bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel protein Moat prevents ectopic epithelial folding by limiting Bazooka/Par3-dependent adherens junctions
Authors: Gu Lingkun , Sauceda Rolin , Brar Jasneet , Fessahaye Ferdos , Joo Minsang , Lee Joan , Nguyan Jacqueline , Teng Marissa , Weng Mo
Published: March 2024

Cortical myosin contraction and cell adhesion work together to promote tissue shape changes, but how they are modulated to achieve diverse morphogenetic outcomes remains unclear. Epithelial folding occurs via apical constriction, mediated by apical accumulation of contractile myosin engaged with adherens junctions, as in Drosophila ventral furrow formation. While levels of contractile myosin correlate with apical constriction, whether levels of adherens junctions modulate apical constriction is unknown. We identified a novel Drosophila genemoatthat maintains low levels of Bazooka/Par3-dependent adherens junctions and thereby restricts apical constriction to ventral furrow cells with high-level contractile myosin. Inmoatmutants, abnormally high levels of Bazooka/Par3-dependent adherens junctions promote ectopic apical constriction in cells with low-level contractile myosin, insufficient for apical constriction in wild type. Such ectopic apical constriction expands infolding behavior from ventral furrow to ectodermal anterior midgut, which normally forms a later circular invagination. Inmoat mutant ventral furrow, a perturbed apical constriction gradient delays infolding. Our results indicate that levels of adherens junctions can modulate the outcome of apical constriction, providing an additional mechanism to define morphogenetic boundaries.

Summary Statement

Characterization of a novel gene moat demonstrates ectopic expansion of apical constriction due to abnormally high levels of Bazooka/Par3-dependent adherens junctions without defects in early patterning gene expression.
CMTM6 maintains B cell-intrinsic CD40 expression to regulate anti-tumor immunity
Authors: Long Yiru , Chen Runqiu , Chang Wenlong , Li Fanglin , Gu Longhua , Sun Jianhua , Chen Jing , Gong Likun
Published: March 2024

Highlights

B cells participate in anti-tumor immunity by influencing the intratumoral infiltration and function of T cells;

CMTM6 cis-interacts with CD40 and inhibits ubiquitin/proteasome-mediated CD40 degradation to maintain CD40 cell membrane levels;

Loss of B cell-intrinsic CMTM6 significantly reduces CD40 signaling-mediated B cell activation, survival, differentiation, T/B cell interaction and anti-tumor immunity;

B cell-intrinsic CMTM6 deficiency leads to a significant reduction in the anti-tumor activity CD40 agonists and ICB therapy.

In Brief

Long et al. demonstrate that B-cell intrinsic CMTM6 regulates CD40 signaling and function via maintaining the cell membrane level of B-cell CD40 through ubiquitin-proteasome pathway inhibition, thereby affecting B cell function, anti-tumor B-cell immunity and the efficacy of CD40 agonist and ICB therapy.

Abstract Figure

Graphic Abstracts

The essential role of B cells and B cell intrinsic molecules in tumor immunity is beginning to be recognized. Tumor cell CMTM6 is a novel tumor immunoregulator involved in maintaining membrane levels of several important molecules, such as PD-L1 and CD58. Host CMTM6 may also play a function in the tumor microenvironment. Here, we found that CMTM6 was highly expressed in splenic B cells and tumor-infiltrating B cells. CMTM6 deficiency resulted in impaired splenic development, germinal center B cell differentiation, memory B cell differentiation, T/B cell interaction and B cell anti-tumor immune responses. Through multi-omics data mining and B-cell agonist screening, we identified that CMTM6 interacted with CD40 and maintained CD40 membrane levels in B cells. CMTM6 cis-interacts with CD40 and inhibits ubiquitin/proteasome-mediated CD40 degradation. CMTM6 deficiency led to impaired CD40 signaling-mediated B cell activation, survival, proliferation, differentiation and T/B cell interaction. In vivo, CMTM6 deficiency leads to a significant decrease in the anti-tumor activity of ICB therapy and B cell-dependent CD40 agonists. Collectively, B-cell intrinsic CMTM6 maintains B cell CD40 levels and signaling to promote B cell function and anti-tumor immunity.
Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis
Authors: Callahan Rosemary C. , Bhagavatula Geetha , Curry Jillian , Staley Alyse W. , Schaefer Rachel E. M. , Minhajuddin Faiz , Zhou Liheng , Neuhart Rane , Atif Shaikh M. , Orlicky David J. , Cartwright Ian M. , Gerich Mark , Theiss Arianne L. , Hall Caroline H. T. , Colgan Sean P. , Onyiah Joseph C.
Published: March 2024

