bluuebunny/crossref_metadata_2025_split huggingface dataset:
A receptor kinase complex refines cambium activity inArabidopsis
Authors: He Qing , Han Jingyi , Wei Wenbin , Pohl Ehmke , Wightman Raymond , Etchells J Peter 
Published: May 2024

SummaryIn plant development, key receptor kinases are often active in disparate cell types, with each requiring vastly different signalling outputs. The ERECTA (ER) receptor kinase and its homologs ERL1 and ERL2 exemplify this pleiotropy. InArabidopsis, they influence stomatal patterning, shoot meristem function, ovule morphogenesis, xylem fiber differentiation, and cell division in the vascular cambium1–6. Such diverse expression and functionality raises the question of how ER signalling can specify such distinct cell behaviours. One mechanism is via cell-type specific interactions with co-receptors, ligands, or other proteins that modulate signalling. However, little is known about ER interactors in the vascular cambium, a bifacial stem cell niche that generates phloem and xylem (Figure 1A). Combinatorial mutations betweenER, ERL1andERL2and receptor kinases of a second family,PXY, PXL1, andPXL2, show severe cambial defects5,7, but the mechanism underpinning these phenotypes is not known. Here we discovered that PXY proteins form protein complexes with ER and ERL2. PXY signalling can be manipulated by altering levels of its cognate ligand, TDIF. In genetic analysis, plant lines in which TDIF levels were altered had dramatic phenotypic changes that required the presence of ER or ERL2. Our results demonstrate that PXY signalling mediated cambium regulation depends on ER signalling and explains ER function in the cambium. Because the cambium produces xylem, which constitutes the wood in vascular plants, our findings position PXY-ER complexes at the centre of the accumulation of this versatile biomaterial and essential carbon sink.
The dithiocarbamate pesticides maneb and mancozeb disturb the metabolism of lipids and xenobiotics in an in vitro model of metabolic dysfunction-associated steatotic liver disease
Authors: Petitjean Kilian , Dicara Giovanna , Bristeau Sébastien , Coppens-Exandier Hugo , Amalric Laurence , Baran Nicole , Savary Camille C. , Corlu Anne , Loyer Pascal , Fromenty Bernard 
Published: May 2024

AbstractPesticides are increasingly recognized to be hepatotoxic but less is known about their toxicity in metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations reported oxidative stress-induced apoptosis in differentiated hepatocyte-like HepaRG cells after a single treatment with a 7-pesticide mixture that included chlorpyrifos, dimethoate, diazinon, iprodione, imazalil, and the dithiocarbamates maneb and mancozeb. These effects were reproduced by maneb, mancozeb, or manganese chloride (MnCl2). Herein, differentiated HepaRG cells cultured for 2 weeks without (-FA) or with (+FA) a mixture of stearic and oleic acids were treated with this 7-pesticide mixture, maneb, mancozeb, or MnCl2along the same period. While these molecules did not induce neutral lipid accumulation in -FA-HepaRG cells, they worsened steatosis in +FA-HepaRG cells. Maneb or MnCl2impaired very low-density lipoprotein (VLDL) secretion and increased fatty acid uptake without altering mitochondrial fatty acid oxidation andde novolipogenesis. Reduced VLDL secretion was associated with decreased mRNA levels of apolipoproteins B and C3 and microsomal triglyceride transfer protein. Zinc supplementation restored VLDL secretion, reduced fatty acid uptake and prevented the exacerbation of steatosis in +FA-HepaRG cells treated with mancozeb or MnCl2. The mixture, maneb, or MnCl2also reduced the mRNA expression and activity of several cytochromes P450 in +FA- and -FA-HepaRG cells. This was associated with impaired biotransformation of diazinon while chlorpyrifos metabolism was unaffected. Hence, maneb, mancozeb and MnCl2disturb the metabolism of lipids and xenobiotics in HepaRG cells, in particular in fatty acid-exposed cells. These findings could have major pathophysiological consequences in dithiocarbamate-exposed individuals with MASLD.
Hybrid lipid-block copolymer membranes enable stable reconstitution of a wide range of nanopores and robust sampling of serum
Authors: Vreeker Edo , Grünewald Fabian , van der Heide Nieck Jordy , Marrink Siewert-Jan , Tych Katarzyna (Kasia) , Maglia Giovanni 
Published: May 2024

