bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of non-charged 7.44 analogs interacting with the NHR2 domain of RUNX1-ETO and exhibiting an improved, selective antiproliferative effect in RUNX-ETO positive cells
Authors: Gopalswamy Mohanraj , Bickel David , Dienstbier Niklas , Tu Jia-Wey , Schott-Verdugo Stephan , Bhatia Sanil , Etzkorn Manuel , Gohlke Holger 
Published: June 2024

AbstractThe RUNX1/ETO fusion protein is a chimeric transcription factor in acute myeloid leukemia (AML) created by chromosomal translocation t(8;21)(q22;q22). t(8;21) abnormality is associated with 12% ofde novoAML cases and up to 40% in the AML subtype M2. Previously, we identified the small-molecule inhibitor7.44, which specifically interferes with NHR2 domain tetramerization of RUNX1/ETO, restores gene expression down-regulated by RUNX1/ETO, inhibits proliferation, and reduces RUNX1/ETO-related tumor growth in a mouse model. However, despite generally favorable physicochemical, pharmacokinetic, and toxicological properties,7.44is negatively charged at physiological pH and was predicted to have low to medium membrane permeability. Here, we identifiedM23,M27,andM10as non-charged analogs of7.44using ligand-based virtual screening,in vivohit identification, biophysical andin vivohit validation, and integrative modeling and ADMET predictions. All three compounds interact with the NHR2 domain and showKD,appvalues of 39-114 µM in Microscale Thermophoresis experiments as well asIC50values of 33-77 μM as to cell viability in RUNX1/ETO-positive KASUMI cells, i.e., are ∼5 to 10-fold more potent than7.44.M23is ∼10-fold more potent than7.44in inhibiting cell proliferation of RUNX1/ETO-positive cells.M23andM27are negligibly protonated or in a ∼1:1 ratio at physiological pH, whileM10has no (de-)protonatable group. The non-protonated species are predicted to be highly membrane-permeable, along with other favorable pharmacokinetic and toxicological properties. These compounds might serve as lead structures for the optimization of binding affinity, bioavailability, and anti-leukemic effects of compounds inhibiting RUNX1/ETO oncogenic function in t(8;21) AML.
Lipid droplets restrict phagosome formation duringCandidachallenge
Authors: Sun Wanwei , Wu Han , Zhao Guimin , Shui Qing , Zhang Lei , Luan Xiaoxi , Chen Tian , Liu Feng , Zheng Yi , Zhao Wei , Qi Xiaopeng , Liu Bingyu , Gao Chengjiang 
Published: June 2024

SUMMARYLipid droplets (LDs) are intracellular organelles which can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages. However, the function of LDs in the phagocytosis remains elusive. Here, we unveil the role of LDs in modulating phagosome formation using a fungal infection model. Specifically, LDs accumulation restricted the quantity of phagosome formation, and protected macrophages from death. Mechanistically, LDs formation competitively consumed intracellular endoplasmic reticulum membrane and altered RAC1 translocation and its GTPase activity, which resulted in limiting phagosomes formation in macrophages during fungi engulfed. Mice withHilpda-deficient macrophages were more susceptible to the lethal sequelae of systemic infection withC. albicans. Notably, administration of ATGL inhibitor Atglistatin improved host outcomes in disseminated fungal infections. Taken together, our study elucidates the mechanism of LDs in controlling phagosomes formation to avoid immune cell death, and offers a potential drug target for treatment ofC. albicansinfections.HighlightsC. albicansinfection induces triglycerides production and LD accumulation in macrophages.LD restricts the quantity of phagosome formation and protects macrophages from death.LD consumes intracellular ER membrane components and alters RAC1 translocation and its GTPase activity.Administration of ATGL inhibitor Atglistatin improves host outcomes in disseminated fungal infections.
Barriers and facilitators of Highly Active Antiretroviral Therapy (HAART) adherence among HIV-positive Women in Southern Ethiopia: A Qualitative study
Authors: Demissie Alemayehu Abebe , Rensburg Elsie Janse van 
Published: June 2024