Colorectal cancer has been linked to chronic colitis and red meat consumption, which can increase colonic iron and heme. Heme oxygenase-1 (Hmox1) metabolizes heme and releases ferrous iron, but its role in colonic tumorigenesis is not well-described. Recent studies suggest that ferroptosis, the iron-dependent form of cell death, protects against colonic tumorigenesis. Ferroptosis culminates in excessive lipid peroxidation that is constrained by the antioxidative glutathione pathway. We observed increased mucosal markers of ferroptosis and glutathione metabolism in the setting of murine and human colitis, as well as murine colonic neoplasia. We obtained similar results in murine and human colonic epithelial organoids exposed to heme and the ferroptosis activator erastin, especially induction ofHmox1. RNA sequencing of colonic organoids from mice with deletion of intestinal epithelialHmox1 (Hmox1ΔIEC) revealed increased ferroptosis and activated glutathione metabolism after heme exposure. In a colitis-associated cancer model we observed significantly fewer and smaller tumors inHmox1ΔIECmice compared to littermate controls. Transcriptional profiling ofHmox1ΔIECtumors and tumor organoids revealed increased ferroptosis and oxidative stress markers in tumor epithelial cells. In total, our findings reveal ferroptosis as an important colitis-associated cancer signature pathway, andHmox1as a key regulator in the tumor microenvironment.
Rarγ -Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer
Authors: Felice Dario De , Alaimo Alessandro , Bressan Davide , Genovesi Sacha , Marmocchi Elisa , Annesi Nicole , Beccaceci Giulia , Dalfovo Davide , Cutrupi Federico , Foletto Veronica , Lorenzoni Marco , Gandolfi Francesco , Kannan Srinivasaraghavan , Verma Chandra S. , Vasciaveo Alessandro , Shen Michael M. , Romanel Alessandro , Chiacchiera Fulvio , Cambuli Francesco , Lunardi Andrea
Published: March 2024

Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in directing body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling promotes cell lineage identity in different tissues is often missing.

Here, leveraging prostate organoid technology, we demonstrated that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and ultimately, proper specification of the prostatic lumen. Mechanistically, RA-dependent RARγ activation promotes the expression of the pioneer factor Foxa1, which synergizes with the androgen pathway for proper luminal expansion, cytoarchitecture and function.FOXA1nucleotide variants are common in human prostate and breast cancers and considered driver mutations, though their pathogenic mechanism is incompletely understood. Combining functional genetics experiments with structural modeling of FOXA1 folding and chromatin binding analyses, we discovered that FOXA1F254E255is a loss-of-function mutation leading to compromised transcriptional function and lack of luminal fate commitment of prostate progenitors.

Overall, we define RA as a crucial instructive signal for glandular identity in adult prostate progenitors. We propose deregulation of vitamin A metabolism as a risk factor for benign and malignant prostate disease, and identified cancer associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

Summary: Retinoic acid signaling orchestrates luminal differentiation of adult prostate progenitors
Cooperative involvement of zipper-interacting protein kinase (ZIPK) and the dual-specificity cell-division cycle 14A phosphatase (CDC14A) in vascular smooth muscle cell migration
Authors: Al-Ghabkari Abdulhameed , Carlson David A. , Haystead Timothy A. J. , MacDonald Justin A.
Published: March 2024

Zipper-interacting protein kinase (ZIPK) is a Ser/Thr protein kinase with regulatory involvement in vascular smooth muscle cell (VSMC) actin polymerization and focal adhesion assembly dynamics. ZIPK silencing can induce cytoskeletal remodeling with disassembly of actin stress fiber networks and coincident loss of focal adhesion kinase (FAK)-pY397 phosphorylation. The link between ZIPK inhibition and FAK phosphorylation is unknown, and critical interactor(s) and regulator(s) are not yet defined. In this study, we further analyzed the ZIPK-FAK relationship in VSMCs. The application of HS38, a selective ZIPK inhibitor, to coronary artery vascular smooth muscle cells (CASMCs) suppressed cell migration, myosin light chain phosphorylation (pT18&pS19) and FAK-pY397 phosphorylation as well. This was associated with the translocation of cytoplasmic FAK to the nucleus. ZIPK inhibition with HS38 was consistently found to suppress the activation of FAK and attenuate the phosphorylation of other focal adhesion protein components (i.e., pCas130, paxillin, ERK). In addition, our study showed a decrease in human cell-division cycle 14A phosphatase (CDC14A) levels with ZIPK-siRNA treatment and increased CDC14A with transient transfection of ZIPK. Proximity ligation assays (PLA) revealed CDC14A localized with ZIPK and FAK. Silencing CDC14A showed an increase of FAK-pY397 phosphorylation. Ultimately, the data presented herein strongly support a regulatory mechanism of FAK in CASMCs by a ZIPK-CDC14A partnership; ZIPK may act as a key signal integrator to control CDC14A and FAK during VSMC migration.
Effects of Hydrolyzed Collagen as a Dietary Supplement on Fibroblast Activation: A Systematic Review
Authors: Querido Inacio Pedro Augusto , Chalupe Felipe Augusto , Vieira Rodolfo P
Published: March 2024

Purpose

Our objective was to conduct a systematic review of the effects of hydrolyzed collagen supplementation on the proliferation and activation of fibroblasts.

Methods

The search was conducted for journals that published articles in the English language, peer-reviewed, meeting the following criteria: a) randomized clinical trials, b) randomized studies in animals or humans, c) in vitro studies, d) studies using hydrolyzed collagens or collagen peptides, d) studies assessing alterations on fibroblasts as primary or secondary outcome. We utilized the main journal databases PUBMED/WEB OF SCIENCE and ongoing reviews by PROSPERO. For bias risk and methodological quality, we used an adaptation of the Downs and Black checklist. Our review followed the PRISMA checklist, conducted from February 2024 to the first week of March 2024, by two independent researchers (P.A.Q.I. and R.P.V.).

