bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting the efficacy of BH3 mimetics through the profiling of multiple protein complexes in acute myeloid leukemia
Authors: Chun Changju , Byun Ja Min , Cha Minkwon , Lee Hongwon , Choi Byungsan , Kim Hyunwoo , Hong Saem , Lee Yunseo , Park Hayoung , Koh Youngil , Yoon Tae-Young 
Published: January 2023

AbstractBH3 mimetics are protein-protein interaction (PPI) inhibitors that saturate anti-apoptotic proteins in the BCL2 family to induce apoptosis in cancer cells, a prominent example of protein complex-targeting therapies. Despite the remarkable success of the BH3 mimetic ABT-199 in treating hematological malignancies, only a fraction of patients respond to ABT-199 and eventually develop resistance, necessitating the predictive biomarkers for both initial responses and resistance development. We here used the single-molecule pull-down and co-immunoprecipitation platform to quantify more than 20 different types of PPI complexes using ∼1.2×106cells in total, revealing the rewired status of the BCL2 family PPI network. By comparing the obtained multi-dimensional data with BH3 mimetic efficacies determinedex vivo, we constructed an analysis model for ABT-199 efficacy that designates the BCL2-BAX and BCLxL-BAK complexes as the primary mediators of drug effectiveness and resistance. We then applied this model to assist in therapeutic decision-making for acute myeloid leukemia patients in a prospective manner. Our work demonstrates a capability for the extensive characterization of PPI complexes in clinical specimens, potentially opening a new avenue of precision medicine for protein complex-targeting therapies.
Mental health services implementation in Colombia – a systematic review
Authors: Alarcón Garavito Germán Andrés , Burgess Rochelle , Dedios Sanguinetti María Cecilia , Peters Laura E.R. , San Juan Norha Vera 
Published: January 2023

AbstractColombia’s mental health services have a complex history shaped by 60 years of armed conflict, a predominantly clinical approach to mental health, and social factors such as inequities and stigma. The 1990 Caracas declaration proposed a shift towards decentralised community mental health services and interventions based on the recovery approach and emphasis on social determinants of mental health in the Americas. Colombia has adopted these approaches in its legal and practical framework in recent years, but implementation has been uneven. This systematic review aims to contribute to mental health services understanding in Colombia by reviewing published studies about mental health services and interventions.A search was conducted to explore peer-reviewed studies on Colombian mental health services across five databases (Medline, PubMed, Scopus, Scielo and BVS [Biblioteca Virtual de Salud in Spanish]) on papers published in the last ten years and without language restrictions. The Consolidated Framework for Implementation Research (CFIR) was used to structure the analysis and identify barriers and facilitators during the implementation of mental health services. We adapted the CFIR to attend to gender, race and age informed by the Socio-Political Economy of Global Mental Health framework, given the importance of these factors to the Colombian health landscape.1 530 records were identified, and 12 articles met all inclusion criteria and were included in the analysis. 8 papers described substance use disorders services, 11 involved multidisciplinary healthcare professionals, and 7 were implemented at a local scale. The primary barriers to implementation were the lack of coordination, high workloads, and low funding. Facilitators included the use of protocols, and the involvement of communities, stakeholders, users, and external champions.Findings suggest the continued importance of community and recovery approaches and efforts to improve coordination between multi-sector actors involved in the mental health spaces (e.g., public, and private organisations, users and their families).
“Climate change and health?”: Knowledge and perceptions among key stakeholders in Puducherry, India
Authors: Shrikhande Shreya S , Merten Sonja , Cambaco Olga , Lee Tristan , Lakshmanasamy Ravivarman , Röösli Martin , Dalvie Mohammad Aqiel , Utzinger Jürg , Cissé Guéladio 
Published: January 2023