AbstractBackgroundAdherence to Highly Active Antiretroviral Therapy (HAART) medication is the major predictor of HIV/AIDS treatment success. Poor adherence to HAART creates the risk of transmitting HIV, deteriorating health conditions, treatment failure, increased occurrences of drug-resistant HIV, morbidity and mortality. The objective of this study was to explore and describe the experiences of HAART adherence among HIV-positive women in Southern Ethiopia.MethodsSemi-structured in-depth interviews (IDIs) were conducted with 12 HIV-positive women in Southern Ethiopia who are adhering and non-adhering to HAART. Interviews were conducted in the local Amharic language and audio recorded with permission from the participants. The interviews were transcribed verbatim, coded for themes, categories and sub-categories and analyzed using a thematic data analysis technic.ResultsThe findings of the study reflected two themes: barriers and facilitators of HAART medication adherence among HIV-positive women. Barriers and facilitators were further categorized into 5 categories. These included patient-related factors, treatment-related factors, psychosocial-related factors, family and community-related factors, and healthcare services-related factors. These categories were further divided into 22 sub-categories. Busy schedule, forgetting the doses, rituals of religion, economic constraints, drug side-effects, pills burden and size, misconceptions about HIV, negative attitudinal disposition towards HAART, refusal to adhere to HAART, depression, lack of hope and courage, stigma and discrimination, relationship with healthcare providers, a working day of HAART clinic, and long waiting time were identified as barriers to HAART adherence. While, family responsibilities, reminder devices, dosage formulation, perceived benefit of HAART, family support, adherence to supporting peer groups, and adherence to counselling/education were identified as facilitators of HAART adherence.ConclusionsAdherence to HAART medication is a major challenge among HIV-positive women in Southern Ethiopia. Therefore, tailored strategies to enhance HAART medication adherence should be targeted addressing the barriers identified in the study.
Long-term outcomes of TAVI patients undergoing different pacing modality: LBBAP versus RVP
Authors: Wang Xi , Xu Yuanning , Zeng Lijun , Tan Kun , Zhang Xueli , Han Xu , Xiong Tianyuan , Zhao Zhengang , Peng Yong , Wei Jiafu , Li Qiao , He Sen , Chen Yong , Zhou Minggang , Li Xi , Wei Xin , Liang Yujia , Zhou Wenxia , Jiang Lingyun , Liu Xingbin , Meng Wei , Zhou Rui , Xiong Guojun , Dai Min , Deng Xiaojian , Feng Yuan , Chen Mao 
Published: June 2024

ABSTRACTBackgroundNew-onset permanent pacemaker implantation (PPMI) is still a common complication after transcatheter aortic valve implantation (TAVI) with adverse clinical outcomes. This study aims to investigate whether left bundle branch area pacing (LBBAP) improves long-term clinical results compared to traditional right ventricular pacing (RVP) in patients requiring PPMI following TAVI.MethodsA total of 237 consecutive patients undergoing RVP (N=117) or LBBAP (N=120) following TAVI were retrospectively included. Long-term outcomes including all-cause death, heart failure rehospitalization (HFH) and left ventricular ejection fraction (LVEF) change compared to baseline were obtained until 5 years post-TAVI.ResultsThe mean age of the overall population was 74 years with a mean surgical risk score as 4.4%. The paced QRS duration was significantly shorter in LBBAP group compared to RVP group (151 ± 18 vs. 122 ±12 ms, P<0.001). There was no difference between two groups in all-cause death (13.7% vs. 13.3%, adjusted HR: 0.76; 95% CI: 0.37 to 1.58; P=0.466) or the composite endpoint of death and HFH (29.9% vs. 19.2%, adjusted HR: 1.22; 95% CI: 0.70 to 2.13; P=0.476), however, the risk of HFH was significantly reduced in LBBAP group compared to RVP at 5 years after TAVI (21.4% vs. 7.5%, adjusted HR: 2.26; 95% CI: 1.01 to 5.08; P=0.048). There was a more marked evolution of LVEF over time in LBBAP group (P=0.046 for LVEF changes over time between groups).ConclusionsLBBAP improved long-term clinical outcomes compared to RVP in patients undergoing PPMI after TAVI in terms of less HFH and better LVEF improvement.
Predicting the effort required to manually mend auto-segmentations
Authors: He Da , Udupa Jayaram K. , Tong Yubing , Torigian Drew A. 
Published: June 2024

