bluuebunny/crossref_metadata_2025 huggingface dataset:
GeneSpectra: a method for context-aware comparison of cell type gene expression across species
Authors: Song Yuyao , Papatheodorou Irene , Brazma Alvis
Published: June 2024

Computational comparison of single cell expression profiles cross-species uncovers functional similarities and differences between cell types. Importantly, it offers the potential to refine evolutionary relationships based on gene expression. Current analysis strategies are limited by the strong hypothesis of ortholog conjecture, which implies that orthologs have similar cell type expression patterns. They also lose expression information from non-orthologs, making them inapplicable in practice for large evolutionary distances. To address these limitations, we devised a novel analytical framework, GeneSpectra, to robustly classify genes by their expression specificity and distribution across cell types. This framework allows for the generalization of the ortholog conjecture by evaluating the degree of ortholog class conservation. We utilise different gene classes to decode species effects on cross-species transcriptomics space and compare sequence conservation with expression specificity similarity across different types of orthologs. We develop contextualised cell type similarity measurements while considering species-unique genes and non-one-to-one orthologs. Finally, we consolidate gene classification results into a knowledge graph, GeneSpectraKG, allowing a hierarchical depiction of cell types and orthologous groups, while continuously integrating new data.
Multisensory Integration of Naturalistic Speech and Gestures in Autistic Adults
Authors: Matyjek Magdalena , Kita Sotaro , Torralba Cuello Mireia , Soto Faraco Salvador
Published: June 2024

Seeing the speaker facilitates auditory speech comprehension through audio-visual integration. This is especially the case in challenging listening conditions, such as in real-life social environments. Autism has been associated with atypicalities in integrating audio-visual information, potentially underlying social difficulties in this population. The present study investigated multisensory integration (MSI) in speech processing among autistic (N=35) and neurotypical (N=35) adults. Participants performed a speech-in-noise task in a realistic multispeaker social scenario with audio-visual, auditory, or visual trials while their brain activity was recorded using EEG. The neurotypical group demonstrated a non-linear audio-visual interaction in alpha suppression, whereas the autistic group showed merely additive processing of these same inputs. Despite these differences in neural correlates, both groups achieved similar behavioural audio-visual facilitation outcomes. These findings suggest that although autistic and neurotypical brains might process multisensory cues differently, they achieve comparable benefits from audio-visual speech. These results contribute to the growing body of literature on MSI atypicalities in autism.
Decoupling individual host response and immune cell engager cytotoxic potency
Authors: Gonzalez Gutierrez Cristina , Aimard Adrien , Biarnes-Pélicot Martine , Kerfelec Brigitte , Puech Pierre-Henri , Robert Philippe , Piazza Francesco , Chames Patrick , Limozin Laurent
Published: June 2024

Immune cell engagers are molecular agents, usually antibody-based constructs, engineered to recruit immune cells against cancer cells and kill them. They represent a versatile and powerful tool for cancer immunotherapy. Despite the multiplication of new engagers tested and accepted in the clinics, how molecular and cellular parameters influence their action is poorly understood. In particular, disentangling the respective role of host immune cells and engager biophysical characteristics is needed to improve their design and efficiency. Focusing here on harnessing antibody dependent Natural Killer cell cytotoxicity, we measure the efficiency of 6 original bispecific antibodies (bsAb), associating an anti-HER2 nanobody and an anti-CD16 nanobody.In vitrocytotoxicity data using primary human NK cells on different target cell lines exposing different antigen densities were collected, exhibiting a wide range of bsAb dose response. In order to rationalize our observations, we introduce a simple multiscale model, postulating that the density of bsAb bridging the two cells is the main parameter triggering the cytotoxic response. We introduce two new microscopic parameters: the surface cooperativity describing bsAb affinity at the bridging step and the threshold of bridge density determining the donor-dependent response. Both parameters permit to rank Abs and donors and to predict bsAb potency as a function of antibodies bulk affinities and receptor surface densities on cells. Our approach thus provides a general way to decouple donor response from immune engagers characteristics, rationalizing the landscape of molecule design.
Single-cell Growth Rate Variability in Balanced Exponential Growth
Authors: Biswas Kuheli , Sanderson Amy E. , Salman Hanna , Brenner Naama
Published: June 2024

Exponential accumulation of cell size and highly expressed proteins is observed in many bacterial species at the single cell level. Exponential rates exhibit cycle-by-cycle fluctuations and correlation across components - different proteins and cell size. In such balanced growth, homeostasis of all variables is maintained simultaneously. In this study, we examine the phenomenological features of growth-rate variability and present a theoretical framework to explain them and the emergence of multi-variable homeostasis. Our findings suggest that homeostasis results from the emergence of a high-dimensional dynamic attractor supporting balanced exponential growth. The stability of this attractor leads to a decay in instantaneous growth rate noise throughout the cell cycle, aligning with empirical findings. We also correctly predict that cells with higher growth rates experience a faster decay in growth rate noise. Surprisingly, our analysis identifies noise generated by uneven cell division as the primary source of variability in growth rates. The theory offers a clear explanation for many observations, validated against extensive single-cell data. The emergence of homeostasis spontaneously from dynamic interactions suggests that specific control mechanisms correcting deviations from a target may be unnecessary.
ACE-2 Blockade & TMPRSS2 Inhibition Mitigate SARS-CoV-2 Severity Following Cigarette Smoke Exposure in Airway Epithelial Cells In Vitro
Authors: Hussain Shah S , Libby Emily Falk , Lever Jacelyn E Peabody , Tipper Jennifer L , Phillips Scott E , Mazur Marina , Li Qian , Campos-Gómez Javier , Harrod Kevin S , Rowe Steven M
Published: June 2024

