bluuebunny/crossref_metadata_2025 huggingface dataset:
More Frequent HIV Viral Load Testing With Point-Of-Care Tests Detects Elevated Viral Load Earlier in Postpartum HIV-Positive Women in a Randomized Controlled Trial in Two Clinics in Johannesburg, South Africa
Authors: Fairlie Lee , Sawry Shobna , Pals Sherri , Sherman Gayle , Williamson Dhelia , Le Roux Jean , Ngeno Bernadette , Berrie Leigh , Diallo Karidia , Cox Mackenzie Hurlston , Mogashoa Mary , Chersich Matthew , Modi Surbhi ,   For the OPPTIM (Optimised Postpartum PMTCT Testing for Infants and their Mothers) Study Team
Published: November 2023

Background:

Elevated maternal HIV viral load (VL) increases vertical transmission risk for breastfeeding children. This randomized controlled trial in Johannesburg primarily evaluated whether 3-monthly point-of-care testing, with laboratory-based standard-of-care testing (arm 2), compared with 6-monthly laboratory-based VL testing (arm 1) in postpartum women living with HIV receiving first-line tenofovir–emtricitabine–efavirenz antiretroviral treatment improved VL suppression, factors associated with nonsuppression, and drug resistance in those with virologic failure.

Methods:

Mother–child pairs were enrolled July 2018–April 2019 at the child's 6/10/14-week clinic visit. Women were randomized 1:1 to arm 1 or 2. Trained staff performed point-of-care VL testing using the Cepheid's Xpert HIV-1 VL assay. We fitted a generalized linear mixed model with VL suppression (<50 copies/mL (cps/mL) and <1000 cps/mL) at enrollment and 6, 12, and 18 months postpartum as the outcome and indicator variables for time, study site, study arm, and interaction variables. The final model tested for a difference by study arm, pooling across time points.

Results:

Of 405 women enrolled (204 arm 1 and 201 arm 2), 249 (61%) remained in follow-up through 18 months. There was no difference in VL suppression between arms at 6, 12, or 18 months. VL suppression rate (<50 cps/mL) at 18 months was 64.8% in arm 1 and 63.0% in arm 2 (P = 0.27). On bivariate analysis, there was an association with late antenatal booking and being in arm 2 for nonsuppressed VL, but no significant association with breastfeeding. HIV drug resistance was found in 12 of 23 participants (52.2%).

Conclusion:

We found no significant difference in VL suppression with more frequent VL testing in postpartum women living with HIV receiving first-line efavirenz-based antiretroviral treatment.
Cancer Treatment Decision-Making for People Living With HIV: Physician-Reported Barriers, Facilitators, and Recommendations
Authors: Khouri Ashley , Stephens Maya J. , Young Jeanette , Galyean Patrick , Knettel Brandon A. , Cherenack Emily M. , Zickmund Susan , Watt Melissa H. , Bartlett John , Pollak Kathryn I. , Ubel Peter A. , Fagerlin Angela , Suneja Gita
Published: November 2023

Background:

Compared with the general cancer population, people living with HIV (PLWH) and cancer are less likely to receive treatment and have significantly elevated cancer-specific mortality for many common cancer types. Physician recommendations drive the cancer therapy that patients receive, yet there is limited information assessing how cancer treatment decisions are made for people living with HIV and cancer. We sought to understand oncologist decision-making in PLWH and cancer by eliciting barriers, facilitators, and recommendations for enhancing care delivery.

Setting:

Participants were recruited between May 2019 and May 2021 from one academic medical center in the western United States (n = 13), another in the southeastern United States (n = 7), and community practices nationwide (n = 5).

Methods:

Using an inductive qualitative approach, we conducted in-depth interviews with 25 oncologists from two academic medical centers and community practices.

Results:

Facilitators of cancer care delivery included readily available information regarding HIV status and stage, interdepartmental communication, and antiviral therapy adherence. Barriers included a lack of formal education on HIV malignancies, perceptions of decreased life expectancy, fear of inadvertent disclosure, and drug–drug interactions. Recommendations included improved provider communication, patient social and mental health resources, and continuing education opportunities.

Conclusion:

The study revealed drivers of cancer treatment decision-making, highlighting physician-reported barriers and facilitators, and recommendations to support treatment decision-making. This is the first known study examining oncologists' perceptions of caring for PLWH. Given that cancer is a leading cause of death among PLWH, there is an urgent need to improve care and outcomes.
Preferences of Pregnant and Postpartum Women for Differentiated Service Delivery in Kenya
Authors: Humphrey John , Wanjama Esther , Carlucci James G. , Naanyu Violet , Were Edwin , Muli Lindah , Alera Marsha , McGuire Alan , Nyandiko Winstone , Songok Julia , Wools-Kaloustian Kara , Zimet Gregory
Published: November 2023

Background:

Differentiated service delivery models are implemented by HIV care programs globally, but models for pregnant and postpartum women living with HIV (PPWH) are lacking. We conducted a discrete choice experiment to determine women's preferences for differentiated service delivery.

Setting:

Five public health facilities in western Kenya.