Results

Eleven studies were included in this review, where our findings reinforce the notion that hydrolyzed collagens or collagen peptides at concentrations of 50-500 μg/ml are sufficient to stimulate fibroblasts in human and animal tissues without inducing toxicity. Different enzymatic processes may confer distinct biological properties to collagens, allowing for scenarios favoring fibroblast promotion or antioxidant effects. Lastly, collagens with lower molecular weights exhibit greater bioavailability to adjacent tissues.

Conclusion

Hydrolyzed collagens or collagen peptides with molecular sizes ranging from <3 - 3000 KDa promote the stimulation of fibroblasts in human tissues.
A single cell RNA sequence atlas of the earlyDrosophilalarval eye
Authors: Raja Komal Kumar Bollepogu , Yeung Kelvin , Li Yumei , Chen Rui , Mardon Graeme
Published: March 2024

TheDrosophilaeye has been an important model to understand principles of differentiation, proliferation, apoptosis and tissue morphogenesis. However, a single cell RNA sequence resource that captures gene expression dynamics from the initiation of differentiation to the specification of different cell types in the larval eye disc is lacking. Here, we report transcriptomic data from 13,000 cells that cover six developmental stages of the larval eye. Our data show cell clusters that correspond to all major cell types present in the eye disc ranging from the initiation of the morphogenetic furrow to the differentiation of each photoreceptor cell type as well as early cone cells. We identify dozens of cell type-specific genes whose function in different aspects of eye development have not been reported. These single cell data will greatly aid research groups studying different aspects of early eye development and will facilitate a deeper understanding of the larval eye as a model system.
Empowering High Throughput Screening of 3D Models: Automated Dispensing of Cervical and Endometrial Cancer Cells
Authors: Seymour Samantha , Cadena Ines , Johnson Mackenzie , Jenne Molly , Adem Iman , Almer Alyssa , Frankovic Rachel , Spence Danielle , Haddadin Andrea , Fogg Kaitlin C.
Published: March 2024

Purpose

Cervical and endometrial cancers pose significant challenges in women’s healthcare due to their high mortality rates and limited treatment options. High throughput screening (HTS) of cervical and endometrial cancerin vitromodels offer a promising avenue for drug repurposing and broadening patient treatment options. Traditional two-dimensional (2D) cell-based screenings have limited capabilities to capture crucial multicellular interactions, that are improved upon in three dimensional (3D) multicellular tissue engineered models. However, manual fabrication of the 3D platforms is both time consuming and subject to variability. Thus, the goal of this study was to utilize automated cell dispensing to fabricate 3D cell-based HTS platforms using the HP D100 Single Cell Dispenser to dispense cervical and endometrial cancer cells.

Methods

We evaluated the effects of automated dispensing of the cancer cell lines by tuning the dispensing protocol to align with cell size measured in solution and the minimum cell number for acceptable cell viability and proliferation. We modified our previously reported coculture models of cervical and endometrial cancer to be in a 384 well plate format and measured microvessel length and cancer cell invasion.

Results

Automatically and manually dispensed cells were directly compared revealing minimal differences between the dispensing methods. These findings suggest that automated dispensing of cancer cells minimally affects cell behavior and can be deployed to decreasein vitromodel fabrication time.

Conclusions

By streamlining the manufacturing process, automated dispensing holds promise for enhancing efficiency and scalability of 3Din vitroHTS platforms, ultimately contributing to advancement in cancer research and treatment.
Exploring the mitochondrial genomes and phylogenetic relationships of eleven Bryconidae species
Authors: Márquez Edna J. , Gómez-Chavarría Daniel A. , Alzate Juan F.
Published: March 2024

Comparative mitogenomics and its evolutionary relationships within Bryconidae remains largely unexplored. To bridge this gap, this study assembled 15 mitogenomes from 11 Bryconidae species, including five newly sequenced.Salminusmitogenomes, exceeding 17,700 bp, exhibited the largest size, contrasting with a median size of 16,848 bp in the remaining species (BryconandChilobrycon). These mitogenomes encode 37 typical mitochondrial genes, including 13 protein-coding, 2 ribosomal RNA, and 22 transfer RNA genes, and exhibit the conserved gene arrangement found in most fish species. Phylogenetic relationships, based on the maximum-likelihood method, revealed that the trans-Andean species (found in northwestern South America) clustered into two main sister clades. One clade comprised the trans-Andean species from the Pacific slope,Brycon chagrensisandChilobrycon deuterodon. The other clade grouped the trans-Andean species from the Magdalena-Cauca Basin with their cis-Andean congeners (found in eastern South America), withBrycon rubricaudaas its sister clade. The lack of monophyly within these genera indicates that the systematic classification of Bryconidae requires further examination. This study provides novel insights into mitogenome characteristics and evolutionary pathways within Bryconidae, standing as crucial information for prospective phylogenetic and taxonomic studies, molecular ecology, and provides a valuable resource for environmental DNA applications.
On the identification of differentially-active transcription factors from ATAC-seq data
Authors: Gerbaldo Felix Ezequiel , Sonder Emanuel , Fischer Vincent , Frei Selina , Wang Jiayi , Gapp Katharina , Robinson Mark D. , Germain Pierre-Luc
Published: March 2024