Cigarette smoking is associated with COVID-19 prevalence and severity, but the mechanistic basis for how smoking alters SARS-CoV-2 pathogenesis is unknown. A potential explanation is that smoking alters the expression of the SARS-CoV-2 cellular receptor and point of entry, angiotensin converting enzyme-2 (ACE-2), and its cofactors including transmembrane protease serine 2 (TMPRSS2). We investigated the impact of cigarette smoking on the expression of ACE-2, TMPRSS2, and other known cofactors of SARS-CoV-2 infection and the resultant effects on infection severity in vitro. Cigarette smoke extract (CSE) exposure increased ACE-2 and TMPRSS2 mRNA expression compared to air control in ferret airway cells, Calu-3 cells, and primary human bronchial epithelial (HBE) cells derived from normal and COPD donors. CSE-exposed ferret airway cells inoculated with SARS-CoV-2 had a significantly higher intracellular viral load versus vehicle-exposed cells. Likewise, CSE-exposure increased both SARS-CoV-2 intracellular viral load and viral replication in both normal and COPD HBE cells over vehicle control. Apoptosis was increased in CSE-exposed, SARS-CoV-2-infected HBE cells. Knockdown of ACE-2 via an antisense oligonucleotide (ASO) reduced SARS-CoV-2 viral load and infection in CSE-exposed ferret airway cells that was augmented by co-administration of camostat mesylate to block TMPRSS2 activity. Smoking increases SARS-CoV-2 infection via upregulation of ACE2 and TMPRSS2.
Using Photoswitching FRET to Define the Interaction Boundaries between the Rab1b GTPase and Secretory Cargo
Authors: Malis Yehonathan , Hirschberg Guy M. , Patterson George H. , Hirschberg Koret
Published: June 2024

FRET is a powerful tool to simultaneously establish and localize interactions between fluorescently tagged proteins with high spatial resolution. Rainey K.H. and Patterson G.H. introduced Photoswitching FRET (psFRET) using the Dronpa Photoswitching fluorescent protein. We present a straightforward detailed method, and a powerful software tool that allows adaptation of psFRET to diverse experimental setups. Image stacks, recording the decay of the Dronpa donor, serve as input to the software utility that includes effective preprocessing options preceding the calculation FRET efficiency at the single pixel level. We applied psFRET to generate interaction maps analyzing diverse interactions between cargo proteins, the GTPase Rab1b, and GRASP65 during ER to Golgi trafficking. Cargo-Rab1b interactions were restricted to the transit period from ER to Golgi. These data lend support to a mechanism whereby cargo sensing may regulate the level of downstream effectors recruitment to secretory membranes by Rab1.
SWEET family transporters act as water conducting carrier proteins in plants
Authors: Selvam Balaji , Paul Arnav , Yu Ya-Chi , Chen Li-Qing , Shukla Diwakar
Published: June 2024

Abstract

Dedicated water channels are involved in the facilitated diffusion of water molecules across the cell membrane in plants. Transporter proteins are also known to transport water molecules along with substrates, however the molecular mechanism of water permeation is not well understood in plant transporters. Here, we show plant sugar transporters from the SWEET (SugarWillEventually beExportedTransporter) family act as water-conducting carrier proteins via a variety of passive and active mechanisms that allow diffusion of water molecules from one side of the membrane to the other. This study provides a molecular perspective on how plant membrane transporters act as water carrier proteins, a topic that has not been extensively explored in literature. Water permeation in membrane transporters could occur via four distinct mechanisms which form our hypothesis for water transport in SWEETs. These hypothesis are tested using molecular dynamics simulations of the outward-facing, occluded, and inward-facing state of AtSWEET1 to identify the water permeation pathways and the flux associated with them. The hydrophobic gates at the center of the transport tunnel act as a barrier that restricts water permeation. We have performedin silicosingle and double mutations of the hydrophobic gate residues to examine the changes in the water conductivity. Surprisingly, the double mutant allows the water permeation to the intracellular half of the membrane and forms a continuous water channel. These computational results are validated by experimentally examining the transport of hydrogen peroxide molecules by the AtSWEET family of transporters. We have also shown that the transport of hydrogen peroxide follows the similar mechanism as water transport in AtSWEET1. Finally, we conclude that similar water-conduction states are also present in other SWEET transporters due to the high sequence and structure conservation exhibited by this transporter family.
Cortical Lesion Expansion in Chronic Traumatic Brain Injury
Authors: Freeman Holly J. , Atalay Alexander S. , Li Jian , Sobczak Evie , Gilmore Natalie , Snider Samuel B. , Healy Brian C , Carrington Holly , Selmanovic Enna , Pruyser Ariel , Bura Lisa , Sheppard David , Hunt David , Seifert Alan C. , Bodien Yelena G. , Hoffman Jeanne M. , Mac Donald Christine L. , Dams-O’Connor Kristen , Edlow Brian L.
Published: June 2024

