.47% had hypertension. Out of all hypertensive people, 57.56% are unaware of their condition, which is very concerning. The study also finds that 28.4% are from urban areas and 71.6% are from rural areas. People living in the Dhaka division had a higher prevalence of hypertension (20.5%), and those in Sylhet had the lowest prevalence of hypertension (6.2%). There also exists a statistically relevant spatial autocorrelation (hypertension: Moran’s I index = 0.27, p<0.001). These are the spatial clustering maps, and according to the LISA cluster map, the Northeast districts are the cold spots (8), while the hotspots (4) are Bagerhat, Rajbari, Pirojpur, and Munshiganj. Approximately more than one-fourth of the adult population of Bangladesh had hypertension. The analysis discovered the hotspots and cold spots of the prevalence of hypertension. These findings could facilitate awareness and treatment of hypertension and therefore serve as support for researchers and policymakers.
Ixodes ricinusbites promote allergic skin inflammation and intestinal tuft and mast cell expansion in mice
Authors: Leyva-Castillo Juan Manuel , Strakosha Maria , Smith Sophia E.M. , Vega-Mendoza Daniela , Elkins Megan , Chou Janet , Vogel Peter , Boulanger Nathalie
Published: July 2024

Background

Tick bites often promote local allergic reactions in the skin and predispose to red meat allergy. The mechanisms involved in these processes are not fully understood. Here we investigated the local changes to the skin and intestine induced by tick bites.

Methods

C3H/HEN or Balb/c mice were subjected to either tick bites byIxodes ricinus(I. ricinus) or mechanical skin injury. Skin or intestine was analyzed a different time point by transcriptomic and histological techniques.

Results

Our results indicate thatI. ricinusbites promote epidermal hyperplasia, spongiosis and an accumulation of eosinophils and mast cells in the bitten skin. In addition,I. ricinusbites promote the expression of genes and activate pathways also induced by mechanical skin injury elicited by tape stripping. Remarkably, similar to tape stripping,I. ricinusbites promote an increase in total serum IgE, and intestinal tuft cell and mast cell expansion.

Conclusion

I. ricinusbites in mice promote cutaneous inflammation that resembles allergic skin inflammation, as well as intestinal changes that could play a role in the predisposition to red meat allergy.
Visualizing the translation landscape in human cells at high resolution
Authors: Zheng Wei , Zhang Yuekang , Wang Jimin , Wang Shuhui , Chai Pengxin , Bailey Elizabeth J , Guo Wangbiao , Devarkar Swapnil C , Wu Shenping , Lin Jianfeng , Zhang Kai , Liu Jun , Lomakin Ivan B , Xiong Yong
Published: July 2024

Obtaining comprehensive structural descriptions of macromolecules within their natural cellular context holds immense potential for understanding fundamental biology and improving health. Here, we present the landscape of protein synthesis inside human cells in unprecedented detail obtained using an approach which combines automated cryo-focused ion beam (FIB) milling andin situsingle-particle cryo-electron microscopy (cryo-EM). With thisin situcryo-EM approach we resolved a 2.19 Å consensus structure of the human 80S ribosome and unveiled its 21 distinct functional states, nearly all higher than 3 Å resolution. In contrast toin vitrostudies, we identified protein factors, including SERBP1, EDF1 and NAC/3, not enriched on purified ribosomes. Most strikingly, we observed that SERBP1 binds to the ribosome in almost all translating and non-translating states to bridge the 60S and 40S ribosomal subunits. These newly observed binding sites suggest that SERBP1 may serve an important regulatory role in translation. We also uncovered a detailed interface between adjacent translating ribosomes which can form the helical polysome structure. Finally, we resolved high-resolution structures from cells treated with homoharringtonine and cycloheximide, and identified numerous polyamines bound to the ribosome, including a spermidine that interacts with cycloheximide bound at the E site of the ribosome, underscoring the importance of high-resolutionin situstudiesinthe complex native environment. Collectively, our work represents a significant advancement in detailed structural studies within cellular contexts.
VIDAS®TB-IGRA accuracy in tuberculosis patients and persons at varying risk of exposure
Authors: Goletti Delia , Banaei Niaz , Batra Rahul , Berger Anne Emmanuelle , Blazevic Azra , Botelho-Nevers Elisabeth , Breen Ronan , Bruiners Natalie , Cambau Emmanuelle , Carbonnelle Etienne , Daley Charles L. , Descotes-Genon Cécile , Gennaro Francesco Di , Doucet-Populaire Florence , Esmail Aliasgar , Estrada Guzman Julia Dolores , Fontana Luc , Gennaro Maria Laura , Handler Deborah , Herrera Torres Rosa María , Hoft Daniel , Ismail Nahed , Isnard Margaux , Lardizabal Alfred , Lesage François Xavier , Lopes Amanda , López Vidal Williams Luciano , Contreras Rene Machado , Manivet Philippe , Marotte Hubert , Méchaï Frédéric , Medjahed-Artebasse Amel , Meldau Richard , Mérieux Yves , Morel Jacques , Mougari Faiza , Oelofse Suzette , Palmieri Fabrizio , Perrot Jean Luc , Petruccioli Elisa , Pride David T. , Tuaillon Edouard , Upton Caryn , Vanker Naadira , Dheda Keertan
Published: July 2024

Background

Detection and treatment of individuals with presumed latent tuberculosis (TB) infection (i.e., excluding active disease; LTBI) is imperative to achieve global TB control, as they represent a potential transmission reservoir. However, more sensitive and user-friendly diagnostic tools are needed.