AbstractBiological nanopores are powerful tools for detecting biomolecules at the single-molecule level, making them appealing as sensors for biological samples. However, the lipid membranes in which nanopores reside can be unstable in the presence of biological fluids. Here, membranes formed with the amphiphilic polymers PMOXA-PDMS-PMOXA and PBD-PEO are tested as potential alternatives for nanopore sensing. We demonstrate that polymer membranes can possess increased stability towards applied potentials and high concentrations of human serum, but that the stable insertion of a wide range of biological nanopores is most often compromised. Alternatively, hybrid polymer-lipid membranes comprising a 1:1 w/w mixture of PBD11PEO8and DPhPC showed high electrical and biochemical stability while creating a suitable environment for all tested nanopores. Analytes such as proteins, DNA and sugars were efficiently sampled, indicating that in hybrid membranes nanopores showed native-like properties. Molecular dynamics simulations revealed that lipids form ∼12 nm domains interspersed by a polymer matrix. Nanopores partitioned into these lipid nanodomains and sequestered lipids possibly offering the same binding strength as in a native bilayer. This work shows that single-molecule analysis with nanopores in [PBD11PEO8+ DPhPC] membranes is feasible and present stable recordings in the presence of human serum. These results pave the way towards novel nanopore-based biosensors.
In vivo Targeting MEK and TNK2/SRC pathways in PTPN11 driven leukemia
Authors: Chang Bill H. , Thiel-Klare Karina , Tyner Jeffrey W. 
Published: May 2024

AbstractPTPN11 encodes for a tyrosine phosphatase implicated in the pathogenesis of hematologic malignancies such as Juvenile Myelomonocytic Leukemia (JMML), Acute Myeloid Leukemia (AML), and Acute Lymphoblastic Leukemia (ALL). Since activating mutations of PTPN11 increase proliferative signaling and cell survival through the RAS/MAPK proliferative pathway there is significant interest in using MEK inhibitors for clinical benefit. Yet, single agent clinical activity has been minimal. Previously, we showed that PTPN11 is further activated by upstream tyrosine kinases TNK2/SRC, and that PTPN11-mutant JMML and AML cells are sensitive to TNK2 inhibition using dasatinib. In order to validate these findings, we adopted a genetically engineered mouse model of PTPN11 driven leukemia using the mouse strain 129S/Sv-Ptpn11tm6Bgn/Mmucd crossed with B6.129P2-Lyz2tm1(cre)Ifo/J. The F1 progeny expressing Ptpn11D61Ywithin hematopoietic cells destined along the granulocyte-monocyte progenitor lineage developed a fatal myeloproliferative disorder characterized by neutrophilia and monocytosis, and infiltration of myeloid cells into the liver and spleen. Cohorts of Ptpn11D61Yexpressing animals treated with combination of dasatinib and trametinib for an extended period of time was well tolerated and had a significant effect in mitigating disease parameters compared to single agents. Finally, a primary patient-derived xenograft model using a myeloid leukemia with PTPN11 F71L also displayed improved disease response to combination. Collectively, these studies point to combined therapies targeting MEK and TNK2/SRC as a promising therapeutic potential for PTPN11-mutant leukemias.Key PointsCombining MEK and TNK2/SRC inhibitors has therapeutic potential in PTPN11 mutant JMML and AML
Deep mutational scanning of influenza A virus NEP reveals pleiotropic mutations in its N-terminal domain
Authors: Teo Qi Wen , Wang Yiquan , Lv Huibin , Mao Kevin J. , Tan Timothy J.C. , Huan Yang Wei , Rivera-Cardona Joel , Shao Evan K. , Choi Danbi , Dargani Zahra Tavakoli , Brooke Christopher B. , Wu Nicholas C. 
Published: May 2024