ATAC-seq has emerged as a rich epigenome profiling technique, and is commonly used to identify Transcription Factors (TFs) underlying given phenomena. A number of methods can be used to identify differentially-active TFs through the accessibility of their DNA-binding motif, however little is known on the best approaches for doing so. Here we benchmark several such methods using a combination of curated datasets with various forms of short-term perturbations on known TFs, as well as semi-simulations. We include both methods specifically designed for this type of data as well as some that can be repurposed for it. We also investigate variations to these methods, and identify three particularly promising approaches (a chromVAR-limma workflow with critical adjustments, monaLisa and a combination of GC smooth quantile normalization and multivariate modeling). We further investigate the specific use of nucleosome-free fragments, the combination of top methods, and the impact of technical variation. Finally, we illustrate the use of the top methods on a novel dataset to characterize the impact on DNA accessibility of TRAnscription Factor TArgeting Chimeras (TRAFTAC), which can deplete TFs – in our case NFkB – at the protein level.

Author summary

Transcription factors regulate gene expression by binding sites in the genome that often harbor a specific DNA motif. The collective accessibility of these motif-matching regions, measured by technologies such as ATAC-seq, can be used to infer the activity of the corresponding transcription factors. Here we use curated datasets of 11 TF-specific perturbations as well as 116 semi-simulated datasets to benchmark various methods for identifying factors that differ in activity between experimental conditions. We investigate important variations in the analysis and make recommendations pertaining to such analysis. Finally, we illustrate the application of the top methods to characterize the effects of a novel method for perturbing transcription factors at the protein level.
Harnessing digital tools for the management of large-scale larviciding operations: a pilot of the ZzappMalaria software system in Obuasi, Ghana
Authors: Williams Ignatius , Desewu Kwame , Asiedu Samuel , Ato Egyir Nicholas , Gluck Dan , Houri-Yafin Arnon , Fialkoff Yonata , Vigodny Arbel
Published: March 2024

Larval source management (LSM) has played a critical role in historical malaria elimination endeavors, yet its application in tropical settings has been hampered by operational hurdles and limited effectiveness. To address these issues, ZzappMalaria Ltd. developed a digital platform for the planning and implementation of LSM campaigns, the features and field efficacy of which are discussed in this paper.

Piloted in collaboration with AngloGold Ashanti Malaria Control Ltd. (AGAMal) in Obuasi, Ghana, the system, comprising a planning tool, a mobile app for fieldworkers and an online dashboard for monitoring and worker management, facilitated the detection of more than 4,000 water bodies and reduced the mosquito population by 62% for a cost of $0.24 per person protected (PPP). The data available does not provide sufficient evidence to conclusively determine whether a reduction in malaria cases occurred; nevertheless, the results underscore the potential of digitization to surmount the operational challenges of large-scale LSM campaigns.
Artificial intelligence-generated smart impression from 9.8-million radiology reports as training datasets from multiple sites and imaging modalities
Authors: Kaviani Parisa , Kalra Mannudeep K. , Digumarthy Subba R , Rodriguez Karen , Agarwal Sheela , Brooks Rupert , En Sovann , Alkasab Tarik , Bizzo Bernardo C. , Dreyer Keith J.
Published: March 2024

Importance

Automatic generation of the impression section of radiology report can help make radiologists efficient and avoid reporting errors.

Objective

To evaluate the relationship, content, and accuracy of an Powerscribe Smart Impression (PSI) against the radiologists’ reported findings and impression (RDF).

Design, Setting, and Participants

The institutional review board approved retrospective study developed and trained an PSI algorithm (Nuance Communications, Inc.) with 9.8 million radiology reports from multiple sites to generate PSI based on information including the protocol name and the radiologists-dictated findings section of radiology reports. Three radiologists assessed 3879 radiology reports of multiple imaging modalities from 8 US imaging sites. For each report, we assessed if PSI can accurately reproduce the RDF in terms of the number of clinically significant findings and radiologists’ style of reporting while avoiding potential mismatch (with the findings section in terms of size, location, or laterality). Separately we recorded the word count for PSI and RDF. Data were analyzed with Pearson correlation and paired t-tests.

Main Outcomes and Measures

The data were ground truthed by three radiologists. Each radiologists recorded the frequency of the incidental/significant findings, any inconsistency between the RDF and PSI as well as the stylistic evaluation overall evaluation of PSI. Area under the curve (AUC), correlation coefficient, and the percentages were calculated.

Results

PSI reports were deemed either perfect (91.9%) or acceptable (7.68%) for stylistic concurrence with RDF. Both PSI (mismatched Haller’s Index) and RDF (mismatched nodule size) had one mismatch each. There was no difference between the word counts of PSI (mean 33±23 words/impression) and RDF (mean 35±24 words/impression) (p>0.1). Overall, there was an excellent correlation (r= 0.85) between PSI and RDF for the evolution of findings (negative vs. stable vs. new or increasing vs. resolved or decreasing findings). The PSI outputs (2%) requiring major changes pertained to reports with multiple impression items.