Methods:

PPWH were enrolled from April to December 2022 and asked to choose between pairs of hypothetical clinics that differed across 5 attributes: clinic visit frequency during pregnancy (monthly vs. every 2 months), postpartum visit frequency (monthly vs. only with routine infant immunizations), seeing a mentor mother (each visit vs. as needed), seeing a clinician (each visit vs. as needed), and basic consultation cost (0, 50, or 100 Kenya Shillings [KSh]). We used multinomial logit modeling to determine the relative effects (β) of each attribute on clinic choice.

Results:

Among 250 PPWH (median age 31 years, 42% pregnant, 58% postpartum, 20% with a gap in care), preferences were for pregnancy visits every 2 months (β = 0.15), postpartum visits with infant immunizations (β = 0.36), seeing a mentor mother and clinician each visit (β = 0.05 and 0.08, respectively), and 0 KSh cost (β = 0.39). Preferences were similar when stratified by age, pregnancy, and retention status. At the same cost, predicted market choice for a clinic model with fewer pregnant/postpartum visits was 75% versus 25% for the standard of care (ie, monthly visits during pregnancy/postpartum).

Conclusion:

PPWH prefer fewer clinic visits than currently provided within the standard of care in Kenya, supporting the need for implementation of differentiated service delivery for this population.
Cirscan: a shiny application to identify differentially active sponge mechanisms and visualize circRNA-miRNA-mRNA networks
Authors: Fraboulet Rose-Marie , Ahmed Yanis Si , Aubry Marc , Corre Sebastien , Galibert Marie-Dominique , Blum Yuna
Published: November 2023

Background

Non-coding RNAs represent a large part of the human transcriptome and have been shown to play an important role in disease such as cancer. However, their biological functions are still incompletely understood. Among noncoding RNAs, circular RNAs (circRNAs) have recently been identified for their microRNA (miRNA) sponge function which allows them to modulate the expression of miRNA target genes by taking on the role of competitive endogenous RNAs (ce-circRNAs). Today, most computational tools are not adapted to the search for ce-circRNAs or have not been developed for the search for ce-circRNAs from user’s transcriptomic data.

Results

In this study, we present Cirscan (CIRcular RNA Sponge CANdidates), an interactive Shiny application that automatically infers circRNA-miRNA-mRNA networks from human multi-level transcript expression data from two biological conditions (e.g. tumor versus normal conditions in the case of cancer study) in order to identify on a large scale, potential sponge mechanisms active in a specific condition. Cirscan ranks each circRNA-miRNA-mRNA subnetwork according to a sponge score that integrates multiple criteria based on interaction reliability and expression level. Finally, the top ranked sponge mechanisms can be visualized as networks and an enrichment analysis is performed to help its biological interpretation. We showed on two real case studies that Cirscan is capable of retrieving sponge mechanisms previously described, as well as identifying potential novel circRNA sponge candidates.

Conclusions

Cirscan can be considered as a companion tool for biologists, facilitating their ability to prioritize sponge mechanisms for experimental validations and identifying potential therapeutic targets. Cirscan is implemented in R, released under the license GPL-3 and accessible on GitLab (https://gitlab.com/geobioinfo/cirscan_Rshiny). The scripts used in this paper are also provided on Gitlab (https://gitlab.com/geobioinfo/cirscan_paper).
Prefrontal cortex signals value category while basal ganglia represent learned values in value learning
Authors: Reza Heydari M. , Ravandi Mohammad Ali Kheirkhah , Hikosaka Okihide , Ghazizadeh Ali
Published: November 2023

Value learning can be variable for objects with the exact same reward but the underlying neural mechanism for such variability is not known. We have addressed this question by recording single-unit activity in the prefrontal cortex (PFC) and substantia nigra reticulata (SNr), two key nodes in cortex-basal ganglia circuitry with crucial roles in value learning, as macaque monkeys learned to associate novel objects with either high or low rewards. Estimating the trial by trial learned values based on choice performance, revealed stark differences between learned values across objects with the same reward outcome. Importantly, while PFC neurons rapidly learned to differentiate objects based on their value category, the firing in SNr correlated with the variability in learned values within a value category. Our results suggest that the variation in objects’ learned values is more likely to be a readout of SNr firing while PFC may provide a top-down teaching signal to basal ganglia to demarcate the value categories.
Chimeric Antigen Cytotoxic Receptors for In-Vivo Engineering of Tumor-targeting Natural Killer Cells
Authors: Diwanji Neha , Getts Daniel , Wang Yuxiao
Published: November 2023

Ex vivo chimeric antigen receptor (CAR) NK cells face challenges in manufacturing, and have limited tumor infiltration and in vivo persistency. A method leveraging mRNA-based delivery for in-vivo engineering of human NK cells could address these issues but has not been established. Here we developed an in-vivo NK cell engineering method by designing CARs that capitalize on inherent NK receptor biology for specific expression and function. These CARs utilize the Immunoreceptor Tyrosine-based Activation Motif (ITAM)-containing signaling adaptor in human NK cells for tumor destruction and cytokine response. We demonstrated that an NKp44-based CAR’s expression and function depend on the signaling adaptor DAP12. This approach enables precise mRNA-driven in-vivo NK cell programming against tumors, ensuring specificity and reducing off-target expression in non-immune healthy tissues.
Integrated Proteomics analysis of baseline protein expression in pig tissues
Authors: Wang Shengbo , Collins Andrew , Prakash Ananth , Fexova Silvie , Papatheodorou Irene , Jones Andrew R. , Vizcaíno Juan Antonio
Published: November 2023