Methods

We evaluated the accuracy for TB infection detection of the new VIDAS®TB-IGRA (bioMérieux), a fully automated, single tube (thus eliminating the need for batch testing) overnight incubation assay, compared to the QuantiFERON®-TB Gold Plus (QFT-Plus, QIAGEN), in a global multi-centre cross-sectional study (NCT04048018) that included patients with TB disease (n=200) or participants at varying levels of TB exposure (n=1460; mixed exposure-risk-population).

Results

VIDAS®TB-IGRA identified TB disease with greater sensitivity than QFT-Plus (97.5%vs. 80.7%,P<0.01%), and yielding significantly fewer false-negatives (2.5%vs. 17.5%;P<0.01%) and indeterminate results (1.0%vs. 9.5%;P=0.02%). In the mixed exposure-risk-population, negative (NPA) and positive percent agreement (PPA) were 90.1% (1097/1217) and 92.1% (223/242), respectively. PPA increased with TB-exposure risk (up to 95.7% for high-risk participants), whereas NPA decreased (starting from 96.9% for low-risk participants). Regression analyses revealed that VIDAS®TB-IGRA had a better fit with the risk-exposure gradient than the QFT-Plus. Specificity in extremely low TB-exposure risk participants (n= 125) was high for both VIDAS®TB-IGRA and QFT-Plus (97.6%vs. 95.2%;P=8.33%).

Conclusions

VIDAS®TB-IGRA displayed greater sensitivity than QFT-Plus, had a lower indeterminate rate, correlated better with an exposure gradient, and was highly specific, suggesting that it is a potentially valuable tool for the diagnosis of LTBI.

Take-home message

The first fully automated interferon-γ-release assay—the bioMérieux VIDAS®TB-IGRA—is highly specific and displays greater sensitivity than QuantiFERON®-TB Gold Plus, and thus represents a valuable new and streamlined diagnostic tool for TB infection.
Tracing the transmission of carbapenem-resistantEnterobacteralesat the patient:ward environmental nexus
Authors: Elton Linzy , Williams Alan , Ali Shanom , Heaphy Jelena , Pang Vicky , Commins Liam , O’Brien Conor , Yetiş Özge , Caine Estelle , Ward Imogen , Muzslay Monika , Yui Samuel , Karia Kush , Shore Ellinor , Rofael Sylvia , Mack Damien , McHugh Timothy D , Wey Emmanuel Q
Published: July 2024

Structured summary

Introduction

Colonisation and infection with Carbapenem-resistant Enterobacterales (CRE) in healthcare settings poses significant risks, especially for vulnerable patients. Genomic analysis can be used to trace transmission routes, supporting antimicrobial stewardship and informing infection control strategies. Here we used genomic analysis to track the movement and transmission of CREs within clinical and environmental samples.

Methods

25 isolates were cultured from clinical patient samples or swabs, that tested positive for OXA-48-like variants using the NG-Test® CARBA-5 test and whole genome sequenced (WGS) using Oxford Nanopore Technologies (ONT). 158 swabs and 52 wastewater samples were collected from the ward environment. 60 isolates (matching clinical isolate genera;Klebsiella, Enterobacter, Citrobacter and Escherichia) were isolated from the environmental samples. Metagenomic sequencing was undertaken on 36 environmental wastewater and swab samples.

Results

21/25 (84%) clinical isolates had >1blaOXAgene and 19/25 (76%) harboured >1blaNDMgene. Enterobacterales were most commonly isolated from environmental wastewater samples 27/52 (51.9%), then stick swabs 5/43 (11.6%) and sponge swabs 5/115 (4.3%). 11/60 (18%) environmental isolates harboured at >1blaOXAgene and 1.9% (1/60) harbouredblaNDM-1.blaOXAgenes were found in 2/36 (5.5%) metagenomic environmental samples.

Discussion

Potential for putative patient-patient and patient-ward transmission was shown. ONT sequencing can expedite clinical decisions whilst awaiting reference laboratory results, providing economic and patient care benefits. Metagenomic sampling needs optimization to improve sensitivity.
The Optimal Prediction Model for Successful External Cephalic Version
Authors: Yerrabelli Rahul Sai , Palsgaard Peggy K. , Shankarappa Priya , Jennings Valerie
Published: July 2024

Objective

The majority of breech fetuses are delivered by Cesarean birth as few physicians are trained in vaginal breech birth. An external cephalic version (ECV) can prevent Cesarean delivery and the associated morbidity in these patients. Current guidelines recommend all patients with breech presentation be offered an ECV attempt. Not all attempts are successful, and an attempt does carry some risks so shared decision-making is necessary. To aid in patient counseling, over a dozen prediction models to predict ECV success have been proposed in the last few years. However, very few models have been externally validated, and thus none have been adopted into clinical practice. This study aims to use data from a United States hospital to provide further data on ECV prediction models.