Conclusion and Relevance

In clinical settings of radiology exam interpretation, the Powerscribe Smart Impression assessed in our study can save interpretation time; a comprehensive findings section results in the best PSI output.
Pattern, treatment modalities and radiological outcome of pediatric femoral shaft fractures treated in Northern,Tanzania
Authors: Kilawa Shindo I. , Pallangyo Anthony J. , Maya Elifuraha G. , Temu Rogers J. , Mandari Faiton N. , Olotu Frank I. , Ofunguo Estomick K. , Sadiq Adnan M. , Massawe Honest H. , Shirima Octavian , Shoo Reginald
Published: March 2024

Background

Femoral shaft fracture is among the most common causes of paediatric hospitalisation, mortality and morbidity worldwide. There is no clear option that is preferable to other treatment modalities, especially between 5 to 16 years and published studies are scarce on radiological outcomes in Sub-Saharan Africa.This study aimed to determine the pattern, treatment modalities and radiological outcome of the paediatric femoral fractures treated at KCMC.

Methodology

A cross-sectional study was conducted for all children with femoral shaft fractures treated at Kilimanjaro Christian Medical Centre from 1stJanuary 2018 to 31stDecember 2022. The approval to conduct the research was obtained from Kilimanjaro College Research Ethics and Review Committee (CRERC) with ethical clearance Reg NO PG 88/2022. In our study we used secondary data and the permission to conduct the research was obtained from KCMC, hence no formal consent was required from patients/parents.The data was accessed from the files and Elecronic Health Management system (EHMS) from 01/04/2023 to 31/07/2023.The radiological outcome; shortening, angulations in six weeks and fracture union, 12 weeks post-management were reviewed with the involvement of a consultant radiologist and the orthopaedic surgeon to obtain the precise information and were recorded on the extraction sheet.

Results

This study included 230 study participants who met the inclusion criteria. The mean age of participants was 9.1 (5.1) years, 41.3%, was aged 6 – 12 years, 82.2% were males, 45.7% were involved in a MTC, and 83.5% had no health insurance. The commonest fracture type was 92.6% closed, 48.7% transverse, and 65.% right side. Non-operatively was used in 50.9% of which 76.8% were treated with late hip Spica. Of those treated operatively, 61.1% were plating.

The majority had good radiological outcomes with acceptable solid union, angulation and shortening. Those patients who were not operated had 94% lower odds of satisfactory radiological outcomes than those who were operated ( AOR=0.06, 95% CI: 0.01 – 0.27 and p<0.001) whereas other factors were not statistically significant.

Conclusion

The majority of the study participants were male and were involved in MTC as the commonest mechanism of injury. Most had closed fractures that mainly presented on the right side and transverse fractures were the most common type. The hip Spica was common non-operatively option; however, plating was the most common operative option. Treatment modality substantially affected radiological outcomes and was statistically significant.
The Relationship Between Neighborhood Safety, Paternal Presence and Somatic Symptoms of Dissociation in Children
Authors: Pacelli Jenna
Published: March 2024

Introduction

Child exposure to prolonged stressful home environments can lead to life-long patterns that are later misdiagnosed in adulthood as anxiety disorders, ADHD and depressive disorders, among others. In theory, paternal involvement and neighborhood safety are strong buffers against toxic stress and therefore dissociative symptoms in children. The relationship between paternal involvement and rates of violence in the neighborhood and rates of dissociative symptoms in children are not yet fully understood. This study investigates the relationship between paternal involvement or neighborhood safety on somatic symptoms of dissociation in children.

Methods

This was a retrospective study based on the open-source dataset from Welfare, Children, and Families: A Three-City Study, Dataset 0005 (Angel et al., 2012). A cross-tab analysis investigated the relationship between 1) the likelihood of neighborhood assaults and 2) how often the child saw/spoke to their father in the last year with the likelihood of a child having a) concentration issues, b) confusion, c) being lost in thought, d) hearing voices and e) staring blankly.

Results

Results show that children who lived in neighborhoods where there were more muggings and assaults were more likely to be staring blankly and have concentration problems. Children who saw or talked to their father less were more likely to have concentration problems. Lastly, children who saw their fathers less often were more likely to hear voices that were not there.

Conclusion

This study showed a relationship between rates of violence in the neighborhood and paternal presence and symptoms of dissociation in children. This suggests that the lived experience of the child affects their cognition and can be impacted by living in unsafe areas and not being able to see or speak with their father. Dissociative symptoms are linked with an increased risk of substance abuse, suicide attempts, heart disease, cancer, and skeletal fractures. Understanding factors that affect dissociation will provide opportunities to prevent childhood dissociation.
ASSESSING THE NET FINANCIAL BENEFITS OF EMPLOYING DIGITAL ENDPOINTS IN CLINICAL TRIALS
Authors: DiMasi Joseph A. , Dirks Abigail , Smith Zachary , Valentine Sarah , Goldsack Jennifer C. , Metcalfe Thomas , Grewal Upinder , Leyens Lada , Conradi Ute , Karlin Daniel , Maloney Lesley , Getz Kenneth A. , Hartog Bert
Published: March 2024

Background

In the last few decades developers of new drugs, biologics, and devices have increasingly leveraged digital health technologies (DHTs) to assess clinical trial digital endpoints. To our knowledge, a comprehensive assessment of the financial net benefits of digital endpoints in clinical trials has not been conducted.