AbstractIntroductionClimate change has far-reaching impacts on human health, which often differ by contextual vulnerabilities and region, with low-and middle income-countries being particularly vulnerable. Recognizing this, India has launched regional climate change and health action plans, the development, strengthening and implementation of which partially depends on how well stakeholders understand the topic. As little is known about this topic, our study aimed to better understand the knowledge and perceptions on the impacts of climate change on health amongst key stakeholders in Puducherry, India.MethodsWe conducted a qualitative study employing key informant interviews with medical doctors, researchers, environmentalists and governmental officials working on the climate change agenda from Puducherry. A total of 16 interviews were conducted. Half of the participants were practicing medical doctors while the other half consisted of medical researchers and government officials. The findings were analysed using the framework method, which allowed for data driven thematic analysis.ResultsWe elucidated that despite elaborating the direct and indirect impacts of climate change on health, there is insufficient education and knowledge about the topic among participants. Knowledge of the public health burden and vulnerabilities influenced the perceived health risks from climate change, with some level of scepticism on the impacts on non-communicable diseases, such as cardiovascular diseases. There was also a felt need for multi-level awareness and intervention programs targeting all societal levels along with recommendations for educational changes and adaptation measures in the region.ConclusionThis study identified a gap in the knowledge and understanding of health impacts of climate change among key stakeholders in Puducherry. It also identified region specific vulnerabilities that can be taken into consideration for strengthening the region’s climate change and health adaptation policy. In light of limited research on this topic, especially in a developing settings, our study lends to an improved understanding of how key stakeholders perceive the impacts of climate change on health.
DksA, ppGpp and RegAB regulate nitrate respiration inParacoccus denitrificans
Authors: Ray Ashvini , Spiro Stephen 
Published: January 2023

ABSTRACTThe periplasmic (NAP) and membrane-associated (Nar) nitrate reductases ofParacoccus denitrificansare responsible for nitrate reduction under aerobic and anaerobic conditions, respectively. Expression of NAP is elevated in cells grown on a relatively reduced carbon and energy source (such as butyrate); it is believed that NAP contributes to redox homeostasis by coupling nitrate reduction to the disposal of excess reducing equivalents. Here we show that deletion of eitherdksA1(encoding one of twodksAhomologs in theP. denitrificansgenome) orrelA/spoT(encoding a bifunctional ppGpp synthetase and hydrolase) eliminates the butyrate-dependent increase innappromoter and NAP enzyme activity. We conclude that ppGpp likely signals growth on a reduced substrate and, together with DksA1, mediates increased expression of the genes encoding NAP. Support for this model comes from the observation thatnappromoter activity is increased in cultures exposed to a protein synthesis inhibitor that is known to trigger ppGpp synthesis in other organisms. We also show that, under anaerobic growth conditions, the redox-sensing RegAB two-component pair acts as a negative regulator of NAP expression and as a positive regulator of expression of the membrane-associated nitrate reductase Nar. ThedksA1andrelA/spoTgenes are conditionally synthetically lethal; the double mutant has a null phenotype for growth on butyrate and other reduced substrates while growing normally on succinate and citrate. We also show that the seconddksAhomolog (dksA2) andrelA/spoThave roles in regulation of expression of the flavohemoglobin Hmp and in biofilm formation.IMPORTANCEParacoccus denitrificansis a metabolically versatile Gram-negative bacterium that is used as a model for studies of respiratory metabolism. The organism can utilize nitrate as an electron acceptor for anaerobic respiration, reducing it to dinitrogen via nitrite, nitric oxide, and nitrous oxide. This pathway (known as denitrification) is important as a route for loss of fixed nitrogen from soil and as a source of the greenhouse gas nitrous oxide. Thus, it is important to understand those environmental and genetic factors that govern flux through the denitrification pathway. Here we identify four proteins and a small molecule (ppGpp) which function as previously unknown regulators of expression of enzymes that reduce nitrate and oxidize nitric oxide.
Knocking out alpha-synuclein in melanoma cells downregulates L1CAM and decreases motility
Authors: Gajendran Nithya , Rajasekaran Santhanasabapathy , Witt Stephan N. 
Published: January 2023