Study Design

This study retrospectively gathered data from Carle Foundation Hospital and used it to test six models previously proposed to predict ECV success. These models were Dahl 2021, Bilgory 2023, López Pérez 2020, Kok 2011, Burgos 2010, and Tasnim 2012 (GNK-PIMS score).

Results

125 patients undergoing 132 ECV attempts were included. 69 attempts were successful (52.2%). Dahl 2021 had the greatest predictive value (AUC 0.779), while Tasnim 2012 performed the worst (AUC 0.626). The remaining models had similar predictive values as each other (AUC 0.68-0.71). Bootstrapping confirmed that all models except Tasnim 2012 had confidence intervals not including 0.5. The bootstrapped 95% AUC confidence interval for Dahl 2021 was 0.71-0.84. In terms of calibration, Dahl 2021 was well calibrated with predicted probabilities matching observed probabilities. Bilgory 2023 and López Pérez were poorly calibrated.

Conclusion

Multiple prediction tools have now been externally validated for ECV success. Dahl 2021 is the most promising prediction tool.

Key Points

Prediction models can be powerful tools for patient counseling

The odds of ECV success can estimated based on patient factors and clinical findings

Of the 6 tested models, only Dahl 2021 appears to have good predictive value and calibration
Analysis of variants in untranslated and promoter regions and breast cancer risk using whole genome sequencing data
Authors: Wilcox Naomi , Tyrer Jonathan P. , Dorling Leila , Dennis Joe , Naven Marc , Abubakar Mustapha , Ahearn Thomas U. , Andrulis Irene L. , Antoniou Antonis C. , Bogdanova Natalia V. , Bojesen Stig E. , Bolla Manjeet K. , Brauch Hiltrud , Camp Nicola J. , Chang-Claude Jenny , Czene Kamila , Dörk Thilo , Gareth Evans D. , Fasching Peter A. , Figueroa Jonine D. , Flyger Henrik , Gardner Eugene J. , González-Neira Anna , Guénel Pascal , Hahnen Eric , Hall Per , Hartman Mikael , Hooning Maartje J. , Jakubowska Anna , Khusnutdinova Elza K. , Kristensen Vessela N. , Li Jingmei , Lindblom Annika , Lophatananon Artitaya , Mannermaa Arto , Manoukian Siranoush , Milne Roger L. , Nuñez-Torres Rocio , Obi Nadia , Panayiotidis Mihalis I. , Park Sue K. , Perry John R.B. , Rashid Muhammad U. , Saloustros Emmanouil , Sawyer Elinor J. , Schmidt Marjanka K. , Southey Melissa C. , Spurdle Amanda B. , Torres Diana , Wang Qin , Simard Jacques , Teo Soo Hwang , Dunning Alison M. , Devilee Peter , Easton Douglas F.
Published: July 2024

Recent exome-wide association studies have explored the role of coding variants in breast cancer risk, highlighting the role of rare variants in multiple genes includingBRCA1, BRCA2, CHEK2, ATMandPALB2, as well as new susceptibility genes e.g.,MAP3K1. These genes, however, explain a small proportion of the missing heritability of the disease. Much of the missing heritability likely lies in the non-coding genome. We evaluated the role of rare variants in the 5’ and 3’ untranslated regions (UTRs) of 18,676 genes, and 35,201 putative promoter regions, using whole-genome sequencing data from UK Biobank on 8,001 women with breast cancer and 92,534 women without breast cancer. Burden tests and SKAT-O tests were performed in UTR and promoter regions. For UTR regions of 35 putative breast cancer susceptibility genes, we additionally performed a meta-analysis with a large breast cancer case-control dataset. Associations for 8 regions at P<0.0001 were identified, including several with known roles in tumorigenesis. The strongest evidence of association was for variants in the 5’UTR ofCDK5R1(P=8.5×10−7). These results highlight the potential role of non-coding regulatory regions in breast cancer susceptibility.
Adaptive adjustment of significance thresholds produces large gains in microbial gene annotations and metabolic insights
Authors: Kananen Kathryn , Veseli Iva A , Quiles Perez Christian J. , Miller Samuel E. , Eren A. Murat , Bradley Patrick H
Published: July 2024