Traumatic brain injury (TBI) is a risk factor for neurodegeneration and cognitive decline, yet the underlying pathophysiologic mechanisms are incompletely understood. This gap in knowledge is in part related to a lack of reliable and efficient methods for measuring cortical lesions in neuroimaging studies. The objective of this study was to develop a semi-automated lesion detection tool and apply it to an investigation of longitudinal changes in brain structure among individuals with chronic TBI. We identified 24 individuals with chronic moderate-to-severe TBI enrolled in the Late Effects of TBI (LETBI) study who had cortical lesions detected by T1-weighted MRI and underwent two MRI scans at least two years apart. Initial MRI scans were performed more than one year post-injury, and follow-up scans were performed 3.1 (IQR=1.7) years later. We leveraged FreeSurfer parcellations of T1-weighted MRI volumes and a recently developed super-resolution technique, SynthSR, to automate the identification of cortical lesions in this longitudinal dataset. Trained raters received the data in a randomized order and manually edited the automated lesion segmentations, yielding a final semi-automated lesion mask for each scan at each time point. Inter-rater variability was assessed in an independent cohort of 10 additional LETBI subjects with cortical lesions. The semi-automated lesion segmentations showed a high level of accuracy compared to “ground truth” lesion segmentations performed via manual segmentation by a separate blinded rater. In a longitudinal analysis of the semi-automated segmentations, lesion volume increased between the two time points with a median volume change of 4.91 (IQR=12.95) mL (p<0.0001). Lesion volume significantly expanded in 40 of 61 measured lesions (65.6%), as defined by a longitudinal volume increase that exceeded inter-rater variability. Longitudinal analyses showed similar changes in lesion volume using the ground-truth lesion segmentations. Inter-scan duration was not associated with the magnitude of lesion growth. Reliable and efficient semi-automated lesion segmentation is feasible in studies of chronic TBI, creating opportunities to elucidate mechanisms of post-traumatic neurodegeneration.
Development and Validation of a Machine Learning Model Integrated with the Clinical Workflow for Inpatient Discharge Date Prediction
Authors: Mahyoub Mohammed A. , Doughetry Kacie , Yadav Ravi , Berio-Dorta Raul , Shukla Ajit
Published: June 2024

Background

Discharge date prediction plays a crucial role in healthcare management, enabling efficient resource allocation and patient care planning. Accurate estimation of the discharge date can optimize hospital operations and facilitate better patient outcomes.

Materials and Methods

In this study, we employed a systematic approach to develop a discharge date prediction model. We collaborated closely with clinical experts to identify relevant data elements that contribute to the prediction accuracy. Feature engineering was used to extract predictive features from both structured and unstructured data sources. XGBoost, a powerful machine learning algorithm, was employed for the prediction task. Furthermore, the developed model was seamlessly integrated into a widely used Electronic Medical Record (EMR) system, ensuring practical usability.

Results

The model achieved a performance surpassing baseline estimates by up to 35.68% in the F1-score. Post-deployment, the model demonstrated operational value by aligning with MS GMLOS and contributing to an 18.96% reduction in excess hospital days.

Conclusions

Our findings highlight the effectiveness and potential value of the developed discharge date prediction model in clinical practice. By improving the accuracy of discharge date estimations, the model has the potential to enhance healthcare resource management and patient care planning. Additional research endeavors should prioritize the evaluation of the model’s long-term applicability across diverse scenarios and the comprehensive analysis of its influence on patient outcomes.
“What’s in a name?”: Using mpox as a case study to understand the importance of communication, advocacy, and information accuracy in disease nomenclature
Authors: Hulland Erin N. , Charpignon Marie-Laure , El Hayek Ghinwa Y. , Desai Angel N. , Majumder Maimuna S.
Published: June 2024

Historically, many diseases have been named after the species or location of discovery, the discovering scientists, or the most impacted population. However, species-specific disease names often misrepresent the true reservoir; location-based disease names are frequently targeted with xenophobia; some of the discovering scientists have darker histories; and impacted populations have been stigmatized for this association. Acknowledging these concerns, the World Health Organization now proposes naming diseases after their causative pathogen or symptomatology. Recently, this guidance has been retrospectively applied to a disease at the center of an outbreak rife with stigmatization and misinformation: mpox (f.k.a. ‘monkeypox’). This disease, historically endemic to west and central Africa, has prompted racist remarks as it spread globally in 2022 in an epidemic ongoing today. Moreover, its elevated prevalence among men who have sex with men has yielded increased stigma against the LGBTQ+ community. To address these prejudicial associations, ‘monkeypox’ was renamed ‘mpox’ in November 2022.