AbstractThe Parkinson’s disease (PD) associated protein, alpha-synuclein (α-syn/SNCA), is highly expressed in aggressive melanomas, which raises the possibility that α-syn has a pro-survival function in melanoma. Herein, we asked whether α-syn modulates the expression of the pro-oncogenic adhesion molecules L1CAM and N-cadherin. We used two human melanoma cell lines (SK-MEL-28, SK-MEL-29),SNCA-knockout (KO) clones, and two human SH-SY5Y neuroblastoma cell lines. In the melanoma lines, loss of α-syn expression resulted in significant decreases in the expression of L1CAM and N-cadherin and concomitant significant decreases in motility. On average, there was a 75% reduction in motility in the fourSNCA-KOs tested compared to control cells. Strikingly, comparing neuroblastoma SH-SY5Y cells that have no detectable α-syn to SH-SY5Y cells that stably express α-syn (SH/+αS), we found that expressing α-syn increased L1CAM and single-cell motility by 54% and 597%, respectively. The reduction in L1CAM level inSNCA-KO clones was not due to a transcriptional effect, rather we found that L1CAM is more efficiently degraded in the lysosome inSNCA-KO clones than in control cells. We propose that α-syn is pro-survival to melanoma (and possibly neuroblastoma) because it promotes the intracellular trafficking of L1CAM.
RepairSwitch: simultaneous functional assessment of homologous recombination vs end joining DNA repair pathways in living cells
Authors: Steinberg Ruchama C. , Liu Jianyong , Vaghasia Ajay M. , Giovinazzo Hugh , Pham Minh-Tam , Tselenchuk Dimitri , Chikarmane Roshan , Haffner Michael C. , Nelson William G. , Yegnasubramanian Srinivasan 
Published: January 2023

ABSTRACTDNA repair pathways are frequently defective in human cancers. DNA double strand breaks (DSBs) are most often repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ). Alterations in repair pathways can indicate sensitivity to therapeutic agents such as PARP inhibitors, cisplatin, and immunotherapy. Thus, functional assays to measure rates of HR and NHEJ are of significant interest. Several methods have been developed to measure rates of HR or NHEJ; however, there is a need for functional cell-based assays that can measure rates by both major DNA DSB pathways simultaneously. Here, we describe the RepairSwitch assay, a flow cytometry assay to assess rates of HR and NHEJ mediated repair of Cas9 programmed DSB simultaneously using a novel fluorescence switching reporter system. The assay exhibits low background signal and is capable of detecting rare repair events in the 1 in 10,000 range. We demonstrate the utility of RepairSwitch by measuring the potency of inhibitors of ATM (KU-60019, KU-55933), DNA-PK (NU7441), and PARP (Olaparib) on modulating DSB repair rates in HEK293FT cells. The selective ATM inhibitor KU-60019 inhibited HR rates with IC50 of 915 nM. Interestingly, KU-60019 exposure led to a dose responsive increase in rates of NHEJ. In contrast, the less selective ATM inhibitor KU-55933, which also has activity on DNA-PK, showed inhibition of both HR and NHEJ. The selective DNA-PK inhibitor NU7441 inhibited NHEJ efficiency with an IC50 of 299 nM, and showed a dose responsive increase in HR. The PARP inhibitor Olaparib showed lower potency in modulating HR and NHEJ. We next used the RepairSwitch assay to assess how pharmacological and genetic inhibition of DNA methyltransferases (DNMT) impacted rates of HR and NHEJ. The DNMT inhibitor decitabine reduced HR, but increased rates of NHEJ, both in a dose responsive manner, in both HEK293FT and HCT116 cells (IC50 for HR of 187 nM and 1.4 uM respectively). Knockout of DNMT1 and DNMT3B increased NHEJ, while knockout of DNMT3B, but not DNMT1, reduced HR. These results illustrate the utility of RepairSwitch as a functional assay for measuring changes in rates of DSB repair induced by pharmacological or genetic perturbation. Furthermore, the findings illustrate the potential for one DNA repair mechanism to compensate in part for loss of another. Finally, we showed that inhibition of DNMT can lead to reduction of HR and increase in NHEJ, providing some additional insight into recently observed synergy of DNMT inhibitors with PARP inhibitors for cancer treatment.
Genomic Landscape of Patients with GermlineRUNX1Variants and Familial Platelet Disorder with Myeloid Malignancy
Authors: Yu Kai , Deuitch Natalie , Merguerian Matthew , Cunningham Lea , Davis Joie , Bresciani Erica , Diemer Jamie , Andrews Elizabeth , Young Alice , Donovan Frank , Sood Raman , Craft Kathleen , Chong Shawn , Chandrasekharappa Settara , Mullikin Jim , Liu Paul P. 
Published: January 2023