Gene function annotations enable microbial ecologists to make inferences about metabolic potential from genomes and metagenomes. However, even tools that use the same database and general approach can differ markedly in the annotations they recover. We compare three popular methods for identifying KEGG Orthologs, applying them to genomes drawn from a range of bacterial families that occupy different host-associated and free-living biomes. Our results show that by adaptively tuning sequence similarity thresholds, sensitivity can be substantially improved while maintaining accuracy. We observe the largest improvements when few reference sequences exist for a given protein family, and when annotating genomes from non-model organisms (such as gut-dwelling Lachnospiraceae). Our results suggest that straightforward heuristic adjustments can broadly improve microbial metabolic predictions.
Neonatal microbiota colonization drives maturation of primary and secondary goblet cell mediated protection in the pre-weaning colon
Authors: Johansson Åsa , Subramani Mahadevan Venkita , Yilmaz Bahtiyar , Nyström Elisabeth , Layunta Elena , Arike Liisa , Sommer Felix , Rosenstiel Philip , Vereecke Lars , Holm Louise Mannerås , Wullaert Andy , Pelaseyed Thaher , Johansson Malin E.V. , Birchenough George M.H.
Published: July 2024

In the distal colon, mucus secreting goblet cells primarily confer protection from luminal microorganisms via generation of a sterile inner mucus layer barrier structure. Bacteria-sensing sentinel goblet cells provide a secondary defensive mechanism that orchestrates mucus secretion in response to microbes that breach the mucus barrier. Previous reports have identified mucus barrier deficiencies in adult germ-free mice, thus implicating a fundamental role for the microbiota in programming mucus barrier generation. In this study, we have investigated the natural neonatal development of the mucus barrier and sentinel goblet cell-dependent secretory responses upon postnatal colonization. Combinedin vivoandex vivoanalyses of pre- and post-weaning colonic mucus barrier and sentinel goblet cell maturation demonstrated a sequential microbiota-dependent development of these primary and secondary goblet cell-intrinsic protective functions, with dynamic changes in mucus processing dependent on innate immune signallingviaMyD88, and development of functional sentinel goblet cells dependent on the NADPH/Dual oxidase family member Duox2. Our findings therefore identify new mechanisms of microbiota-goblet cell regulatory interaction and highlight the critical importance of the pre-weaning period for the normal development of colonic barrier function.
Deubiquitinase JOSD1 tempers hepatic proteotoxicity
Authors: Chowdhury Saheli , Sen Abhishek , Das Debajyoti , Chakrabarti Partha
Published: July 2024

Derangements in protein homeostasis and associated proteotoxicity mark acute, chronic, and drug-induced hepatocellular injury. Metabolic dysfunction-associated proteasomal inhibition and the use of proteasome inhibitors often underlie such pathological hepatic proteotoxicity. In this study, we sought to identify a candidate deubiquitinating enzyme (DUB) responsible for reversing the proteotoxic damage. To this end, we performed a siRNA screening wherein 96 DUBs were individually knocked down in HepG2 cells under proteasomal inhibitor-induced stress for dual readouts, apoptosis, and cell viability. Among the putative hits, we chose JOSD1, a member of the Machado-Josephin family of DUBs that reciprocally increased cell viability and decreased cell death under proteotoxicity. JOSD1-mediated mitigation of proteotoxicity was further validated in primary mouse hepatocytes by gain and loss of function studies. Marked plasma membrane accumulation of monoubiquitinated JOSD1 in proteotoxic conditions is a prerequisite for its protective role while the enzymatically inactive JOSD1 C36A mutant was conversely polyubiquitinated, does not have membrane localization and fails to reverse proteotoxicity. Mechanistically, JOSD1 physically interacts with the suppressor of cytokine signaling 1 (SOCS1), deubiquitinates it and enhanced its stability under proteotoxic stress. Indeed, SOCS1 expression is necessary and sufficient for the hepatoprotective function of JOSD1.In vivo, adenovirus-mediated ectopic expression or depletion of JOSD1 in mice liver respectively protect or aggravate hepatic injury when challenged with proteasome blocker Bortezomib. Our study thus unveils JOSD1 as a potential candidate for ameliorating hepatocellular damage in liver diseases.
Temporal continuity of habitat strengthens covariation between plant and arbuscular mycorrhizal fungal communities
Authors: Shimono Ayako , Inoue Taiki , Shiga Hiroki , Uchiyama Kentaro , Yaida Yuki A. , Ushimaru Atushi , Kenta Tanaka
Published: July 2024

Old grassland is considered one of the most biodiverse terrestrial ecosystems. The habitat temporal continuity may promote the accumulation of host species and symbiont arbuscular mycorrhizal fungi (AMF) diversity and strengthen symbiont interactions. We tested the hypothesis that covariation between AMF and plant communities is stronger in old grasslands. We compared the relationship between AMF and plant communities in forests and in new and old semi-natural grasslands in Japan. DNA was extracted from bulk roots collected at each site and from roots ofMiscanthus sinensisat each grassland site. AMF operational taxonomic unit was characterized on the basis of small subunitrRNAgene sequences. Old grasslands harboured the highest diversity of AMF among vegetation types. The AMF compositions were significantly related to those of plant species. The covariation of plant–AMF communities was stronger in old grasslands than in new grasslands. Individuals ofM. sinensiswere found to share AMF with bulk roots comprising different species. This suggests that AMF form a common mycorrhizal network among several coexisting plants of different species. Increasing AMF diversity in the shared rhizosphere has been proposed to lead to more efficient utilization of soil nutrients and to increase overall benefits of plant–AMF facilitation.
The bodily appearance of a virtual partner affects the activity of the action observation and action monitoring systems in a minimally interactive task
Authors: Pesci U.G. , Moreau Q. , Era V. , Candidi M.
Published: July 2024