We used publicly available data from Google Search Trends to determine which countries were quicker to adopt this name change—and understand factors that limit or facilitate its use. Specifically, we built regression models to quantify the relationship between ’mpox’ search intensity in a given country and the country’s type of political regime, robustness of sociopolitical and health systems, level of pandemic preparedness, extent of gender and educational inequalities, and temporal evolution of mpox cases through December 2023. Our results suggest that, when compared to ‘monkeypox’ search intensity, ’mpox’ search intensity was significantly higher in countries with any history of mpox outbreaks or higher levels of LGBTQ+ acceptance; meanwhile, ‘mpox’ search intensity was significantly lower in countries governed by leaders who had recently propagated infectious disease misinformation.

Among infectious diseases with stigmatizing names, mpox is among the first to be revised retrospectively. While the adoption of a given disease name will be context-specific—depending in part on its origins and the affected subpopulations—our study provides generalizable insights, applicable to future changes in disease nomenclature.
The association between limiting longstanding illness and serious psychological distress in adolescents: A secondary analysis of the UK Millennium Cohort Study
Authors: Palliser Gareth M. , Fraser Lorna K. , Mooney Kate E. , Jarvis Stuart W.
Published: June 2024

Background

Previous studies have shown associations between specific limiting longstanding illnesses and mental health difficulties using cross-sectional studies in the UK. This study explored the association between having any limiting longstanding illness and serious psychological distress or of currently receiving treatment for depression or serious anxiety at age 17 years.

Methods

A secondary analysis of the UK Millennium Cohort Study was conducted. Outcome measures were dichotomised responses from the self-administered Kessler-6 questionnaire for nonspecific psychological distress, and self-reported currently receiving treatment for depression or serious anxiety. Limiting longstanding illness data and covariates were taken from questionnaires with parents and adolescents, from birth up to age 17 years. Data were analysed using multiple binary logistic regression, first using complete-case analysis, and then using multiple imputation using chained equations.

Results

Adolescents with a history of limiting longstanding illness were at an increased odds of both serious psychological distress (odds ratio = 1.53, 95%CI = 1.27-1.86) and self-reporting currently receiving treatment for depression or serious anxiety at age 17 years (odds ratio = 3.02, 95%CI 2.24-4.07).

Conclusion

Children and young people with a limiting longstanding illness are at increased risk of having serious psychological distress, depression, and serious anxiety. Practitioners should be aware of this and routine screening for psychological distress, plus additional preventative support, may be beneficial.
Geographical distribution and the impact of socio-environmental indicators on incidence of Mpox in Ontario, Canada
Authors: Ugwu Chigozie Louisa J. , Asgary Ali , Wu Jianhong , Kong Jude , Bragazzi Nicola Luig , Orbinski James , Woldegerima Woldegebriel Assefa
Published: June 2024

Background: Ontario, being one of Canada's largest provinces, has been central to the high incidence of human Mpox. Research is scarce on how socio-environmental factors influence Mpox incidences. This study seeks to explore potential geographical correlations and the relationship between indicators of social marginalization and Mpox incidence rate in Ontario. Methodology: We used surveillance data on confirmed human Mpox cases from May 1, 2022, to March 31, 2024, extracted from the Public Health Ontario website for this study. Spatial autocorrelation of Mpox incidence was investigated using spatial methods including Moran’s Index, Getis–Ord Gi*statistic, and spatial scan statistic. Following this, we adopted a generalized Poisson regression (GPR) model to estimate the incidence rate ratios (IRRs) based on the association between Ontario PHU-level marginalization and Mpox incidence, while adjusting for age and sex. The goodness-of-fit of the models was assessed using the Akaike Information Criterion (AIC), Akaike’s Information Criterion corrected (AICc), and the Bayesian Information Criterion (BIC). Results: Spatial scan statistics, LISA, and Getis-Ord Gi*statistics revealed similar results for PHUs with the highest rates of Mpox in Ontario. Our study detected statistically significantly higher Mpox cases in Toronto, Ottawa, Peterborough, Kingston, Peel, Wellington-Dufferin-Guelph, Middlesex-London, Halton region, Brant County, Hamilton, and Haldimand-Norfolk PHUs ([[EQUATION]]). Higher rates of Mpox infection in Ontario were associated with ethnic concentration (racialized, migrants or visible minority)  [[EQUATION]]), and  male gender ( [[EQUATION]]) and residential instability ( ). Conclusion: We identified major Mpox hotspots in Toronto. According to our model results, the high incidence rate may be influenced by the greater population of internal migrant population and younger individuals. Based on these insights, we recommend targeted interventions in the high-risk neighborhoods. Efforts to improve Mpox diagnosis and promote health equity among socioeconomically vulnerable populations, including racial and ethnic minorities, should be implemented.
Neuroanatomical Features of NAA10- and NAA15-Related Neurodevelopmental Syndromes
Authors: Patel Rahi , Makwana Rikhil , Christ Carolina , Marchi Elaine , Ung Nathaniel , Harpell Randie , Miyake Christina Y. , Gropman Andrea L. , Lyon Gholson J. , Whitehead Matthew T.
Published: June 2024

Background

NAA10-related (Ogden Syndrome) andNAA15-related neurodevelopmental syndromes present with varying degrees of intellectual disability, hypotonia, congenital cardiac abnormalities, seizures, and delayed speech and motor development. While there is much data on the clinical manifestations of these conditions, there are few radiologic reports describing the neuroanatomical abnormalities present on imaging.