AbstractGermlineRUNX1mutations lead to familial platelet disorder with associated myeloid malignancies (FPDMM), which is characterized by thrombocytopenia and a life-long risk (35-45%) of hematological malignancies. We recently launched a longitudinal natural history study for patients with FPDMM at the NIH Clinical Center. Among 29 families with research genomic data, 28 different germlineRUNX1variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 24 of 54 (44.4%) non-malignant patients, somatic mutations were detected in at least one of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes.BCORwas the most frequently mutated gene (in 9 patients), and multipleBCORmutations were identified in 4 patients. Mutations in 7 other CHIP or AML driver genes (DNMT3A, TET2, NRAS, SETBP1, SF3B1, KMT2C, andLRP1B) were also found in more than one non-malignant patient. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations inNFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in elderly patients. In summary, there are diverse types of germlineRUNX1mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring dynamic changes of somatic mutations prospectively will benefit patients’ clinical management and reveal mechanisms for progression to myeloid malignancies.Key PointsComprehensive genomic profile of patients with FPDMM with germlineRUNX1mutations.Rising clonal hematopoiesis related secondary mutations that may lead to myeloid malignancies.
Adaptive optical two-photon fluorescence microscopy probes cellular organization of ocular lenses in vivo
Authors: Paidi Santosh Kumar , Zhang Qinrong , Yang Yuhan , Xia Chun-Hong , Ji Na , Gong Xiaohua 
Published: January 2023

AbstractThe mammalian ocular lens is an avascular multicellular organ that grows continuously throughout life. Traditionally, its cellular organization is investigated using dissected lenses, which eliminates in vivo environmental and structural support. Here, we demonstrated that two-photon fluorescence microscopy (2PFM) can visualize lens cells in vivo. To maintain subcellular resolution at depth, we employed adaptive optics (AO) to correct aberrations due to ocular and lens tissues, which led to substantial signal and resolution improvements. Imaging lens cells up to 980 μm deep, we observed novel cellular organizations including suture-associated voids, enlarged vacuoles, and large cavities, contrary to the conventional view of a highly ordered organization. We tracked these features longitudinally over weeks and observed the incorporation of new cells during growth. Taken together, non-invasive longitudinal in vivo imaging of lens morphology using AO 2PFM will allow us to directly observe the development or alterations of lens cellular organization in living animals.
Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology
Authors: Aguado Julio , Amarilla Alberto A. , Taherian Fard Atefeh , Albornoz Eduardo A. , Tyshkovskiy Alexander , Schwabenland Marius , Chaggar Harman K. , Modhiran Naphak , Gómez-Inclán Cecilia , Javed Ibrahim , Baradar Alireza A. , Liang Benjamin , Dharmaratne Malindrie , Pietrogrande Giovanni , Padmanabhan Pranesh , Freney Morgan E. , Parry Rhys , Sng Julian D.J. , Isaacs Ariel , Khromykh Alexander A. , Rojas-Fernandez Alejandro , Davis Thomas P. , Prinz Marco , Bengsch Bertram , Gladyshev Vadim N. , Woodruff Trent M. , Mar Jessica C. , Watterson Daniel , Wolvetang Ernst J. 
Published: January 2023