One pending question in social neuroscience is whether interpersonal interactions are processed differently by the brain depending on the bodily characteristics of the interactor, i.e., their physical appearance. To address this issue, we engaged participants in a minimally interactive task with an avatar either showing bodily features or not while recording their brain activity using Electroencephalography (EEG) in order to investigate indices of action observation and action monitoring processing. Multivariate results showed that bodily compared to non-bodily appearance modulated parieto-occipital neural patterns throughout the entire duration of the observed movement and that, importantly, such patterns differ from the ones related to initial shape processing. Furthermore, among the electrocortical indices of action monitoring, only the early observational Positivity (oPe) was responsive to the bodily appearance of the observed agent under the specific task requirement to predict the partner movement. Taken together, these findings broaden the understanding of how bodily appearance shapes the spatiotemporal processing of an interactor’s movements. This holds particular relevance in our modern society, where human-virtual agent interactions are rapidly becoming ubiquitous.
IsRNAcirc: 3D structure prediction of circular RNAs based on coarse-grained molecular dynamics simulation
Authors: Jiang Haolin , Xu Yulian , Tong Yunguang , Zhang Dong , Zhou Ruhong
Published: July 2024

As an emerging class of RNA molecules, circular RNAs play pivotal roles in various biological processes, thereby determining their three-dimensional (3D) structure is crucial for a deep understanding of their biological significances. Similar to linear RNAs, the development of computational methods for circular RNA 3D structure prediction is challenging, especially considering the inherent flexibility and potentially long length of circular RNAs. Here, we introduce an extension of our previous IsRNA2 model, named IsRNAcirc, to enable circular RNA 3D structure predictions through coarse-grained molecular dynamics simulations. The workflow of IsRNAcirc consists of four main steps, including input preparation, end closure, structure prediction, and model refinement. Our results demonstrate that IsRNAcirc can provide reasonable 3D structure predictions for circular RNAs, which significantly reduce the locally irrational elements contained in the initial input. Moreover, for a validation test set comprising 34 circular RNAs, our IsRNAcirc can generate 3D models with better scores than the template-based 3dRNA method. These findings demonstrate that our IsRNAcirc method is a promising tool to explore the structural details along with intricate interactions of circular RNAs.

Author Summary

Knowledge of the 3D structure of circular RNA molecules can help us better understand their roles in eukaryotic cells. However, experimental determination of circular RNA 3D structure remains challenging, with currently only one complete circular RNA 3D structure available in the Protein Data Bank. Thus, extending from their linear counterparts, computational methods that can predict circular RNA 3D structure are urgently needed. In particular, physics-basedde novo3D structure prediction methods are promising due to their powerful sampling capability in the conformational space, which avoid the problem of limited available templates in template-based approaches. We have developed IsRNAcirc, a new physics-based method that employs an accurate coarse-grained force field and replica-exchange molecular dynamics simulations to predict the 3D structure of circular RNAs. IsRNAcirc is shown to significantly reduce the number of locally irrational structures in the input trials, which are caused by the lack of suitable templates and the improper assembly of fragments. Furthermore, in the absence of experimental reference structures, the predicted 3D models were validated using the popular scoring functions, such as DFIRE-RNA and rsRNASP, demonstrating that IsRNAcirc outperforms the template-based 3dRNA method in generating low-energy conformations.
Multi-scale modelling of location- and frequency-dependent synaptic plasticity induced by transcranial magnetic stimulation in the dendrites of pyramidal neurons
Authors: Hananeia Nicholas , Ebner Christian , Galanis Christos , Cuntz Hermann , Opitz Alexander , Vlachos Andreas , Jedlicka Peter
Published: July 2024

Background

Repetitive transcranial magnetic stimulation (rTMS) induces long-term changes of synapses, but the mechanisms behind these modifications are not fully understood. Al- though there has been progress in the development of multi-scale modeling tools, no com- prehensive module for simulating rTMS-induced synaptic plasticity in biophysically realistic neurons exists..

Objective

We developed a modelling framework that allows the replication and detailed prediction of long-term changes of excitatory synapses in neurons stimulated by rTMS.

Methods

We implemented a voltage-dependent plasticity model that has been previously established for simulating frequency-, time-, and compartment-dependent spatio-temporal changes of excitatory synapses in neuronal dendrites. The plasticity model can be incorporated into biophysical neuronal models and coupled to electrical field simulations.