AbstractAuto-segmentation is one of the critical and foundational steps for medical image analysis. The quality of auto-segmentation techniques influences the efficiency of precision radiology and radiation oncology since high-quality auto-segmentations usually require limited manual correction. Segmentation metrics are necessary and important to evaluate auto-segmentation results and guide the development of auto-segmentation techniques. Currently widely applied segmentation metrics usually compare the auto-segmentation with the ground truth in terms of the overlapping area (e.g., Dice Coefficient (DC)) or the distance between boundaries (e.g., Hausdorff Distance (HD)). However, these metrics may not well indicate the manual mending effort required when observing the auto-segmentation results in clinical practice.In this article, we study different segmentation metrics to explore the appropriate way of evaluating auto-segmentations with clinical demands. The mending time for correcting auto-segmentations by experts is recorded to indicate the required mending effort. Five well-defined metrics, the overlapping area-based metric DC, the segmentation boundary distance-based metric HD, the segmentation boundary length-based metrics surface DC (surDC) and added path length (APL), and a newly proposed hybrid metric Mendability Index (MI) are discussed in the correlation analysis experiment and regression experiment. In addition to these explicitly defined metrics, we also preliminarily explore the feasibility of using deep learning models to predict the mending effort, which takes segmentation masks and the original images as the input.Experiments are conducted using datasets of 7 objects from three different institutions, which contain the original computed tomography (CT) images, the ground truth segmentations, the auto-segmentations, the corrected segmentations, and the recorded mending time. According to the correlation analysis and regression experiments for the five well-defined metrics, the variety of MI shows the best performance to indicate the mending effort for sparse objects, while the variety of HD works best when assessing the mending effort for non-sparse objects. Moreover, the deep learning models could well predict efforts required to mend auto-segmentations, even without the need of ground truth segmentations, demonstrating the potential of a novel and easy way to evaluate and boost auto-segmentation techniques.
UV LED Wastewater Disinfection: The Future is Upon Us Full-scale installation and auditing of 280nm UV LED disinfection reactor
Authors: MacIsaac Sean A , Reid Bailey , Ontiveros Carolina , Linden Karl G , Stoddart Amina K , Gagnon Graham A 
Published: June 2024

AbstractThe world’s first full-scale, 280 nm UV LED reactor for wastewater disinfection was tested at flows of 545 and 817 m3day-1. The system achieved a >3 average log reduction of total coliform at 545 m3day-1and the 817 m3day-1flow rate achieved over a >2.5 average log reduction for all operational conditions. The delivered fluence of the full-scale system ranged from 28-148 mJ cm-2and aligns with a UV auditing study that was conducted prior to the installation of the wastewater reactor. These results benchmark the performance that can be achieved by UV LED disinfection and further connect bench-scale disinfection results with full-scale performance. The approach established in this manuscript provides a novel tool for utilities when considering emerging UV disinfection technologies. In summary, this study establishes that UV LEDs are an effective wastewater disinfectant at-scale and are comparable to conventional low-pressure UV systems. This is the first instance where the efficacy of UV LEDs for municipal wastewater disinfection has been demonstrated using a large-scale installation at a functioning wastewater facility.Graphical Abstract
TBtypeR: Sensitive detection and sublineage classification of low-frequencyMycobacterium tuberculosiscomplex mixed infections
Authors: Munro Jacob E , Coussens Anna K , Bahlo Melanie 
Published: June 2024