The availability of an increasingly large amount of public proteomics datasets presents an opportunity for performing combined analyses to generate comprehensive organism-wide protein expression maps across different organisms and biological conditions.Sus scrofa, the domestic pig, is a model organism relevant for food production and for human biomedical research. Here we reanalyzed 14 public proteomics datasets from the PRIDE database coming from pig tissues to assess baseline (without any biological perturbation) protein abundance in 14 organs, encompassing a total of 20 healthy tissues from 128 samples. The analysis involved the quantification of protein abundance in 599 mass spectrometry runs.

We compared protein expression patterns among different pig organs and examined the distribution of proteins across these organs. Then, we studied how protein abundances compared across different datasets and studied the tissue specificity of the detected proteins. Of particular interest, we conducted a comparative analysis of protein expression between pig and human tissues, revealing a high degree of correlation in protein expression among orthologs, particularly in brain, kidney, heart, and liver samples.

We have integrated the protein expression results into the Expression Atlas resource for easy access and visualisation of the protein expression data individually or alongside gene expression data.
Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations
Authors: Fu Yi , Zhao Tianxiao , Clark Finnegan , Nomikou Sofia , Tsirigos Aristotelis , Lionnet Timothée
Published: November 2023

The transfer of regulatory information between distal loci on chromatin is thought to involve physical proximity, but key biophysical features of these contacts remain unclear. For instance, it is unknown how close and for how long two loci need to be in order to productively interact. The main challenge is that it is currently impossible to measure chromatin dynamics with high spatiotemporal resolution at scale. Polymer simulations provide an accessible and rigorous way to test biophysical models of chromatin regulation, yet there is a lack of simple and general methods for extracting the values of model parameters. Here we adapt the Nelder-Mead simplex optimization algorithm to select the best polymer model matching a given Hi-C dataset, using theMYClocus as an example. The model’s biophysical parameters predict a compartmental rearrangement of theMYClocus in leukemia, which we validate with single-cell measurements. Leveraging trajectories predicted by the model, we find that loci with similar Hi-C contact frequencies can exhibit widely different contact dynamics. Interestingly, the frequency of productive interactions between loci exhibits a non-linear relationship with their Hi-C contact frequency when we enforce a specific capture radius and contact duration. These observations are consistent with recent experimental observations and suggest that the dynamic ensemble of chromatin configurations, rather than average contact matrices, is required to fully predict productive long-range chromatin interactions.
STARQ: Domain-Invariant Brainstem Nuclei Segmentation and Signal Quantification
Authors: Kaiser Julia , Luong Dana , Sung Eunseo , Iqbal Asim , Sahni Vibhu
Published: November 2023

Abstract

Brainstem nuclei are hard to distinguish due to very few distinctive features which makes detecting them with high accuracy extremely difficult. We introduce StARQ that builds on SeBRe, a deep learning-based framework to segment regions of interest. StARQ provides new functionalities for automated segmentation of brainstem nuclei at high granularity, and quantification of underlying neural features such as axonal tracings, and synaptic punctae. StARQ will serve as a toolbox for generalized brainstem analysis, enabling reliable high-throughput computational analysis with open-source models.
Bidirectional chemogenetic modulation of claustral activity causes altered cortical dynamics
Authors: Zahacy Ryan , Ma Yonglie , Winship Ian R. , Jackson Jesse , Chan Allen W.
Published: November 2023

In recent years, there has been a growing interest in understanding the function of the claustrum. The claustrum is a thin, long, subcortical structure with dense connections to the cortex. Despite these extensive connections, the manner in which the claustrum influences broader cortical activity remains unclear. We used mesoscale calcium fluorescence imaging to examine resting state cortical activity (1-5Hz) and sensory-evoked responses in lightly anesthetized mice, before and after bi-directional chemogenetic modulation of claustrum-prefrontal neurons. Claustrum inhibition resulted in increased activity in anterior-medial cortical areas, whereas claustrum excitation resulted in decreased activity in anterior-medial cortical regions. Claustrum inhibition also led to an increased local coupling between areas of frontal cortex, a decreased correlation between anterior medial regions-of-interest (ROIs) and lateral and posterior ROIs, and an increased sensory evoked response in the visual cortex. These results are consistent with the finding that the claustrum has a large feed-forward inhibitory effect on the PFC, and the concept that specific claustrocortical pathways may modulate recruit and synchronize activity in topographically distinct cortical modules. Together these results show that neural activity in the claustrum modulates the excitability of prefrontal cortical networks, suggesting a potential target for prefrontal-dependent behaviors such as learning, attention, and stress regulation.
Widefield in vivo imaging system with two fluorescence and two reflectance channels, a single sCMOS detector, and shielded illumination
Authors: Doran Patrick R. , Fomin-Thunemann Natalie , Tang Rockwell P. , Balog Dora , Zimmerman Bernhard , Kilic Kivilcim , Martin Emily A. , Kura Sreekanth , Fisher Harrison P. , Chabbott Grace , Herbert Joel , Rauscher Bradley C. , Jiang John X. , Sakadzic Sava , Boas David A. , Devor Anna , Chen Ichun Anderson , Thunemann Martin
Published: November 2023