Data and Methods

We obtained data from the Digital Medicine Society (DiMe) Library of Digital Endpoints and the U.S. clinical trials registry, ClinicalTrials.gov. The benefit metrics are changes in trial phase duration and enrollment associated with the use of digital endpoints. The cost metric was obtained from an industry survey of the costs of including digital endpoints in clinical trials. We developed an expected net present value (eNPV) model of the cash flows for new drug development and commercialization to assess financial value. The value measure is the increment in eNPV that occurs when digital endpoints are employed. We also calculated a return on investment (ROI) as the ratio of the estimated increment in eNPV to the mean digital endpoint implementation cost.

Results

For phase 2 trials, the increase in eNPV varied from $2.2 million to $3.3 million, with ROIs between 32% to 48% per indication. The net benefits were substantially higher for phase 3 trials, with the increase in eNPV varying from $27 million to $48 million, with ROIs that were four to seven times the investment.

Conclusions

The use of digital endpoints in clinical trials can provide substantial extra value to sponsors developing new drugs, with high ROIs.
Neurofilament light and glial fibrillary acidic protein in mood and anxiety disorders: A systematic review and meta-analysis
Authors: Kang Matthew JY , Grewal Jasleen , Eratne Dhamidhu , Malpas Charles , Chiu Wei-Hsuan , Katisko Kasper , Solje Eino , Santillo Alexander F , Mitchell Philip B. , Hopwood Malcolm , Velakoulis Dennis
Published: March 2024

Abstract

Background

Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuronal injury measurable in cerebrospinal fluid (CSF) and blood. Despite their potential as diagnostic tests for neurodegenerative disorders, it is unclear how they behave in mood and anxiety disorders. We conducted a systematic review and meta-analysis to investigate whether NfL and GFAP concentrations were altered in adults with mood and anxiety disorders compared to healthy controls.

Methods

The study was prospectively registered on PROSPERO (CRD42023434617). We followed the PRISMA guidelines, searched PubMed, Web of Science, PsycINFO, MEDLINE and Embase up to the 31/05/2023, and assessed relevant studies and their risk of bias. The primary outcome was the standardised mean difference (SMD) and 95% confidence interval (95% CI) of NfL and GFAP concentrations, which was pooled using a random-effects model adopting the restricted maximum likelihood estimator.

Results

Twenty-one studies met inclusion criteria, comprising of 2327 individuals (695 major depression, 502 bipolar disorder, and 1130 controls). When we compared people with major depression and controls, there was no difference in NfL (SMD = 0.29; 95% CI: -0.10, 0.68) nor GFAP (SMD = 0.47; 95% CI: -0.74, 1.68). In people with bipolar disorder, NfL was significantly elevated compared to controls (SMD = 0.58; 95% CI: 0.16, 0.99). However, the subgroup analysis including more sensitive assay kits (blood Simoa and CSF ELISA), found no significant difference (SMD = 0.40; 95% CI: -0.04, 0.85). Only one study studied GFAP in bipolar disorder. No studies explored NfL nor GFAP concentrations in anxiety disorders.

Discussion

We found that NfL and GFAP concentrations were not elevated in depression. In bipolar disorder, NfL concentration was elevated, though not in the sensitivity analysis. Our study informs clinicians about how to interpret these emerging biomarkers in determining whether a person’s symptoms are caused by a neurodegenerative or mood disorder.
Effects of individual components of remote monitoring for implantable cardioverter defibrillators or cardiac resynchronisation therapy defibrillators: protocol for a systematic review and component network meta-analysis
Authors: Okazaki Makiko , Sekiguchi Natsuko , Sahashi Yuki , Noma Hisashi , Mihara Takahiro
Published: March 2024

Introduction

Currently, the standard of care for patients with cardiac implantable electronic devices (CIEDs) such as implantable cardioverter-defibrillators (ICD) and cardiac resynchronisation therapy-defibrillators (CRT-D) involves a combination of in-person outpatient visits and remote monitoring (RM). RM consists of scheduled remote device interrogation and automated transmission of prespecified alerts (alert transmission) at varying frequencies depending on manufacturers and institutions. However, the effects of RM factors on prognosis remain unclear. This systematic review and component network meta-analysis (CNMA) will aim to investigate which RM components (device interrogation, alert transmission, and data transmission frequency) have the greatest impact on prognosis in patients with ICD or CRT-D.

Methods and analysis

A systematic review will be conducted using MEDLINE (PubMed), Embase, the Cochrane Central Register of Controlled Trials, the Web of Science, Clinical Trials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), the European Union Clinical Trials Register (EU-CTR), and the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR). We will include randomised controlled trials (RCTs) assessing the effect of RM on patient outcomes in individuals with ICD or CRT-D. The primary outcome will be hospitalisation due to cardiovascular disease, heart failure, and device-related complications. Two authors will independently conduct literature screening, data extraction, and risk of bias assessment. Random-effects model pairwise meta-analysis, random-effects network meta-analysis (NMA), and additive CNMA will be applied in data synthesis. To assess the quality of evidence, we will employ the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for pairwise meta-analysis and the Confidence in Network Meta-Analysis (CINeMA) approach for NMA.