ABSTRACTThe influenza A virus nuclear export protein (NEP) is a multifunctional protein that is essential for the viral life cycle and has very high sequence conservation. However, since the open reading frame of NEP largely overlaps with that of another influenza viral protein, non-structural protein 1, it is difficult to infer the functional constraints of NEP based on sequence conservation analysis. Besides, the N-terminal of NEP is structurally disordered, which further complicates the understanding of its function. Here, we systematically measured the replication fitness effects of >1,800 mutations of NEP. Our results show that the N-terminal domain has high mutational tolerance. Additional experiments demonstrate that N-terminal domain mutations pleiotropically affect viral transcription and replication dynamics, host cellular responses, and mammalian adaptation of avian influenza virus. Overall, our study not only advances the functional understanding of NEP, but also provides insights into its evolutionary constraints.
Self-assembly of microstructured protein coatings with programmable functionality for fluorescent biosensors
Authors: Jo Suna , Pearson Erin , Yoon Donghoon , Kim Jungkwun , Park Won Min 
Published: May 2024

AbstractProteins, as genetically programmable functional macromolecules, hold immense potential as biocompatible self-assembling building blocks. Despite their versatility in building coating materials, it has been often hindered from programming their functionality genetically. In this study, we demonstrate a modular self-assembly of protein coatings that are genetically programmable for a biosensor application. We designed recombinant fusion protein building blocks to form microstructured coatings on diverse substrates, such as glass or polymer, through a thermally triggered liquid-liquid phase separation and an orthogonal high-affinity coiled-coil interaction. We incorporated fluorescence proteins into coatings and controlled protein density to enable fluorescence imaging and quantification in a low-resource setting. Then, we created a coating for a calcium biosensor using a genetically engineered calcium indicator protein. This protein coating served as the foundation for our smartphone-based fluorescence biosensor, which successfully measured free calcium concentrations in the millimolar range at which extracellular calcium homeostasis is maintained. Using this fluorescence biosensor, we were able to detect abnormal physiological conditions such as mild or moderate hypercalcemia. We envision that this modular and genetically programmable functional protein coating platform could be extended to the development of highly accessible, low-cost fluorescent biosensors for a variety of targets.
Effect of SNEDDS Loading Pentagamavunon-0 on Memory Impairment and Neurogenesis in Mice with Monosodium Glutamate-Induced Alzheimer’s Disease-Like Symptoms
Authors: Anas Yance , Susidarti Ratna Asmah , Martien Ronny , Yuniarti Nunung 
Published: May 2024

ABSTRACTPentagamavunon-0 (PGV-0), a curcumin analog, has antioxidant and HDAC2 inhibitory properties. It affects neurogenesis and cognitive function in Alzheimer’s disease (AD). Targeting neurogenesis is a strategy currently being developed for AD treatment. This study investigates the therapeutic potential of self-nanoemulsifying drug delivery systems loaded with PGV-0 (SNEDDS PGV-0) on spatial learning, memory impairment, and gene expression-related neurogenesis in mice with monosodium glutamate (MSG) induced AD-like symptoms. MSG 4 g/kg was injected (sc.) into 4-week-old Balb/C mice seven times every alternate day, followed by treatment for 60 days with CMC-Na 0.5%, PGV-0 suspension, SNEDDS PGV-0, and donepezil-HCl. The open-field test, novel object recognition, and 8-radial arm maze test were employed to assess the neurobehavioral performance of mice. Neurogenesis-related gene expression (dcx, nestin, Hes5, and NFIA) was quantified through qPCR analysis. Spatial learning and memory in mice declined with MSG treatment. SNEDDS PGV-0 effectively alleviates mice’s cognitive and memory deficits, as shown in improvements in behavioral parameters, including the Discrimination Index, Recognition Index, and Memory Score. It also restores mRNA expression of several essential neurogenesis-related genes, including dcx, Hes5, and NFIA. SNEDDS PGV-0 demonstrates promising potential as a neurogenesis promoter, making it a viable drug candidate for AD or other neurodegenerative pathologies.
Unraveling the impact of host genetics and factors on the urinary microbiome in a young population
Authors: Zou Leying , Zhang Zhe , Chen Junhong , Guo Ruijin , Tong Xin , Ju Yanmei , Lu Haorong , Yang Huanming , Wang Jian , Zong Yang , Xu Xun , Jin Xin , Xiao Liang , Jia Huijue , Zhang Tao , Liu Xiaomin 
Published: May 2024