Significance: Widefield microscopy of the entire dorsal part of mouse cerebral cortex enables large-scale (mesoscopic) imaging of neuronal activity with fluorescent indicators as well as hemodynamics via oxy- and deoxyhemoglobin absorption. Versatile and cost-effective imaging systems are needed for large-scale, color-multiplexed imaging of multiple fluorescent and intrinsic contrasts. Aim: Develop a system for mesoscopic imaging of two fluorescent and two reflectance channels. Approach: Excitation of red and green fluorescence is achieved through epi-illumination. Hemoglobin absorption imaging is achieved using 525- and 625nm LEDs positioned around the objective lens. An aluminum hemisphere placed between objective and cranial window provides diffuse illumination of the brain. Signals are recorded sequentially by a single sCMOS detector. Results: We demonstrate performance of our imaging system by recording large-scale spontaneous and stimulus-evoked neuronal, cholinergic, and hemodynamic activity in awake head-fixed mice with a curved crystal skull window expressing the red calcium indicator jRGECO1a and the green acetylcholine sensor GRABACh3.0 . Shielding of illumination light through the aluminum hemisphere enables concurrent recording of pupil diameter changes. Conclusions: Our widefield microscope design with single camera can be used to acquire multiple aspects of brain physiology and is compatible with behavioral readouts of pupil diameter.
CONSULT-II: Accurate taxonomic identification and profiling using locality-sensitive hashing
Authors: Şapcı Ali Osman Berk , Rachtman Eleonora , Mirarab Siavash
Published: November 2023

Taxonomic classification of short reads and taxonomic profiling of metagenomic samples are well-studied yet challenging problems. The presence of species belonging to ranks without close representation in a reference dataset is particularly challenging. While k-mer-based methods have performed well in terms of running time and accuracy, they tend to have reduced accuracy for such novel species. Here, we show that using locality-sensitive hashing (LSH) can increase the sensitivity of the k-mer-based search. Our method, which combines LSH with several heuristics techniques including soft LCA labeling and voting is, more accurate than alternatives in both taxonomic classification of individual reads and abundance profiling.
Indirect Reciprocity Undermines Indirect Reciprocity Destabilizing Large-Scale Cooperation
Authors: Schnell Eric , Muthukrishna Michael
Published: November 2023

Previous models suggest that indirect reciprocity (reputation) can stabilize large-scale human cooperation1. The logic behind these models2–7and experiments6,8is that a strategy in which individuals conditionally aid others based on their reputation for engaging in costly cooperative behavior serves as a punishment that incentivizes large-scale cooperation without the second-order free-rider problem. However, these models and experiments fail to account for individuals belonging to multiple groups with reputations that can be in conflict. Here we extend these models such that individuals belong to a smaller, “local” group embedded within a larger, “global” group. This introduces competing strategies for conditionally aiding others based on their cooperative behavior in the local or global group. Our analyses reveal that the reputation for cooperation in the smaller local group can undermine cooperation in the larger global group, even when the theoretical maximum payoffs are higher in the larger global group. This model reveals that indirect reciprocity alone is insufficient for stabilizing large-scale human cooperation because cooperation at one scale can be considered defection at another. These results deepen the puzzle of large-scale human cooperation.
Prevalence of Avian Influenza Virus in Synanthropic Birds Associated with an Outbreak of Highly Pathogenic Strain EA/AM H5N1
Authors: Ringenberg Jourdan M. , Weir Kelsey , Humberg Lee , Voglewede Carl , Oswald Mitch , Root J. Jeffrey , Dilione Krista , Casey Evan , Milleson Michael , Linder Timothy , Lenoch Julianna
Published: November 2023

The 2022 – 2023 highly pathogenic avian influenza (HPAI) virus outbreak of H5N1 Eurasian lineage goose/Guangdong clade 2.3.4.4b is the largest in North American history and has significantly impacted wild bird populations and domestic poultry across the United States. Synanthropic birds may play an important role in transmitting the virus laterally to other wild bird species and domestic poultry. Understanding the prevalence of HPAI H5N1 in different avian orders may help inform management decisions and potential risk factors for both wild and domestic bird populations. Following the confirmation of infection of HPAI H5N1 in domestic poultry at two commercial premises in IN, USA, we sampled and tested 266 synanthropic avian species within the Columbiformes and Passeriformes orders and found no detection of the virus at either location. Additionally, laboratories within the National Animal Health Laboratory Network were queried for influenza Type A rRT-PCR assay test results from morbidity and mortality events in wild birds, consisting of 10,786 birds tested across eight orders and 1,666 avian influenza virus detections. Query results were assessed by taxonomic groups for viral prevalence and suggested that the virus most often was observed in predatory and scavenging birds. Although detections were found in non-predatory synanthropic birds including the orders Columbiformes, Galliformes, and Passeriformes, the risk of transmission from and between these groups appears comparatively low, with apparent prevalence rates of 0.0090, 0.0688, and 0.0147, respectively. The highest prevalence was observed in raptors (0.2514), with prevalence rates in exclusively scavengingCathartidaereaching up to 0.5333. There is strong evidence that consumption of infected tissues is a key pathway for transmission of avian influenza viruses. Understanding the impact of the 2022 – 2023 HPAI outbreak in wild bird populations can provide pertinent information on viral transmission, disease ecology, and risk to humans and agriculture.
A Novel human IL-23A Overexpressing Mouse Model of Systemic Lupus Erythematosus
Authors: Christodoulou-Vafeiadou Eleni , Geka Christina , Iliopoulou Lida , Ntari Lydia , Denis Maria C. , Karagianni Niki , Kollias George
Published: November 2023