Ethics and dissemination

Ethics approval is not required as this study will use existing published data. The results will be submitted for publication in a peer-reviewed journal.

PROSPERO registration number

CRD42024517406.
The Association between Active Membership in Voluntary Organizations and Homonegativity
Authors: Khanehpaza Amirhossein , Pongpirul Krit , Jeeyapant Atthanee
Published: March 2024

Homonegativity adversely affects the health and well-being of homosexuals in society, making it vital to identify factors associated with it. This study investigates whether active membership in voluntary organizations correlates with homonegativity. We analyzed the latest World Values Survey dataset, spanning 2017 to 2022, which encompasses 63 countries. Our findings suggest that active membership in certain voluntary organizations correlates with homonegativity levels among both men and women across various age groups. Specifically, active participation in sports or recreational organizations, professional associations, art, music, or educational organizations, and humanitarian or charitable organizations was found to be negatively correlated with homonegativity in specific gender-age groups, albeit with varying degrees of association strength. We postulate that this correlation might hint at causation, suggesting that active membership in these organizations promotes greater tolerance towards homosexuals and homosexuality. Furthermore, our analysis indicates that demographic and socio-economic variables, the political freedom of the respondent’s country, and the respondent’s life satisfaction are also linked to homonegativity.
Integrated group antenatal and pediatric care in Haiti: A comprehensive care accompaniment model
Authors: Jean-Baptiste Meredith C. , Julmisse Marc , Adeyemo Oluwatosin , Julmiste Thamar , Illuzzi Jessica L.
Published: March 2024

Introduction

The J9 Plus (J9) maternal-child accompaniment program is based on four pillars: group antenatal care (GANC), group pediatric care, psychosocial support, and community-based care. We aimed to evaluate the impact of the J9 model of care on perinatal outcomes.

Methodology

We conducted a convergent mixed methods study of maternal-newborn dyads born in 2019 at Hôpital Universitaire de Mirebalais. Quantitative data was collected retrospectively to compare dyads receiving J9 care to usual care. A secondary analysis of qualitative data described patient perspectives of J9 care.

Results

Antenatal care attendance was significantly higher among women in J9 (n=524) compared to usual care (n=523), with 490(93%) and 189(36%) having >4 visits, respectively; p <0.001, as was post-partum visit attendance [268(51%) compared to 82(16%), p<0.001] and use of post-partum family planning methods [99(19%) compared to 47(9%), p=0.003]. Incidence of severe pre-eclampsia was significantly lower in the J9 group [44(9%)] compared to the usual care group [74(14%)], p <0.001. Maternal and neonatal mortality and low birth weight did not differ across groups, but with earlier interventions, cesarean delivery [103(20%) and 82(16%), p<0.001] and preterm birth [169 (34%)] and 128 (27%), p=0.041] were higher in the J9 group compared to usual care, respectively. In the qualitative analysis, ease of access to high-quality care, meaningful social support, and maternal empowerment through education were identified as key contributors to these outcomes.

Conclusion

Compared to usual care, the J9 Plus maternal-child accompaniment model of care is associated with increased engagement in antenatal and postpartum care, increased utilization of post-partum family planning, and lower rates of severe pre-eclampsia, which remains a leading cause of maternal mortality in Haiti. The J9 accompaniment approach to care is an empowering model that has the potential to be replicated in similar settings to improve quality of care and outcomes globally.
Protein complex heterogeneity and topology revealed by electron capture charge reduction and surface induced dissociation
Authors: Shaw Jared B. , Harvey Sophie R. , Du Chen , Xu Zhixin , Edgington Regina M. , Olmedillas Eduardo , Saphire Erica Ollmann , Wysocki Vicki H.
Published: March 2024

We illustrate the utility of native mass spectrometry (nMS) combined with a fast, tunable gas-phase charge reduction, electron capture charge reduction (ECCR), for the characterization of protein complex topology and glycoprotein heterogeneity. ECCR efficiently reduces the charge states of tetradecameric GroEL, illustrating Orbitrapm/zmeasurements to greater than 100,000m/z. For pentameric C-reactive protein and tetradecameric GroEL, our novel device combining ECCR with surface induced dissociation (SID) reduces the charge states and yields more topologically informative fragmentation. This is the first demonstration that ECCR yields more native-like SID fragmentation. ECCR also significantly improved mass and glycan heterogeneity measurements of heavily glycosylated SARS-CoV-2 spike protein trimer and thyroglobulin dimer. Protein glycosylation is important for structural and functional properties and plays essential roles in many biological processes. The immense heterogeneity in glycosylation sites and glycan structure poses significant analytical challenges that hinder a mechanistic understanding of the biological role of glycosylation. Without ECCR, average mass determination of glycoprotein complexes is available only through charge detection mass spectrometry or mass photometry. With narrowm/zselection windows followed by ECCR, multiple glycoformm/zvalues are apparent, providing quick global glycoform profiling and providing a future path for glycan localization on individual intact glycoforms.
Generative interpolation and restoration of images using deep learning for improved 3D tissue mapping
Authors: Joshi Saurabh , Forjaz André , Sang Han Kyu , Shen Yu , Queiroga Vasco , Xenes Daniel , Matelsk Jordan , Wester Brock , Munoz Barrutia Arrate , Kiemen Ashley L. , Wu Pei-Hsun , Wirtz Denis
Published: March 2024