Objective

Our goal was to provide neuroimaging analyses for a subset of probands withNAA10-andNAA15-related neurodevelopmental symptoms and assess severity, common radiologic anomalies, and changes over time to better understand the pathophysiology of these disease processes.

Materials and Methods

Neuroimaging studies from 26 probands (18 with pathogenic variants inNAA10, 8 with pathogenic variants inNAA15) were collected and analyzed. Size of the cerebrum, brainstem, and cerebellum, as well as myelination, brain malformations, globus pallidus hyperintensity, brain lesions, 4th ventricle size, tegmentovermian angle, cisterna magna size, pituitary size, olfactory tract, palate arch, and choroid plexus abnormalities were analyzed. In depth medical histories were also collected on all probands, including genetic testing results and social, cognitive, and developmental history. The Vineland 3 Adaptive Behavior Scale was also administered to the parents to assess functional status of the probands.

Results

On average, individuals with Ogden Syndrome had 5.7 anatomical abnormalities (standard deviation (SD) = 3.0), whereas those with NAA15 related neurodevelopmental syndrome had 2.8 (SD = 2.3) (p = .02). Probands who had more anatomical abnormalities tended to score worse on Vineland assessments, suggesting a possible correlation between the two. Structural-functional anatomic differences seen were preserved such that individuals with greater defects on, for example, motor regions of their scans tested worse on motor portions of the Vineland. Probands followed longitudinally demonstrated several changes between scans, most commonly in the cerebellum, brainstem, and degree of myelination. Such changes were only observed for probands withNAA10variants in our cohort.

Conclusion

Despite clinical imaging being reported as being predominantly “normal” during routine clinical care, this analysis of a cohort of patients withNAA10-related (Ogden Syndrome) andNAA15-related neurodevelopmental syndrome by one neuroradiologist has established a range of subtle abnormalities. We hope these findings guide future research and diagnostic studies for this patient population.
Artificial Intelligence Performance in Testing Microfluidics for Point-of-Care
Authors: Doganay Mert Tunca , Chakraborty Purbali , Moukthika Sri , Jammalamadaka Soujanya , Battalapalli Dheerendranath , Draz Mohamed S.
Published: June 2024

Artificial intelligence (AI) is revolutionizing medicine by automating tasks like image segmentation and pattern recognition. These AI approaches support seamless integration with existing platforms, enhancing diagnostics, treatment, and patient care. While recent advancements have demonstrated AI superiority in advancing microfluidics for point of care diagnostics, a gap remains in comparative evaluations of AI algorithms in testing microfluidics. We conducted a comparative evaluation of AI models specifically for the two-class classification problem of identifying the presence or absence of bubbles in microfluidic channels under various imaging conditions. Using a model microfluidic system with a single channel loaded with 3D transparent objects (bubbles), we challenged each of the tested machine learning (ML) (n = 6) and deep learning (DL) (n = 9) models across different background settings. Evaluation revealed that the Random Forest ML model achieved 95.52% sensitivity, 82.57% specificity, and 97% AUC, outperforming other ML algorithms. Among DL models suitable for mobile integration, DenseNet169 demonstrated superior performance, achieving 92.63% sensitivity, 92.22% specificity, and 92% AUC. Remarkably, DenseNet169 integration into a mobile POC system demonstrated exceptional accuracy (> 0.84) in testing microfluidics at under challenging imaging settings. Our study confirms the transformative potential of AI in healthcare, emphasizing its capacity to revolutionize precision medicine through accurate and accessible diagnostics. The integration of AI into healthcare systems holds promise for enhancing patient outcomes and streamlining healthcare delivery.
Mapping the Shadows: A Comprehensive Exploration of Breast Ironing’s Effects on Women and Girls through a Systematic and Scoping Review
Authors: Ajibade Benjamin Olusola , Ubah Prince , Kainesie John , Suleiman Umma , Omoruyi Maxwell , Tolulope Olubunmi Adediran-Ibegbunam
Published: June 2024

Background

The research paper titled "Mapping the Shadows: A Comprehensive Exploration of Breast Ironing’s Effects on Women and Girls through a Systematic/Scoping Review" examines the cultural practice of breast ironing (BI) and its significant impact on the physical, psychological, and social well-being of women and girls. It explores the biopsychosocial implications of breast ironing on women, assesses knowledge and attitudes towards the practice, and analyses its prevalence and consequences.

Methods

This study employs a systematic/scoping review design following the PRISMA guidelines to collect and analyse qualitative and quantitative data. Data collection involved a comprehensive search of online databases, including EBSCO, PubMed, Google Scholar, and others. Four investigators conducted independent searches using specific keywords related to breast ironing. The inclusion criteria focused on studies examining the biopsychosocial impact of breast ironing within the past 10 years. The data were analysed using thematic analysis, chi-square tests, and logistic regression models.

Results

The practice of breast ironing results in severe physical and psychological trauma, including pain, tissue damage, infections, abscesses, and breast cancer. Psychologically, victims experience anxiety, depression, low self-esteem, and PTSD. The study found significant barriers to healthcare access due to stigma and lack of awareness. The prevalence of breast ironing is highest in the Littoral region (53%), with varying rates across other regions. Chi-square tests revealed significant relationships between BI and health outcomes, such as severe pain and family health issues (p-value < 0.001). Logistic regression indicated a strong association between BI exposure and negative health outcomes.