AbstractMixed infections comprising multipleMycobacterium tuberculosisComplex (MTBC) strains are observed in populations with high incidence rates of tuberculosis (TB), yet the difficulty to detect these via conventional diagnostic approaches has resulted in their contribution to TB epidemiology and treatment outcomes being vastly underrecognised. In endemic regions, detection of all component strains is crucial for accurate reconstruction of TB transmission dynamics. Currently available tools for detecting mixed infections from whole genome sequencing (WGS) data have insufficient sensitivity to detect low-frequency mixtures with less than 10% minor strain fraction, leading to a systematic underestimation of the frequency of mixed infection. Our R package, TBtypeR, identifies mixed infections from whole genome sequencing by comparing sample data to an expansive phylogenetic SNP panel of over 10,000 sites and 164 MTBC strains. A statistical likelihood is derived for putative strain mixtures based on the observed reference and alternative allele counts at each site under the binomial distribution. This provides robust and high-resolution sublineage classification for both single- and mixed-infections with as low as 1% minor strain frequency. Benchmarking with simulatedin silicoandin vitromixture data demonstrates the superior performance of TBtypeR over existing tools, particularly in detecting low frequency mixtures. We apply TBtypeR to 5,000 MTBC WGS from a published dataset and find a 6-fold higher rate of mixed infection than existing methods. The TBtypeR R package and accompanying end-to-end Nextflow pipeline are available at github.com/bahlolab/TBtypeR.
A mechanism for telomere-specific telomere length regulation
Authors: Teplitz Gabriela M. , Pasquier Emeline , Bonnell Erin , Laurentiis Evelina De , Bartle Louise , Lucier Jean-François , Sholes Samantha , Greider Carol W. , Wellinger Raymund J. 
Published: June 2024

Summary ParagraphTelomeric DNA, composed of short, direct repeats, is of crucial importance for chromosome stability. Due to intrinsic problems with replicating this DNA, the repeat tracts shorten at each cell division. Once repeat tracts become critically short, a telomeric stress signal induces cellular senescence and division arrest, which eventually may lead to devastating age-related degenerative diseases associated with dysfunctional telomers. Conversely, maintenance of telomere length by telomerase upregulation is a hallmark of cancer. Therefore, telomere length is a critical determinant of telomere function. How telomere length is established and molecular mechanisms for telomere-specific length regulation remained unknown. Here we show that subtelomeric chromatin is a determinant for how telomere equilibrium set-length is established incis. The results demonstrate that telomerase recruitment mediated by the telomere-associated Sir4 protein is modulated on chromosome 3L in a telomere-specific way. Increased Sir4 abundance on subtelomeric heterochromatin of this specific telomere leads to telomere lengthening of only that telomere incis, but not at other telomeres. Therefore, this work describes a mechanism for a how telomere-specific repeat tract length can be established. Further, our results will force the evaluation of telomere length away from a generalized view to a more telomere-specific consideration.
ATF4 and mTOR regulate metabolic reprogramming in TGF-β-treated lung fibroblasts
Authors: Shin Kun Woo D , Atalay M Volkan , Cetin-Atalay Rengul , O’Leary Erin M , Glass Mariel E , Houpy Szafran Jennifer C , Woods Parker S , Meliton Angelo Y , Shamaa Obada R , Tian Yufeng , Mutlu Gökhan M. , Hamanaka Robert B. 
Published: June 2024

ABSTRACTIdiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that fibroblast activation is supported by metabolic reprogramming, including the upregulation of thede novosynthesis of glycine, the most abundant amino acid found in collagen protein. How fibroblast metabolic reprogramming is regulated downstream of TGF-β is incompletely understood. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote increased expression of the enzymes required forde novoglycine synthesis; however, whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single cell RNAseq data sets and found increased expression of ATF4 and mTOR metabolic targets in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.
DCXknockout ferret reveals a neurogenic mechanism in cortical development
Authors: Wang Wei , Yin Chonghai , Wen Shaonan , Liu Zeyuan , Wang Bosong , Zeng Bo , Sun Le , Zhou Xin , Zhong Suijuan , Zhang Junjing , Ma Wenji , Wu Qian , Wang Xiaoqun 
Published: June 2024