The development of novel imaging platforms has improved our ability to collect and analyze large three-dimensional (3D) biological imaging datasets. Advances in computing have led to an ability to extract complex spatial information from these data, such as the composition, morphology, and interactions of multi-cellular structures, rare events, and integration of multi-modal features combining anatomical, molecular, and transcriptomic (among other) information. Yet, the accuracy of these quantitative results is intrinsically limited by the quality of the input images, which can contain missing or damaged regions, or can be of poor resolution due to mechanical, temporal, or financial constraints. In applications ranging from intact imaging (e.g. light-sheet microscopy and magnetic resonance imaging) to sectioning based platforms (e.g. serial histology and serial section transmission electron microscopy), the quality and resolution of imaging data has become paramount.

Here, we address these challenges by leveraging frame interpolation for large image motion (FILM), a generative AI model originally developed for temporal interpolation, for spatial interpolation of a range of 3D image types. Comparative analysis demonstrates the superiority of FILM over traditional linear interpolation to produce functional synthetic images, due to its ability to better preserve biological information including microanatomical features and cell counts, as well as image quality, such as contrast, variance, and luminance. FILM repairs tissue damages in images and reduces stitching artifacts. We show that FILM can decrease imaging time by synthesizing skipped images. We demonstrate the versatility of our method with a wide range of imaging modalities (histology, tissue-clearing/light-sheet microscopy, magnetic resonance imaging, serial section transmission electron microscopy), species (human, mouse), healthy and diseased tissues (pancreas, lung, brain), staining techniques (IHC, H&E), and pixel resolutions (8 nm, 2 µm, 1mm). Overall, we demonstrate the potential of generative AI in improving the resolution, throughput, and quality of biological image datasets, enabling improved 3D imaging.
To prosper, live long: understanding the sources of reproductive skew and extreme reproductive success in structured populations
Authors: Snyder Robin E. , Ellner Stephen P.
Published: March 2024

In many species, a few individuals produce most of the next generation. How much of this reproductive skew is driven by variation among individuals in fixed traits, how much by external factors, and how much by random chance? And what does it take to have truly exceptional lifetime reproductive output (LRO)? In the past, we and others have partitioned the variance of LRO as a proxy for reproductive skew. Here we explain how to partition LRO skewness itself into contributions from fixed trait variation; four forms of ''demographic luck'' (birth state, fecundity luck, survival trajectory luck, and growth trajectory luck); and two kinds of ``environmental luck'' (birth environment, and environment trajectory). Each of these is further partitioned into contributions at different ages. We also determine what we can infer about individuals with exceptional LRO. We find that reproductive skew is largely driven by random variation in lifespan, and exceptional LRO generally results from exceptional lifespan. Other kinds of luck frequently bring skewness down, rather than increasing it. In populations where fecundity varies greatly with environmental conditions, getting a good year at the right time can be an alternate route to exceptional LRO, so that LRO is less predictive of lifespan.
Asynchronous temporal variance in learning behaviour and neural gene expression in a butterfly
Authors: Ter Yi Ting , Westerman Erica L.
Published: March 2024

Mate preference learning, including imprinting-like learning, is pervasive across animal taxa, and can affect the selection and maintenance of certain phenotypes. However, not much is known about the temporal dynamics behind imprinting-like learning, or the genetic underpinnings underlying it. To uncover the temporal dynamics of imprinting-like learning, from both a behavioural and transcriptional perspective, we conducted learning and RNA-Seq time series using the butterflyBicyclus anynana, a species where both sexes learn mate preferences. We exposed females to an unfamiliar, unpreferred male phenotype (4-spotted male) for five different exposure (training) periods, ranging from 30 minutes to three hours, and recorded their choice between the preferred, familiar male phenotype (2-spotted) and 4-spotted males in mate choice trials conducted two days after training. We also assessed differential gene expression of naïve females and females exposed to trainer males for these same five exposure periods, to identify temporal patterns in gene expression associated with learning. While we found that the longest exposure had the strongest effect on preference learning, we did not observe a linear effect of exposure time on learning. We also show that the highest peak of differentially expressed genes (DEGs) was after one hour of exposure. While a number of genes were uniquely DE at each time point, one gene, associated with transcription initiation, was differentially expressed during learning across all five time points. We observed a similar decreasing trend in both gene expression and learned response after 1.5 hours of exposure, offering new insights to possible attention and forgetting mechanisms. Therefore, our results indicate that both gene expression and learning are temporally dynamic, and not linear through time. They also highlight the role of transcription in mate preference learning and memory formation in Lepidoptera, and illustrate that imprinting-like learning may exhibit similar molecular temporal dynamics as associative learning.