Results

We show that the plasticity modelling framework replicates long-term potentiation (LTP)-like plasticity in hippocampal CA1 pyramidal cells evoked by 10-Hz repetitive magnetic stimulation (rMS). This plasticity was strongly distance dependent and concentrated at the proximal synapses of the neuron. We predicted a decrease in the plasticity amplitude for 5 Hz and 1 Hz protocols with decreasing frequency. Finally, we successfully modelled plasticity in distal synapses upon local electrical theta-burst stimulation (TBS) and predicted proximal and distal plasticity for rMS TBS. Notably, the rMS TBS-evoked synaptic plasticity exhibited robust facilitation by dendritic spikes and low sensitivity to inhibitory suppression.

Conclusion

The plasticity modelling framework enables precise simulations of LTP-like cellular effects with high spatio-temporal resolution, enhancing the efficiency of parameter screening and the development of plasticity-inducing rTMS protocols.

Highlights

First rigorously validated model of TMS-induced long-term synaptic plasticity in ex- tended neuronal dendrites that goes beyond point-neuron and mean-field modelling

Robust simulations of experimental data on LTP-like plasticity in the proximal dendrites of CA1 hippocampal pyramidal cells evoked by 10 Hz repetitive magnetic stimulation (rMS)

Replication of distal synaptic plasticity for a local electrical theta burst stimulation (TBS) protocol

Prediction of distal and proximal LTP-like plasticity for rMS TBS

1 Hz rMS does not induce long-term depression
A Safe and Effective New Method for Thin Cornea Cross-linking
Authors: Zhou Shengmei , Lin Zhirong , Hong Yi , Liao Yi
Published: July 2024

The mechanical properties of the collagen matrix determine the corneal regularity. Thus, corneal thinning, cone-like protrusion, and loss of corneal astigmatism characterize corneal ecstatic diseases, including keratoconus and post-LASIK ectasia. Currently, riboflavin (RF)/ultraviolet A (UVA) based corneal collagen cross-linking (CXL) is commonly used in clinics to stiffen cornea and halt disease progression in patients. However, due to tissue damage, especially irreversible endothelium loss, standard RF/UVA protocol is only allowed in eyes with corneal thickness over 400 μm after epithelium debridement. Thus, lots of patients with thin cornea have limited therapeutic options. Here, we introduced a new strategy to cross-link cornea collagens using synthesized photo-initiators lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) and visible blue light (BL). The LAP/BL protocol could effectively increase corneal stiffness, similar to the RF/UVA protocol in both porcine and rabbit cornea. When the LAP/BL protocol was used, both epithelial wound healing, stromal cell repopulation, and corneal edema recovery rates were accelerated compared with the RF/UVA protocol. More importantly, as BL is used instead of UVA, corneal endothelium was mostly preserved in both rabbit and mouse models even when cornea thickness was as thin as 100 μm. In summary, we propose that the LAP/BL protocol is a safe and effective choice for thin cornea CXL.
An orbitocortical-thalamic circuit suppresses binge alcohol-drinking
Authors: Gimenez-Gomez P , Le T , Zinter M , M’Angale P , Duran-Laforet V , Freels TG , Pavchinskiy R , Molas S , Schafer DP , Tapper AR , Thomson T , Martin GE
Published: July 2024

Alcohol consumption remains a significant global health challenge, causing millions of direct and indirect deaths annually. Intriguingly, recent work has highlighted the prefrontal cortex, a major brain area that regulates inhibitory control of behaviors, whose activity becomes dysregulated upon alcohol abuse. However, whether an endogenous mechanism exists within this brain area that limits alcohol consumption is unknown. Here we identify a discrete GABAergic neuronal ensemble in the medial orbitofrontal cortex (mOFC) that is selectively recruited during binge alcohol-drinking and intoxication. Upon alcohol intoxication, this neuronal ensemble suppresses binge drinking behavior. Optogenetically silencing of this population, or its ablation, results in uncontrolled binge alcohol consumption. We find that this neuronal ensemble is specific to alcohol and is not recruited by other rewarding substances. We further show, using brain-wide analysis, that this neuronal ensemble projects widely, and that its projections specifically to the mediodorsal thalamus are responsible for regulating binge alcohol drinking. Together, these results identify a brain circuit in the mOFC that serves to protect against binge drinking by halting alcohol intake. These results provide valuable insights into the complex nature of alcohol abuse and offers potential avenues for the development of mOFC neuronal ensemble-targeted interventions.
Torque Teno Sus Virus 1: A Potential Surrogate Pathogen to Study Pig-Transmitted Transboundary Animal Diseases
Authors: Li Xiaolong , Parker Brandon M. , Boughton Raoul K. , Beasley James C. , Smyser Timothy J. , Austin James D. , Pepin Kim M. , Miller Ryan S. , Vercauteren Kurt C. , Wisely Samantha M.
Published: July 2024