SUMMARYDoublecortin (DCX) is one of the major causal proteins leading to lissencephaly and subcortical band heterotopia in human patients. However, our understanding of this disease, as well as the function of DCX during neurogenesis, remains limited due to the absence of suitable animal models that accurately represent human phenotypes. Here, we conducted a comprehensive examination of the neocortex at different stages inDCXknockout ferrets. We corroborated the neurogenic functions ofDCXin progenitors. Loss of function of DCX led to the over-proliferation of neural progenitors and the truncation of basal processes of radial glial cells, which contributed to the thickening of cortices and the stalling of neurons underneath the cortical plate during neurogenic stages, respectively. We also present the first-ever cell atlas of the lissencephaly disease model, which embraces an almost reversed neuronal lamination distribution in the neocortex compared to the normal controls. Furthermore, we discovered alterations in molecular signatures tied to epilepsy, a condition frequently observed in lissencephaly patients. We also provided compelling evidence that the distribution of GABAergic inhibitory neurons in the cortex is intricately linked to glutamatergic excitatory neurons in a subtype-specific manner. In conclusion, our research offers new insights to expand our understanding of DCX’s functions and enrich our comprehension of lissencephaly’s intricacies.HighlightsDCXferrets phenocopy human lissencephaly and subcortical band heterotopia syndromeDCXis required for NPC proliferation and radial glial basal fiber extensionThe atlas of lissencephalic cortex is illustrated using snRNA-seq and spatial transcriptomeInhibitory neurons couple to excitatory neurons in a cell-type specific manner
Factors impacting Indian healthcare supply chain performance and influence in the public and private sector: the mediating role of blockchain technology adoption
Authors: Dhingra Sarthak , Raut Rakesh , Kumar Mukesh , Naik B. Koteswara Rao 
Published: June 2024

PurposeThis study aims to identify several perspectives that affect the adoption of blockchain technology in India (BCTA) and evaluate their impact. To study the sector’s influence on adoption and the impact of BCTA on the performance of the Indian healthcare supply chain (HSCP) using BCTA as a mediating variable.Design/methodology/approachIn this study, we first developed a conceptual model based on Organizational Information Processing Theory and Technology-Organization-Environment, then formulated hypotheses. Based on this, a questionnaire was developed, and data were gathered from experts in the Indian healthcare industry who were familiar with blockchain technology. AMOS 19 was used to analyze data using structural equation modelling.FindingsAll the factors have a significant positive influence on BCTA. Healthcare supply chain factors influenced the adoption most dominantly, followed by technological, environmental, organizational and record-keeping unit factors. Both the public and private sectors of HSCP benefited significantly from BCTA.Practical implicationsThis research work is fruitful for healthcare practitioners, top management, academicians and policymakers in assessing BCTA’s impact on the HSCP.Originality/valueWe have attempted to evaluate the possible BCTA impact on HSCP. BCTA as a mediating variable and considering different perspectives for a holistic view of adoption in the Indian context add to this work’s originality.
Halal cosmetics repurchase intention: theory of consumption values perspective
Authors: Rachman Eva Syariefah , Amarullah Dudi 
Published: June 2024

Purpose
By applying the theory of consumption value as a conceptual framework, this study aims to investigate the impact of consumption values, namely, functional value (FV), conditional value (CV), social value (SV), emotional value (EV) and epistemic value (EPV) on attitude and repurchase intention in the Halal cosmetics context.

Design/methodology/approach
Considering the increasing transmission cases of the new variant of COVID-19, online questionnaires were distributed to 233 Muslim consumers in Indonesia to collect data. The hypotheses were then validated using partial least square-structural equation modeling.

Findings
The results showed that FV, CV, SV, EV and EPV positively affect consumer attitudes toward Halal cosmetics. The attitude toward Halal cosmetics also positively affects Halal cosmetics repurchase intention.

Research limitations/implications
Two limitations are recognized for future studies, including the generalizability in consumer generation and the obscurity of what predictors determine consumer consumption values.

Practical implications
Halal cosmetics marketers must ensure that the positioning strategy and the value proposition contain elements of consumption values (functional, conditional, social, emotional and epistemic). In addition, an appropriate marketing communication strategy needs to be developed to strengthen consumer awareness and increase consumer knowledge regarding the values offered related to Halal cosmetics.

Originality/value
To the best of the authors’ knowledge, this study is the first attempt to comprehensively address the theory of consumption values by considering all consumption values to understand consumer repurchase intentions in the context of Halal cosmetics.