Objective

Interleukin-23 (IL-23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases like psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model (TghIL23A) overexpressing human IL23A, providing a valuable tool for investigating the pathogenic role of hIL23A and evaluating the efficacy of anti-human-IL23A therapeutics.

Methods

TghIL23A mice were generated via microinjection of CBAxC57BL/6 zygotes with a fragment of the human IL23A gene, flanked by its 5’-regulatory sequences and the 3’UTR of human beta-globin. The TghIL23A pathology was assessed through hematological and biochemical analyses, cytokine and anti-nuclear antibody detection, histopathological examination of skin and renal tissues. The response to the anti-hIL23A therapeutic agent guselkumab, was evaluated in groups of 8 mixed-sex mice receiving subcutaneous treatment twice weekly for 10 weeks, using clinical, biomarker and histopathological readouts.

Results

TghIL23A mice exhibited interactions between hIL23A and mouse IL23/IL12p40, and developed a chronic multiorgan autoimmune disease marked by proteinuria, anti-dsDNA antibodies, severe inflammatory lesions in the skin and milder phenotypes in the kidneys and lungs. The TghIL23A pathological features exhibited significant similarities to those observed in human SLE patients.

Conclusions

We have generated and characterized a novel genetic mouse model of SLE, providing proof-of-concept for the etiopathogenic role of hIL-23A. This new model has a normal lifespan and integrates several characteristics of the human disease’s complexity and chronicity making it an attractive preclinical tool for studying IL23-dependent pathogenic mechanisms and assessing the efficacy of anti-hIL23A or modeled disease-related therapeutics.
Temperature influences the excretion time and parasitic load ofTrypanosoma cruziin theTriatoma infestansvector
Authors: Álvarez-Duhart B. , Clavijo-Baquet S. , Valenzuela-Perez L. , Maya J.D. , Saavedra M. , Ortiz S. , Muñoz-San Martín C. , Bacigalupo A. , Cattan P. E.
Published: November 2023

Trypanosoma cruziis a protozoan parasite transmitted by triatomine insect vectors, which expel their infectious dejections when they feed, causing Chagas disease in humans. The transmission and incidence of this vector-borne disease depend on the vital traits of its vectors, includingTriatoma infestans, the main vector in Southern South America. Being an ectothermic species, its metabolism and its vital traits respond to temperature fluctuations. Here, we evaluated if changes in the average and variability of temperature expected with climate change modify: (i) the extrinsic incubation period (EIP) ofT. cruziwithin the vectorT. infestans, (ii) its parasitic load, and (iii) the probability that its dejections wereT. cruzi-positive. We acclimated triatomines infected with Dm28cT. cruzistrain to two constant and two variable temperature treatments and measuredT. cruziin their dejections by qPCR over a 42-day period. We observed that individuals in warm-temperature treatments showed lower EIP and higher parasitic load than cold-temperature treatments. Also, temperature variability can increase the parasitic load peak in cold-temperature treatments. Consequently, in a climate change scenario, there might be an increase in the vector capacity ofT. infestansand probably a change in the risk of vectorial transmission ofT. cruzi.
Fibrillar adhesion dynamics govern the timescales of nuclear mechano-response via the vimentin cytoskeleton
Authors: Beedle Amy E.M. , Jaganathan Anuja , Albajar-Sigalés Aina , Yavitt F. Max , Bera Kaustav , Andreu Ion , Granero-Moya Ignasi , Zalvidea Dobryna , Kechagia Zanetta , Wiche Gerhard , Trepat Xavier , Ivaska Johanna , Anseth Kristi S. , Shenoy Vivek B. , Roca-Cusachs Pere
Published: November 2023

The cell nucleus is continuously exposed to external signals, of both chemical and mechanical nature. To ensure proper cellular response, cells need to regulate not only the transmission of these signals, but also their timing and duration. Such timescale regulation is well described for fluctuating chemical signals, but if and how it applies to mechanical signals reaching the nucleus is still unknown. Here we demonstrate that the formation of fibrillar adhesions locks the nucleus in a mechanically deformed conformation, setting the mechanical response timescale to that of fibrillar adhesion remodelling (∼1 hour). This process encompasses both mechanical deformation and associated mechanotransduction (such as via YAP), in response to both increased and decreased mechanical stimulation. The underlying mechanism is the anchoring of the vimentin cytoskeleton to fibrillar adhesions and the extracellular matrix through plectin 1f, which maintains nuclear deformation. Our results reveal a mechanism to regulate the timescale of mechanical adaptation, effectively setting a low pass filter to mechanotransduction.
Opening the species box: What parsimonious microscopic models of speciation have to say about macroevolution
Authors: Couvert Élisa , Bienvenu François , Duchamps Jean-Jil , Erard Adélie , Miró Pina Verónica , Schertzer Emmanuel , Lambert Amaury
Published: November 2023

In the last two decades, lineage-based models of diversification, where species are viewed as particles that can divide (speciate) or die (become extinct) at rates depending on some evolving trait, have been very popular tools to study macroevolutionary processes. Here, we argue that this approach cannot be used to break down the inner workings of species diversification and that “opening the species box” is necessary to understand the causes of macroevolution, but that too detailed speciation models also fail to make robust macroevolutionary predictions.