Understanding the epidemiology and transmission dynamics of transboundary animal diseases (TADs) among wild pigs (Sus scrofa) will aid in preventing the introduction or containment of TADs among wild populations. Given challenges associated with studying TADs in free-ranging populations, a surrogate pathogen system forin situstudies of pathogen dynamics would be ideal to elucidate how pathogens may circulate and be maintained within populations, how they may spillover into domestic populations, and how disease spread may be mitigated. We assessed the suitability of Torque teno sus virus 1 (TTSuV1) to serve as a surrogate pathogen for molecular epidemiological studies in wild pigs by investigating the prevalence, persistence, correlation with host health status and genetic variability at two study areas: Archbold’s Buck Island Ranch in Florida and Savannah River Site in South Carolina. We then conducted a molecular epidemiological case study within the Archbold’s Buck Island Ranch site to determine how analysis of this pathogen could inform transmission studies. Prevalence was high at both study areas (40%,n= 190). Phylogenetic analyses revealed high levels of genetic variability within and between study sites. Our case study showed that pairwise host relatedness and geographic distance were highly correlated to pairwise viral genetic similarity. Molecular epidemiological analyses revealed a distinct pattern of direct transmission from pig to pig occurring within and between family groups. Our results suggest TTSuV1 is highly suitable for molecular epidemiological analyses and will be useful for futurein situstudies of transmission dynamics in wild pigs.
Agent-Based Modeling of Virtual Tumors Reveals the Critical Influence of Microenvironmental Complexity on Immunotherapy Efficacy
Authors: Wang Yixuan , Bergman Daniel R. , Trujillo Erica , Fernald Anthony A. , Li Lie , Pearson Alexander T. , Sweis Randy F. , Jackson Trachette L.
Published: July 2024

Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy because they allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs, despite similarities in key immune parameters, initial conditions of simulation, and early temporal trajectories of the cell populations.
A scene with an invisible wall - navigational experience shapes visual scene representation
Authors: Li Shi Pui Donald , Shao Jiayu , Lu Zhengang , McCloskey Michael , Park Soojin
Published: July 2024

Human navigation heavily relies on visual information. Although many previous studies have investigated how navigational information is inferred from visual features of scenes, little is understood about the impact of navigational experience on visual scene representation. In this study, we examined how navigational experience influences both the behavioral and neural responses to a visual scene. During training, participants navigated in the virtual reality (VR) environments which we manipulated navigational experience while holding the visual properties of scenes constant. Half of the environments allowed free navigation (navigable), while the other half featured an ‘invisible wall’ preventing the participants to continue forward even though the scene was visually navigable (non-navigable). During testing, participants viewed scene images from the VR environment while completing either a behavioral perceptual identification task (Experiment1) or an fMRI scan (Experiment2). Behaviorally, we found that participants judged a scene pair to be significantly more visually different if their prior navigational experience varied, even after accounting for visual similarities between the scene pairs. Neurally, multi-voxel pattern of the parahippocampal place area (PPA) distinguished visual scenes based on prior navigational experience alone. These results suggest that the human visual scene cortex represents information about navigability obtained through prior experience, beyond those computable from the visual properties of the scene. Taken together, these results suggest that scene representation is modulated by prior navigational experience to help us construct a functionally meaningful visual environment.
Maternal genetic variants in kinesin motor domains prematurely increase egg aneuploidy
Authors: Biswas Leelabati , Tyc Katarzyna M. , Aboelenain Mansour , Sun Siqi , Dundović Iva , Vukušić Kruno , Liu Jason , Guo Vanessa , Xu Min , Scott Richard T. , Tao Xin , Tolić Iva M. , Xing Jinchuan , Schindler Karen
Published: July 2024

The female reproductive lifespan depends on egg quality, particularly euploidy. Mistakes in meiosis leading to egg aneuploidy are common, but the genetic landscape causing this is not well understood due to limited phenotypic data. We identify genetic determinants of reproductive aging via egg aneuploidy using a biobank of maternal exomes linked with maternal age and embryonic aneuploidy data. We found 404 genes with variants enriched in individuals with high egg aneuploidy rates and implicate kinesin protein family genes in aneuploidy risk. Experimental perturbations showed that motor domain variants in these genes increase aneuploidy in mouse oocytes. A knock-in mouse model validated that a specific variant in kinesinKIF18Aaccelerates reproductive aging and diminishes fertility. These findings suggest potential non-invasive biomarkers for egg quality, aiding personalized fertility medicine.

One sentence summary

The study identifies novel genetic determinants of reproductive aging linked to egg aneuploidy by analyzing maternal exomes and demonstrates that variants in kinesin genes, specificallyKIF18A, contribute to increased aneuploidy and accelerated reproductive aging, offering potential for personalized fertility medicine.
Radiomic-Based Approaches in the Multi-metastatic Setting: A Quantitative Review
Authors: Geady Caryn , Patel Hemangini , Peoples Jacob , Simpson Amber , Haibe-Kains Benjamin
Published: July 2024

Background

Radiomics traditionally focuses on analyzing a single lesion within a patient to extract tumor characteristics, yet this process may overlook inter-lesion heterogeneity, particularly in the multi-metastatic setting. There is currently no established method for combining radiomic features in such settings, leading to diverse approaches with varying strengths and limitations. Our quantitative review aims to illuminate these methodologies, assess their replicability, and guide future research toward establishing best practices, offering insights into the challenges of multi-lesion radiomic analysis across diverse datasets.