AbstractThe significance of the urinary microbiome in maintaining health and contributing to disease development is increasingly recognized. However, a comprehensive understanding of this microbiome and its influencing factors remains elusive. Utilizing whole metagenomic and whole-genome sequencing, along with detailed metadata, we characterized the urinary microbiome and its influencing factors in a cohort of 1579 Chinese individuals. Our findings unveil the distinctiveness of the urinary microbiome from other four body sites, delineating five unique urotypes dominated byGardnerella vaginalis, Sphingobium fluviale, Lactobacillus iners, Variovorax sp PDC80andAcinetobacter junii, respectively. We identified 108 host factors significantly influencing the urinary microbiome, collectively explaining 12.92% of the variance in microbial composition. Notably, gender-related factors, including sex hormones, emerged as key determinants in defining urotype groups, microbial composition and pathways, with the urinary microbiome exhibiting strong predictive ability for gender (AUC=0.843). Furthermore, we discovered 43 genome-wide significant associations between host genetic loci and specific urinary bacteria,Acinetobacterin particular, linked to 8 host loci (p< 5×10-8). These associations were also modulated by gender and sex hormone levels. In summary, our study provides novel insights into the impact of host genetics and other factors on the urinary microbiome, shedding light on its implications for host health and disease.
Prediction of Conformational Ensembles and Structural Effects of State-Switching Allosteric Mutants in the Protein Kinases Using Comparative Analysis of AlphaFold2 Adaptations with Sequence Masking and Shallow Subsampling
Authors: Raisinghani Nishank , Alshahrani Mohammed , Gupta Grace , Tian Hao , Xiao Sian , Tao Peng , Verkhivker Gennady 
Published: May 2024

AbstractDespite the success of AlphaFold2 approaches in predicting single protein structures, these methods showed intrinsic limitations in predicting multiple functional conformations of allosteric proteins and have been challenged to accurately capture of the effects of single point mutations that induced significant structural changes. We systematically examined several implementations of AlphaFold2 methods to predict conformational ensembles for state-switching mutants of the ABL kinase. The results revealed that a combination of randomized alanine sequence masking with shallow multiple sequence alignment subsampling can significantly expand the conformational diversity of the predicted structural ensembles and capture shifts in populations of the active and inactive ABL states. Consistent with the NMR experiments, the predicted conformational ensembles for M309L/L320I and M309L/H415P ABL mutants that perturb the regulatory spine networks featured the increased population of the fully closed inactive state. On the other hand, the predicted conformational ensembles for the G269E/M309L/T334I and M309L/L320I/T334I triple ABL mutants that share activating T334I gate-keeper substitution are dominated by the active ABL form. The proposed adaptation of AlphaFold can reproduce the experimentally observed mutation-induced redistributions in the relative populations of the active and inactive ABL states and capture the effects of regulatory mutations on allosteric structural rearrangements of the kinase domain. The ensemble-based network analysis complemented AlphaFold predictions by revealing allosteric mediating centers that often directly correspond to state-switching mutational sites or reside in their immediate local structural proximity, which may explain the global effect of regulatory mutations on structural changes between the ABL states. This study suggested that attention-based learning of long-range dependencies between sequence positions in homologous folds and deciphering patterns of allosteric interactions may further augment the predictive abilities of AlphaFold methods for modeling of alternative protein sates, conformational ensembles and mutation-induced structural transformations.
Ensemble Meta-Learning using SVM for Improving Cardiovascular Disease Risk Prediction
Authors: Punn Narinder Singh , Dewangan Deepak Kumar 
Published: May 2024