We set up a general framework for parsimonious models of speciation that rely on a minimal number of mechanistic principles: (i) reproductive isolation is caused by excessive dissimilarity between genotypes; (ii) dissimilarity results from a balance between differentiation processes and homogenizing processes; and (iii) dissimilarity can feed back on these processes by decelerating homogenization.

We classify such models according to the main homogenizing process : (1) clonal evolution models (ecological drift), (2) models of genetic isolation (gene flow) and (3) models of isolation by distance (spatial drift). We review these models and their specific predictions on macroscopic variables such as species abundances, speciation rates, interfertility relationships or phylogenetic tree structure.

We propose new avenues of research by displaying conceptual questions remaining to be solved and new models to address them: the failure of speciation at secondary contact, the feedback of dissimilarity on homogenization, the emergence in space of breeding barriers.
SOX4 exerts contrasting regulatory effects on labor-associated gene promoters in myometrial cells
Authors: Khader Nawrah , Shchuka Virlana M. , Dorogin Anna , Shynlova Oksana , Mitchell Jennifer A.
Published: November 2023

The uterine muscular layer, or myometrium, undergoes profound changes in global gene expression during its progression from a quiescent state during pregnancy to a contractile state at the onset of labor. In this study, we investigate the role of SOX family transcription factors in myometrial cells and provide evidence for the role of SOX4 in regulating labor-associated genes. We show thatSox4has elevated expression in the murine myometrium during a term laboring process and in two mouse models of preterm labor. Additionally, SOX4 differentially affects labor-associated gene promoter activity in cooperation with activator protein 1 (AP-1) dimers. SOX4 exerted no effect on theGja1promoter; a JUND-specific activation effect at theFospromoter; a positive activation effect on theMmp11promoter with the AP-1 dimers; and surprisingly, we noted that the reporter expression of thePtgs2promoter in the presence of JUND and FOSL2 was repressed by the addition of SOX4. Our data indicate SOX4 may play a diverse role in regulating gene expression in the laboring myometrium in cooperation with AP-1 factors. This study enhances our current understanding of the regulatory network that governs the transcriptional changes associated with the onset of labor and highlights a new molecular player that may contribute to the labor transcriptional program.
Comparison of radiography and computed tomography for condylar fracture risk assessment in Thoroughbred racehorses
Authors: Irandoust S. , O’Neil L. , Stevenson C.M. , Franseen F.M. , Ramzan P.H.L. , Powell S.E. , Brounts S.H. , Loeber S.J. , Ergun D.L. , Whitton R.C. , Henak C.R. , Muir P.
Published: November 2023

Background

Catastrophic injury has a low incidence but leads to the death of many Thoroughbred racehorses annually. Effective screening for injury risk needs to solve the false negative diagnostic sensitivity problem.

Objectives

To determine sensitivity, specificity, and reliability for condylar stress fracture risk assessment from fetlock digital radiographs (DR) and standing computed tomography (sCT) imaging (Asto CT Equina®).

Study design

Controlledex vivoexperiment.

Methods

A blinded set of DR and sCT images of the thoracic limb fetlock were prepared from 31 Thoroughbred racehorses and reviewed by four veterinarians. Observers evaluated the condyles and parasagittal grooves (PSG) of the third metacarpal subchondral bone (MC3) for the extent of dense bone and lucency/fissure and assigned a risk assessment grade for condylar stress fracture based on imaging findings. Sensitivity and specificity for detection of subchondral structural changes in the condyles and PSG of the third metacarpal bone and for risk assessment for condylar stress fracture were determined by comparison with a reference assessment. Agreement between each observer and the reference assessment and reliability between observers were determined. Intra-observer repeatability was also assessed.

Results

Intra-observer repeatability was identified for both DR and sCT imaging. Sensitivity for detection of structural change was lower than specificity for both imaging methods and all observers. For horses with a normal level of risk, observer assessment often agreed with the reference assessment. Sensitivity for risk assessment was lower than specificity for all observers. For horses with a high risk of serious injury, observers generally underestimated the level of risk. Diagnostic sensitivity of risk assessment was improved with sCT imaging, particularly for horses with elevated risk of injury. Assessment reliability was better with sCT than DR.

Main limitations

Theex vivostudy design influenced DR image sets regarding limb positioning and image contrast compared within vivoDR imaging.