Methods

We conducted a comprehensive literature search to identify methods for integrating data from multiple lesions in radiomic analyses. We replicated these methods using either the author’s code or by reconstructing them based on the information provided in the papers. Subsequently, we applied these identified methods to three distinct datasets, each depicting a different metastatic scenario.

Results

We compared ten mathematical methods for combining radiomic features across three distinct datasets, encompassing a total of 16,850 lesions in 3,930 patients. Performance of these methods was evaluated using the Cox proportional hazards model and benchmarked against univariable analysis of total tumor volume. We observed variable performance in methods across datasets. However, no single method consistently outperformed others across all datasets. Notably, while some methods surpassed total tumor volume analysis in certain datasets, others did not. Averaging methods showed higher median performance in patients with colorectal liver metastases, and in soft tissue sarcoma, concatenation of radiomic features from different lesions exhibited the highest median performance among tested methods.

Conclusions

Radiomic features can be effectively selected or combined to estimate patient-level outcomes in multi-metastatic patients, though the approach varies by metastatic setting. Our study fills a critical gap in radiomics research by examining the challenges of radiomic-based analysis in this setting. Through a comprehensive review and rigorous testing of different methods across diverse datasets representing unique metastatic scenarios, we provide valuable insights into effective radiomic analysis strategies.
Regeneration recapitulates many embryonic processes, including reuse of developmental regulatory regions
Authors: Loubet-Senear Kaitlyn , Srivastava Mansi
Published: July 2024

The wide distribution of regenerative capacity across the animal tree of life raises the question of how regeneration has evolved in distantly-related animals. Given that whole-body regeneration shares the same end-point – formation of a functional body plan – as embryonic development, it has been proposed that regeneration likely recapitulates developmental processes to some extent. Therefore, understanding how developmental processes are reactivated during regeneration is important for uncovering the evolutionary history of regeneration. Comparative transcriptomic studies in some species have revealed shared gene expression between development and regeneration, but it is not known whether these shared expression profiles correspond to shared functions, and which mechanisms activate expression of developmental genes during regeneration. We sought to address these questions using the acoelHofstenia miamia, which is amenable to studies of both embryonic development and whole-body regeneration. By examining functionally validated regeneration processes during development at single-cell resolution, we found that whereas patterning and cellular differentiation are largely similar, wound response programs have distinct dynamics between development and regeneration. Chromatin accessibility analyses revealed that regardless of playing concordant or divergent roles during regeneration and development, genes expressed in both processes are frequently controlled by the same regulatory regions, potentially via utilization of distinct transcription factor binding sites. This study extends the known correspondence of development and regeneration from broad transcriptomic similarity to include patterning and differentiation processes. Further, our work provides a catalog of regulatory regions and binding sites that potentially regulate developmental genes during regeneration, fueling comparative studies of regeneration.
Oxygen metabolism in descendants of the archaeal-eukaryotic ancestor
Authors: Appler Kathryn E. , Lingford James P. , Gong Xianzhe , Panagiotou Kassiani , Leão Pedro , Langwig Marguerite , Greening Chris , Ettema Thijs J. G. , De Anda Valerie , Baker Brett J.
Published: July 2024

Asgard archaea were pivotal in the origin of complex cellular life. Hodarchaeales (Asgardarchaeota class Heimdallarchaeia) were recently shown to be the closest relatives of eukaryotes. However, limited sampling of these archaea constrains our understanding of their ecology and evolution1–3, including their anticipated role in eukaryogenesis. Here, we nearly double the number of Asgardarchaeota metagenome-assembled genomes (MAGs) to 869, including 136 new Heimdallarchaeia (49 Hodarchaeales) and several novel lineages. Examining global distribution revealed Hodarcheales are primarily found in coastal marine sediments. Detailed analysis of their metabolic capabilities revealed guilds of Heimdallarchaeia are distinct from other Asgardarchaeota. These archaea encode hallmarks of aerobic eukaryotes, including electron transport chain complexes (III and IV), biosynthesis of heme, and response to reactive oxygen species (ROS). The predicted structural architecture of Heimdallarchaeia membrane-bound hydrogenases includes additional Complex-I-like subunits potentially increasing the proton motive force and ATP synthesis. Heimdallarchaeia genomes encode CoxD, which regulates the electron transport chain (ETC) in eukaryotes. Thus, key hallmarks for aerobic respiration may have been present in the Asgard-eukaryotic ancestor. Moreover, we found that Heimdallarchaeia is present in a variety of oxic marine environments. This expanded diversity reveals these Archaea likely conferred energetic advantages during early stages of eukaryogenesis, fueling cellular complexity.