AbstractAging is the primary risk factor for most neurodegenerative diseases, and recently coronavirus disease 2019 (COVID-19) has been associated with severe neurological manifestations that can eventually impact neurodegenerative conditions in the long-term. The progressive accumulation of senescent cellsin vivostrongly contributes to brain aging and neurodegenerative co-morbidities but the impact of virus-induced senescence in the aetiology of neuropathologies is unknown. Here, we show that senescent cells accumulate in physiologically aged brain organoids of human origin and that senolytic treatment reduces inflammation and cellular senescence; for which we found that combined treatment with the senolytic drugs dasatinib and quercetin rejuvenates transcriptomic human brain aging clocks. We further interrogated brain frontal cortex regions in postmortem patients who succumbed to severe COVID-19 and observed increased accumulation of senescent cells as compared to age-matched control brains from non-COVID-affected individuals. Moreover, we show that exposure of human brain organoids to SARS-CoV-2 evoked cellular senescence, and that spatial transcriptomic sequencing of virus-induced senescent cells identified a unique SARS-CoV-2 variant-specific inflammatory signature that is different from endogenous naturally-emerging senescent cells. Importantly, following SARS-CoV-2 infection of human brain organoids, treatment with senolytics blocked viral retention and prevented the emergence of senescent corticothalamic and GABAergic neurons. Furthermore, we demonstrate in human ACE2 overexpressing mice that senolytic treatment ameliorates COVID-19 brain pathology following infection with SARS-CoV-2.In vivotreatment with senolytics improved SARS-CoV-2 clinical phenotype and survival, alleviated brain senescence and reactive astrogliosis, promoted survival of dopaminergic neurons, and reduced viral and senescence-associated secretory phenotype gene expression in the brain. Collectively, our findings demonstrate SARS-CoV-2 can trigger cellular senescence in the brain, and that senolytic therapy mitigates senescence-driven brain aging and multiple neuropathological sequelae caused by neurotropic viruses, including SARS-CoV-2.
Establishment of Wnt ligand-receptor organization and cell polarity in theC. elegansembryo
Authors: Recouvreux Pierre , Pai Pritha , Torro Rémy , Ludányi Mónika , Mélénec Pauline , Boughzala Mariem , Bertrand Vincent , Lenne Pierre-François 
Published: January 2023

AbstractDifferent signaling mechanisms concur to ensure robust tissue patterning and cell fate instruction during animal development. Most of these mechanisms rely on signaling proteins that are produced, transported and detected. The spatiotemporal dynamics of signaling molecules is largely unknown, yet it determines signal activity’s range and time frame. Here, we use theCaenorhabditis elegansembryo to study how Wnt ligands, an evolutionarily conserved family of signaling proteins, dynamically organize to establish cell polarity in a developing tissue. We identify how locally produced Wnt ligands spread to transmit information to distant target cells. With quantitative live imaging, we show that the Wnt ligands diffuse extracellularly through the embryo over a timescale shorter than the cell cycle. We extract diffusion coefficients of Wnt ligands and their receptor Frizzled (Fz) and characterize their co-localization. Integrating our different measurements and observations in a simple computational framework, we show how fast diffusion in the embryo can polarize target cells. Our results support diffusion-based long-range Wnt signaling, which is consistent with the dynamics of developing processes.
GraphGPSM: a global scoring model for protein structure using graph neural networks
Authors: He Guangxing , Liu Jun , Liu Dong , Guijun Zhang 
Published: January 2023

AbstractThe scoring models used for protein structure modeling and ranking are mainly divided into unified field and protein-specific scoring functions. Although protein structure prediction has made tremendous progress since CASP14, the modeling accuracy still cannot meet the requirements to a certain extent. Especially, accurate modeling of multi-domain and orphan proteins remains a challenge. Therefore, an accurate and efficient protein scoring model should be developed urgently to guide the protein structure folding or ranking through deep learning. In this work, we propose a protein structure global scoring model based on equivariant graph neural network (EGNN), named GraphGPSM, to guide protein structure modeling and ranking. We construct an EGNN architecture, and a message passing mechanism is designed to update and transmit information between nodes and edges of the graph. Finally, the global score of the protein model is output through a multilayer perceptron. Residue-level ultrafast shape recognition is used to describe the relationship between residues and the overall structure topology, and distance and direction encoded by Gaussian radial basis functions are designed to represent the overall topology of the protein backbone. These two features are combined with Rosetta energy terms, backbone dihedral angles, and inter-residue distance and orientations to represent the protein model and embedded into the nodes and edges of the graph neural network. The experimental results on the CASP13, CASP14, and CAMEO test sets show that the scores of our developed GraphGPSM have a strong correlation with the TM-score of the models, which are significantly better than those of the unified field score function REF2015 and the state-of-the-art local lDDT-based scoring models ModFOLD8, ProQ3D, and DeepAccNet etc. The modeling experimental results on 484 test proteins demonstrate that GraphGPSM can greatly improve the modeling accuracy. GraphGPSM is further used to model 35 orphan proteins and 57 multi-domain proteins. The results show that the average TM-score of the models predicted by GraphGPSM is 13.2% and 7.1% higher than that of the models predicted by AlphaFold2. GraphGPSM also participates in CASP15 and achieves competitive performance in global accuracy estimation.