AbstractCardiovascular diseases (CVDs) remain a leading cause of mortality worldwide, posing a significant public health challenge. Early identification of individuals at high risk of CVD is crucial for timely intervention and prevention strategies. Machine learning techniques are increasingly being applied in healthcare for their ability to uncover complex patterns within large, multidimensional datasets. This study introduces a novel ensemble meta-learning framework designed to enhance cardiovascular disease (CVD) risk prediction. The framework strategically combines the predictive power of diverse machine learning algorithms – logistic regression, K nearest neighbors, decision trees, gradient boosting, gaussian Naive Bayes and XGBoost. Predicted probabilities from these base models are integrated using support vector machine as meta-learner. Rigorous performance evaluation over publicly available dataset demonstrates the improved performance of this ensemble approach compared to individual. This research highlights the potential of ensemble meta-learning techniques to improve predictive modeling in healthcare.
Comparison of the Vaginal and Labial Dimensions of Nullipara Ethnic Chinese and Western Women
Authors: Stevens Lisa , Masteling Mariana , Srinivasa Raju Kruthi , Mastrovito Sara , Ashton-Miller James A. , DeLancey John O. L. 
Published: May 2024

AbstractIntroduction and HypothesisVaginal dimensions have clinical and surgical implications. We sought to quantify the differences between vaginal and labial dimensions in healthy ethnic Chinese and Western women with normal pelvic organ support.MethodsThis is a cross-sectional study of a convenience sample of ethnic Chinese nullipara (n = 33) and Western nullipara (n= 33) women recruited for research purposes. For each subject, magnetic resonance imaging was used to quantify the vaginal and labial dimensions. Specifically, we identified the anterior and posterior vaginal wall, the outline of the cervix in the mid-sagittal and coronal planes, and the distance from the labia majora to the hymenal ring at the urethral meatus.ResultsThe vaginal and labial dimensions of ethnic Chinese nullipara were 9-21 % smaller than those of Western nullipara; however, the relative orientation of the cervix to the vaginal opening was not different.ConclusionsSignificant group differences in vaginal and labial dimensions were found, with Chinese nullipara dimensions being up to 21% smaller than those of Western nullipara.Brief SummaryEthnic Chinese women have smaller vaginal and labial dimensions than Western women. These differences have clinical and surgical implications.
Auto QSAR-based Active learning docking for hit identification of potential inhibitors ofPlasmodium falciparumHsp90 as antimalarial agents
Authors: Matlhodi Thato , Makatsela Lisema Patrick , Dongola Tendamudzimu Harmfree ,   Mthokozisi Blessing Cedric Simelane, Shonhai Addmore , Gumede Njabulo Joyfull , Mokoena Fortunate 
Published: May 2024

AbstractMalaria which is mainly caused byPlasmodium falciparumparasite remains a devastating public health concern, necessitating the need to develop new antimalarial agents.P. falciparumheat shock protein 90 (Hsp90), is indispensable for parasite survival and a promising drug target. Inhibitors targeting the ATP-binding pocket of the N-terminal domain have anti-Plasmodiumeffects. We proposed ade novoactive learning (AL) driven method in tandem with docking to predict inhibitors with unique scaffolds and preferential selectivity towards PfHsp90. Reference compounds, predicted to bind PfHsp90 at the ATP-binding pocket and possessing anti-Plasmodiumactivities, were used to generate 10,000 unique derivatives and to build the Auto-quantitative structures activity relationships (QSAR) models. Glide docking was performed to predict the docking scores of the derivatives and > 15,000 compounds obtained from the ChEMBL database. Re-iterative training and testing of the models was performed until the optimum Kennel-based Partial Least Square (KPLS) regression model with a regression coefficient R2 = 0.75 for the training set and squared correlation prediction Q2 = 0.62 for the test set reached convergence. Rescoring using induced fit docking and molecular dynamics simulations enabled us to prioritize 15 ATP/ADP-like design ideas for purchase. The compounds exerted moderate activity towardsP. falciparumNF54 strain with IC50values of ≤ 6μM and displayed moderate to weak affinity towards PfHsp90 (KDrange: 13.5-19.9μM) comparable to the reported affinity of ADP. The most potent compound was FTN-T5 (PfN54 IC50:1.44μM; HepG2/CHO cells SI≥ 29) which bound to PfHsp90 with moderate affinity (KD:7.7μM), providing a starting point for optimization efforts. Our work demonstrates the great utility of AL for the rapid identification of novel molecules for drug discovery (i.e., hit identification). The potency of FTN-T5 will be critical for designing species-selective inhibitors towards developing more efficient agents against malaria.