Conclusions

Risk assessment through screening with diagnostic imaging is a promising approach to improve injury prevention in racing Thoroughbreds. Knowledge of sensitivity and specificity of fetlock lesion detection by DR and sCT provides critical guidance regarding development of improved screening programs for racehorses using diagnostic imaging. We found improved detection of MC3 subchondral structural change and risk assessment for condylar stress fracture with sCTex vivo.
Democratizing Protein Language Models with Parameter-Efficient Fine-Tuning
Authors: Sledzieski Samuel , Kshirsagar Meghana , Baek Minkyung , Berger Bonnie , Dodhia Rahul , Ferres Juan Lavista
Published: November 2023

Proteomics has been revolutionized by large pre-trained protein language models, which learn unsupervised representations from large corpora of sequences. The parameters of these models are then fine-tuned in a supervised setting to tailor the model to a specific downstream task. However, as model size increases, the computational and memory footprint of fine-tuning becomes a barrier for many research groups. In the field of natural language processing, which has seen a similar explosion in the size of models, these challenges have been addressed by methods for parameter-efficient fine-tuning (PEFT). In this work, we newly bring parameter-efficient fine-tuning methods to proteomics. Using the parameter-efficient method LoRA, we train new models for two important proteomic tasks: predicting protein-protein interactions (PPI) and predicting the symmetry of homooligomers. We show that for homooligomer symmetry prediction, these approaches achieve performance competitive with traditional fine-tuning while requiring reduced memory and using three orders of magnitude fewer parameters. On the PPI prediction task, we surprisingly find that PEFT models actually outperform traditional fine-tuning while using two orders of magnitude fewer parameters. Here, we go even further to show that freezing the parameters of the language model and training only a classification head also outperforms fine-tuning, using five orders of magnitude fewer parameters, and that both of these models outperform state-of-the-art PPI prediction methods with substantially reduced compute. We also demonstrate that PEFT is robust to variations in training hyper-parameters, and elucidate where best practices for PEFT in proteomics differ from in natural language processing. Thus, we provide a blueprint to democratize the power of protein language model tuning to groups which have limited computational resources.
Navigating the manifold of single-cell gene coexpression to discover interpretable gene programs
Authors: Ozbay Sinan , Parekh Aditya , Singh Rohit
Published: November 2023

During development and differentiation, transcriptional regulation in the cell often occurs at the level of gene programs (i.e., sets of co-varying genes), rather than isolated genes. It is therefore crucial to identify differential program expression over time, or across case-vs-control samples. However, this has remained difficult: gene programs are inferred by analyzing gene coexpression, and mathematical operations on the latter are nontrivial. Gene coexpression is quantified as a symmetric positive-definite matrix, on which even basic quantities such as arithmetic differences are neither mathematically sound nor biologically interpretable. Here we exploit the structure of the Riemannian manifold of gene coexpression matrices to propose a novel abstraction of gene coexpression that is mathematically well-founded while being computationally tractable and statistically rigorous. Importantly, it also captures biological similarity better than standard coexpression. This conceptual advance enables us to introduce Sceodesic, an algorithm that invokes the log-Euclidean metric from differential geometry to quantify coexpression patterns specific to each cell state, and organizes them into a study-wide panel of interpretable gene programs. Applied to nine single-cell RNA-seq datasets, Sceodesic outperforms existing methods in early detection of cell fate commitment by leveraging differential expression of gene programs, and is also effective in discovering disease-linked programs in multi-sample studies. By respecting the manifold of gene coexpression matrices, Sceodesic resolves a longstanding challenge in relating biological variability to statistical analyses of single-cell RNA-seq data and enables the discovery of gene programs driving differentiation and disease.

Software availability

https://singhlab.net/Sceodesic
Minimization of the E. coli ribosome, aided and optimized by community science
Authors: Tangpradabkul Tiyaporn , Palo Michael , Townley Jill , Hsu Kenneth B. ,   Eterna participants, Smaga Sarah , Das Rhiju , Schepartz Alanna
Published: November 2023

The ribosome is a ribonucleoprotein complex found in all domains of life. Its role is to catalyze protein synthesis, the messenger RNA (mRNA)-templated formation of amide bonds between α-amino acid monomers. Amide bond formation occurs within a highly conserved region of the large ribosomal subunit known as the peptidyl transferase center (PTC). Here we describe the stepwise design and characterization of mini-PTC 1.1, a 284-nucleotide RNA that recapitulates many essential features of theEscherichia coliPTC. Mini-PTC 1.1 folds into a PTC-like structure under physiological conditions, even in the absence of r-proteins, and engages small molecule analogs of A- and P-site tRNAs. The sequence of mini-PTC 1.1 differs from the wild typeE. coliribosome at 12 nucleotides that were installed by a cohort of citizen scientists using the on-line video game Eterna. These base changes improve both the secondary structure and tertiary folding of mini-PTC 1.1 as well as its ability to bind small molecule substrate analogs. Here, the combined input from Eterna citizen-scientists and RNA structural analysis provides a robust workflow for the design of a minimal PTC that recapitulates many features of an intact ribosome.
Human organoid modeling of congenital malformations caused by RFX6 mutations reveal an essential role for this transcription factor in establishing and maintaining duodenal identity upstream of PDX1
Authors: Sanchez J. Guillermo , Rankin Scott , Paul Emily , McCauley Heather A. , Kechele Daniel O. , Enriquez Jacob R. , Jones Nana-Hawa , Greeley Siri AW , Letourneau-Friedberg Lisa , Zorn Aaron M. , Krishnamurthy Mansa , Wells James M.
Published: November 2023