Conclusion

Breast ironing is a harmful cultural practice with substantial negative impacts on the health and well-being of women and girls. Comprehensive interventions, including legal measures, community education, and support services, are crucial to eradicate this practice and protect the rights and health of affected individuals.
Controlling semiconductor growth with structured de novo protein interfaces
Authors: Saragovi Amijai , Pyles Harley , Kwon Paul , Hanikel Nikita , Dávila-Hernández Fátima A. , Bera Asim K. , Kang Alex , Brackenbrough Evans , Vafeados Dionne K. , Allen Aza , Stewart Lance , Baker David
Published: June 2024

Protein design now enables the precise arrangement of atoms on the length scales (nanometers) of inorganic crystal nuclei, opening up the possibility of templating semiconductor growth. We designed proteins presenting regularly repeating interfaces presenting functional groups likely to organize ions and water molecules, and characterized their ability to bind to and promote nucleation of ZnO. Utilizing the scattering properties of ZnO nanoparticles, we developed a flow cytometry based sorting methodology and identified thirteen proteins with ZnO binding interfaces. Three designs promoted ZnO nucleation under conditions where traditional inorganic binding peptides and control proteins were ineffective. Incorporation of these interfaces into higher order assemblies further enhanced nucleation. These findings demonstrate the potential of using protein design to modulate semiconductor growth and generate protein-semiconductor hybrid materials.

One Sentence Summary

In this study we designed a library of potential inorganic binding de novo proteins and identified structured protein interfaces with the capacity to bind to and promote the growth of zinc oxide, a semiconductor material that is not observed in native systems.
Modulation of ribosomal subunit associations by eIF6 is critical for mitotic exit and cancer progression
Authors: Roshan Poonam , Biswas Aparna , Anagnos Stella , Luebbers Riley , Harish Kavya , Ahmed Sinthyia , Li Megan , Nguyen Nicholas , Zhou Gao , Tedeschi Frank , Hathuc Vivian , Lin Zhenguo , Hamilton Zachary , Origanti Sofia
Published: June 2024

Moderating the pool of active ribosomal subunits is critical for maintaining global translation rates. A factor crucial for modulating the 60S ribosomal subunits is eukaryotic translation initiation factor 6. Release of eIF6 from 60S is essential to permit 60S interactions with 40S. Here, using the N106S mutant of eIF6, we show that disrupting eIF6 interaction with 60S leads to an increase in vacant 80S. It further highlights a dichotomy in the anti-association activity of eIF6 that is distinct from its role in 60S biogenesis and shows that the nucleolar localization of eIF6 is not dependent on uL14-BCCIP interactions. Limiting active ribosomal pools markedly deregulates translation especially in mitosis and leads to chromosome segregation defects, mitotic exit delays and mitotic catastrophe. Ribo-Seq analysis of the eIF6-N106S mutant shows a significant downregulation in the translation efficiencies of mitotic factors and specifically transcripts with long 3′UTRs. eIF6-N106S mutation also limits cancer invasion, and this role is correlated with the overexpression of eIF6 only in high-grade invasive cancers suggesting that deregulation of eIF6 is probably not an early event in cancers. Thus, this study highlights the segregation of eIF6 functions and its role in moderating 80S availability for mitotic translation and cancer progression.
Revealing the Biophysics of Lamina-Associated Domain Formation by Integrating Theoretical Modeling and High-Resolution Imaging
Authors: Dhankhar Monika , Guo Zixian , Kant Aayush , Basir Ramin , Joshi Rohit , Heo Su Chin , Mauck Robert L. , Lakadamyali Melike , Shenoy Vivek B.
Published: June 2024

The interactions between chromatin and the nuclear lamina orchestrate cell type-specific gene activity by forming lamina-associated domains (LADs) which preserve cellular characteristics through gene repression. However, unlike the interactions between chromatin segments, the strength of chromatin-lamina interactions and their dependence on cellular environment are not well understood. Here, we develop a theory to predict the size and shape of peripheral heterochromatin domains by considering the energetics of chromatin-chromatin interactions, the affinity between chromatin and the nuclear lamina and the kinetics of methylation and acetylation9in human mesenchymal stem cells (hMSCs). Through the analysis of super-resolution images of peripheral heterochromatin domains using this theoretical framework, we determine the nuclear lamina-wide distribution of chromatin-lamina affinities. We find that the extracted affinity is highly spatially heterogeneous and shows a bimodal distribution, indicating regions along the lamina with strong chromatin binding and those exhibiting vanishing chromatin affinity interspersed with some regions exhibiting a relatively diminished chromatin interactions, in line with the presence of structures such as nuclear pores. Exploring the role of environmental cues on peripheral chromatin, we find that LAD thickness increases when hMSCs are cultured on a softer substrate, in correlation with contractility-dependent translocation of histone deacetylase 3 (HDAC3) from the cytosol to the nucleus. In soft microenvironments, chromatin becomes sequestered at the nuclear lamina, likely due to the interactions of HDAC3 with the chromatin anchoring protein LAP2β,increasing chromatin-lamina affinity, as well as elevated levels of the intranuclear histone methylation. Our findings are further corroborated by pharmacological interventions that inhibit contractility, as well as by manipulating methylation levels using epigenetic drugs. Notably, in the context of tendinosis, a chronic condition characterized by collagen degeneration, we observed a similar increase in the thickness of peripheral chromatin akin to that of cells cultured on soft substrates consistent with theoretical predictions. Our findings underscore the pivotal role of the microenvironment in shaping genome organization and highlight its relevance in pathological conditions.
Kinesin-1 mediates proper ER folding of the CaV1.2 channel and maintains mouse glucose homeostasis
Authors: Tanaka Yosuke , Farkhondeh Atena , Yang Wenxing , Ueno Hitoshi , Noda Mitsuhiko , Hirokawa Nobutaka
Published: June 2024

Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is a principal mechanism for systemic glucose homeostasis, of which regulatory mechanisms are still unclear. Here we show that kinesin molecular motor KIF5B is essential for GSIS through maintaining the voltage-gated calcium channel CaV1.2 levels, by facilitating an Hsp70-to-Hsp90 chaperone exchange to pass through the quality control in the endoplasmic reticulum (ER). Phenotypic analyses of KIF5B conditional knockout (cKO) mouse beta cells revealed significant abolishment of glucose-stimulated calcium transients, which altered the behaviors of insulin granules via abnormally stabilized cortical F-actin. KIF5B and Hsp90 colocalize to microdroplets on ER sheets, where CaV1.2 but not Kir6.2 is accumulated. In the absence of KIF5B, CaV1.2 fails to be transferred from Hsp70 to Hsp90 and is likely degraded via the proteasomal pathway. KIF5B and Hsc70 overexpression increased CaV1.2 expression via enhancing its chaperone binding. Thus, ER sheets may serve as the place of KIF5B- and Hsp90-dependent chaperone exchange, which predominantly facilitates CaV1.2 production in beta cells and properly enterprises GSIS against diabetes.
EhRacM differentially regulates macropinocytosis and motility in the enteric protozoan parasiteEntamoeba histolytica
Authors: Shimoyama Misato , Nakada-Tsukui Kumiko , Nozaki Tomoyoshi
Published: June 2024

Macropinocytosis is an evolutionarily conserved endocytic process that plays a vital role in internalizing extracellular fluids and particles in cells. This non-selective endocytic pathway is crucial for various physiological functions such as nutrient uptake, sensing, signaling, antigen presentation, and cell migration. While macropinocytosis has been extensively studied in macrophages and cancer cells, the molecular mechanisms of macropinocytosis in pathogens are less understood. It has been known thatEntamoeba histolytica, the causative agent of amebiasis, exploits macropinocytosis for survival and pathogenesis. Since macropinocytosis is initiated by actin polymerization, leading to the formation of membrane ruffles and the subsequent trapping of solutes in macropinosomes, actin cytoskeleton regulation is crucial. Thus, this study focuses on unraveling the role of well-conserved actin cytoskeleton regulators, Rho small GTPase family proteins, in macropinocytosis inE. histolytica. Through gene silencing of highly transcribedEhrho/Ehracgenes and following flow cytometry analysis, we identified that silencingEhracMenhances dextran macropinocytosis and affects cellular migration persistence. Live imaging and interactome analysis unveiled the cytosolic and vesicular localization of EhRacM, along with its interaction with signaling and membrane traffic-related proteins, shedding light on EhRacM’s multiple roles. Our findings provide insights into the specific regulatory mechanisms of macropinocytosis among endocytic pathways inE. histolytica, highlighting the significance of EhRacM in both macropinocytosis and cellular migration.

Author Summary

Entamoeba histolyticais an intestinal protozoan parasite that causes amoebic dysentery and liver abscesses in humans. This organism exploits macropinocytosis, a cellular process that engulfs extracellular fluids and particles, for its survival and pathogenicity. Although macropinocytosis is well-characterized in immune cells and cancer cells as it is essential for nutrient uptake, its mechanisms in pathogens, such asE. histolytica, remain less explored. Our research focused on the molecular mechanisms underpinning macropinocytosis in this parasite, specifically examining the role of Rho small GTPase family proteins. These proteins are critical regulators of the actin cytoskeleton in eukaryotic cells. Our study reveals that one specific Rho small GTPase, EhRacM, is in the maturation of macropinosomes as well as in directing linear cell migration. The physiological significance of EhRacM in regulating both macropinocytosis and migration opens new avenues for understanding the role of Rho small GTPases in these signaling pathways, which could eventually lead to the development of new control measures against diseases caused by this parasite.
A role for the putative error-prone polymeraseREV1in DNA damage and antifungal drug resistance inCandida albicans
Authors: Agyare-Tabbi Michelle R. , Uthayakumar Deeva , Francis Desiree , Maroc Laetitia , Grant Chris , McQueen Peter , Westmacott Garret , Shaker Hajer , Skulska Iwona , Gagnon-Arsenault Isabelle , Boisvert Jonathan , Landry Christian R. , Shapiro Rebecca S.
Published: June 2024