The gastrointestinal (GI) tract consists of highly specialized organs from the proximal esophagus to the distal colon, each with unique functions. Rare congenital malformations of the GI tract, including organ atresia, agenesis or mis-patterning are linked to gene mutations although the molecular basis of these malformations has been poorly studied due to lack of model systems to study human development. We identified a patient with compound heterozygous mutations in the transcription factor RFX6 with pancreatic agenesis as previously described. In addition, the patient had duodenal mal-rotation and atresia suggesting that establishment of the proximal small intestine was impaired in these patients. To identify the molecular basis of the intestinal malformation we generated induced pluripotent stem cell lines from this patient, and derived human intestinal organoid (HIOs) to identify how mutations in RFX6 impact intestinal patterning and function. We identified that the duodenal identity of HIOs and patient tissues had adopted a more distal small intestinal signature, including expression of SATB2, normally expressed in the ileum and colon. CRISPR-mediated correction of RFX6 restored duodenal identity, including expression of PDX1, which is required for duodenal development. Using transcriptomic approaches in HIOs and Xenopus embryos we identified that PDX1 is a downstream transcriptional target of RFX6 and that PDX1 expression in a RFX6 mutant background was sufficient to rescue duodenal identity. However, RFX6 had a PDX1-independent role in regulating expression of components of WNT, HH, and BMP signaling pathways that are critical for establishing early regional identity in the GI tract. In summary, we have identified that RFX6 is one of the most upstream regulators early intestinal patterning in vertebrates and that it acts by regulating key transcriptional and signaling pathways.
Initial clinical evidence on biperiden as antiepileptogenic after traumatic brain injury. A Randomized Clinical Trial
Authors: Foresti Maira Licia , Garzon Eliana , de Moraes Mariana Teichner , Valeriano Rafael PS , Santiago João Paulo , dos Santos Gustavo Mercenas , Longo Natália Mata , Baise Carla , Andrade Joaquina CQF , Susemihl Maria Alice , Naffah Mazzacoratti Maria da Graça , Paiva Wellingson Silva , de Andrade Almir Ferreira , Teixeira Manuel Jacobsen , Mello Luiz E
Published: November 2023

There is currently no available drug to prevent the development of post-traumatic epilepsy. insufficient evidence regarding the effect of biperiden in preventing post-traumatic epilepsy after TBI. The combined effect of variables known to have an impact on the likelihood of developing late post-traumatic seizures and its unbalanced frequency in the different groups is an aspect to be considered and underpins the need for larger studies.

Highlights

Prior research suggests anticholinergics may prevent post-traumatic epilepsy

There was insufficient evidence on biperiden’s role in preventing PTE after TBI

Variable impact on post-traumatic epilepsy underscores need for broader studies

Graphical Abstract
Secreted protein profiling of human aortic smooth muscle cells identifies vascular disease associations
Authors: Aherrahrou Rédouane , Baig Ferheen , Theofilatos Konstantinos , Lue Dillon , Beele Alicia , Örd Tiit , Kaikkonen Minna U , Aherrahrou Zouhair , Cheng Qi , Ghosh Saikat , Karnewar Santosh , Karnewar Vaishnavi , Finn Aloke , Owens Gary K. , Joner Michael , Mayr Manuel , Civelek Mete
Published: November 2023

Background

Smooth muscle cells (SMCs), which make up the medial layer of arteries, are key cell types involved in cardiovascular diseases (CVD), the leading cause of mortality and morbidity worldwide. In response to microenvironment alterations, SMCs dedifferentiate from a “contractile” to a “synthetic” phenotype characterized by an increased proliferation, migration, production of extracellular matrix (ECM) components, and decreased expression of SMC-specific contractile markers. These phenotypic changes result in vascular remodeling and contribute to the pathogenesis of CVD, including coronary artery disease (CAD), stroke, hypertension, and aortic aneurysms. Here, we aim to identify the genetic variants that regulate ECM secretion in SMCs and predict the causal proteins associated with vascular disease-related loci identified in genome-wide association studies (GWAS).

Methods

Using human aortic SMCs from 123 multi-ancestry healthy heart transplant donors, we collected the serum-free media in which the cells were cultured for 24 hours and conducted Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of the conditioned media.

Results

We measured the abundance of 270 ECM and related proteins. Next, we performed protein quantitative trait locus mapping (pQTL) and identified 20 loci associated with secreted protein abundance in SMCs. We functionally annotated these loci using a colocalization approach. This approach prioritized the genetic variant rs6739323-A at the 2p22.3 locus, which is associated with lower expression of LTBP1 in SMCs and atherosclerosis-prone areas of the aorta, and increased risk for SMC calcification. We found that LTBP1 expression is abundant in SMCs, and its expression at mRNA and protein levels was reduced in unstable and advanced atherosclerotic plaque lesions.

Conclusions

Our results unravel the SMC proteome signature associated with vascular disorders, which may help identify potential therapeutic targets to accelerate the pathway to translation.