Antimicrobial-induced DNA damage, and subsequent repair via upregulation of DNA repair factors, including error-prone translesion polymerases, can lead to the increased accumulation of mutations in the microbial genome, and ultimately increased risk of acquired mutations associated with antimicrobial resistance. While this phenotype is well described in bacterial species, it is less thoroughly investigated amongst microbial fungi. Here, we monitor DNA damage induced by antifungal agents in the fungal pathogenCandida albicans, and find that commonly used antifungal drugs are able to induce DNA damage, leading to the upregulation of transcripts encoding predicted error-prone polymerases and related factors. We focus onREV1, encoding a putative error-prone polymerase, and find that while deleting this gene inC. albicansleads to increased sensitivity to DNA damage, it also unexpectedly renders cells more likely to incur mutations and evolve resistance to antifungal agents. We further find that deletion ofREV1leads to a significant depletion in the uncharacterized protein Shm1, which itself plays a role in fungal mutagenesis. Together, this work lends new insight into previously uncharacterized factors with important roles in the DNA damage response, mutagenesis, and the evolution of antifungal drug resistance.
Predicting substrates for orphan Solute Carrier Proteins using multi-omics datasets
Authors: Zhang Y. , Newstead S. , Sarkies P.
Published: June 2024

Solute carriers (SLC) are integral membrane proteins responsible for transporting a wide variety of metabolites, signaling molecules and drugs across cellular membranes. Despite key roles in metabolism, signaling and pharmacology, around one third of SLC proteins are ‘orphans’ whose substrates are unknown. Experimental determination of SLC substrates is technically challenging given the wide range of possible physiological candidates. Here, we develop a predictive algorithm to identify correlations between SLC expression levels and intracellular metabolite concentrations by leveraging existing cancer multi-omics datasets. Our predictions recovered known SLC-substrate pairs with high sensitivity and specificity compared to simulated random pairs. CRISPR loss-of-function screen data and metabolic pathway adjacency data further improved the performance of our algorithm. In parallel, we combined drug sensitivity data with SLC expression profiles to predict new SLC-drug interactions. Together, we provide a novel bioinformatic pipeline to predict new substrate predictions for SLCs, offering new opportunities to de-orphanise SLCs with important implications for understanding their roles in health and disease.
Complementary roles of EPS, T3SS and Expansin for virulence ofErwinia tracheiphila, the causative agent of cucurbit wilt
Authors: Rocha Jorge , Shapiro Lori R. , Chimileski Scott , Kolter Roberto
Published: June 2024

Erwinia tracheiphila(Smith) is a recently emerged plant pathogen that causes severe economic losses in cucurbit crops in temperate Eastern North America.E. tracheiphilais xylem restricted, and virulence is thought to be related to Exopolysaccharides (EPS) and biofilm formation, which occlude the passage of sap in xylem vessels and causes systemic wilt. However, the role of EPS and biofilm formation, and their contribution to disease in relation to other virulence loci are unknown. Here, we use deletion mutants to explore the roles of EPS, Hrp Type III secretion system (Hrp T3SS) and Expansin in plant colonization and virulence. Then, we quantify the expression of the genes encoding these factors during infection. Our results show that Exopolysaccharides are essential forE. tracheiphilasurvival in host plants, while Hrp T3SS and Expansin are dispensable for survival but needed for systemic wilt symptom development. EPS and Hrp T3SS display contrasting expression patterns in the plant, reflecting their relevance in different stages of the infection. Finally, we show that expression of theepsandhrpT3SS operons is downregulated in mildly increased temperatures, suggesting a link between expression of these virulence factors and geographic restriction ofE. tracheiphilato temperate regions. Our work highlights howE. tracheiphilavirulence is a complex trait where several loci are coordinated during infection. These results further shed light into the relationship between virulence factors and the ecology of this pathosystem, which will be essential for developing sustainable management strategies for this emerging pathogen.
Filamentous bacteriophages induce proinflammatory responses in intestinal epithelial cells
Authors: Varadan Ambarish C. , Grasis Juris A.
Published: June 2024

Bacteriophages are the dominant members of the human enteric virome and can shape bacterial communities in the gut; however, our understanding of how they directly impact health and disease is limited. Previous studies have shown that specific bacteriophage populations are expanded in patients with Crohn’s disease (CD) and ulcerative colitis (UC), suggesting that fluctuations in the enteric virome may contribute to intestinal inflammation. Based on these studies, we hypothesized that a high bacteriophage burden directly induces intestinal epithelial responses. We found that filamentous inoviruses M13 and Fd induced dose-dependent IL-8 expression in the human intestinal epithelial cell line HT-29 to a greater degree than their lytic counterparts T4 and ϕX174 did. We also found that M13, but not Fd, reduced bacterial internalization in HT-29 cells. This led us to investigate the mechanism underlying M13-mediated inhibition of bacterial internalization by examining the antiviral and antimicrobial responses in these cells. M13 upregulated Type I and III IFN expression and augmented short-chain fatty acid (SCFA)-mediated LL-37 expression in HT-29 cells. Taken together, our data establish that inoviruses directly affect human intestinal epithelial cells. These results provide new insights into the complex interactions between bacteriophages and the intestinal mucosa, which may underlie disease pathogenesis.