bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoproximity biotinylation reveals the axon initial segment proteome
Authors: Zhang Wei , Fu Yu , Peng Luxin , Ogawa Yuki , Ding Xiaoyun , Rasband Anne , Zhou Xinyue , Shelly Maya , Rasband Matthew N. , Zou Peng 
Published: March 2023

ABSTRACTThe axon initial segment (AIS) is a specialized neuronal compartment required for action potential generation and neuronal polarity. However, understanding the mechanisms regulating AIS structure and function has been hindered by an incomplete knowledge of its molecular composition. Here, using immuno-proximity biotinylation we further define the AIS proteome and its dynamic changes during neuronal maturation. Among the many AIS proteins identified, we show that SCRIB is highly enriched in the AIS bothin vitroandin vivo,and exhibits a periodic architecture like the axonal spectrin-based cytoskeleton. We found that ankyrinG interacts with and recruits SCRIB to the AIS. However, loss of SCRIB has no effect on ankyrinG. This powerful and flexible approach further defines the AIS proteome and provides a rich resource to elucidate the mechanisms regulating AIS structure and function.
A novel role of macrophage PIST protein in regulatingLeishmania majorinfection
Authors: Banerjee Sourav , Gadpayle Mandip Pratham , Das Swagata , Samanta Suman , Datta Rupak , Maiti Sankar 
Published: March 2023

AbstractPDZ protein interacting specifically with Tc10 or PIST is a mammaliantrans-Golgi resident protein that regulates subcellular sorting of plasma membrane receptors. PIST has recently been found to play an important role in regulating viral pathogenesis. Alteration in PIST expression is linked to the reprogramming of cell surface receptors which is crucial in determining herpes simplex virus1 infection. In this context, PIST is crucial in triggering autophagy via Beclin 1 -PI3KC3 pathway. However, there is complete lack in our knowledge on the role of this protein in any parasitic infection.Leishmaniaparasites infect their host macrophage cells via phagocytosis and their survival within the parasitophorous compartment has recently been found to be dependent on host autophagy by a yet to be identified mechanism. UsingLeishmania major(L. major)-macrophage infection model system we, for the first-time report here that in infected macrophages Golgi resident PIST protein migrates towards the parasite containing compartment. We have also found that PIST associates with Beclin 1, however, not with LC3 withinL. majorparasite containing compartment of infected macrophages. Further, we performed genetic ablation of PIST by siRNA and observed that knockdown of macrophage PIST in turn helps in parasite replication. Contrary to this, overexpression of PIST in macrophages restricted the multiplication ofL. major. Collectively, our study for the first time reveals that PIST is essential in regulating intracellular parasite,L. majorinfection within macrophage cells.Summary StatementMammalian PIST protein plays a crucial role in regulating cellular trafficking events. Here, we showed that PIST status is altered withinLeishmania majorparasite infected macrophages. Further, we confirmed that PIST is essential in restricting parasite growth. Additionally, a potential interacting axis between PIST and Beclin 1 is identified during infection.
OneOPES, a combined enhanced sampling method to rule them all
Authors: Rizzi Valerio , Aureli Simone , Ansari Narjes , Gervasio Francesco Luigi 
Published: March 2023

AbstractEnhanced sampling techniques have revolutionised molecular dynamics (MD) simulations, enabling the study of rare events and the calculation of free energy differences in complex systems. One of the main families of enhanced sampling techniques uses physical degrees of freedom called collective variables (CVs) to accelerate a system’s dynamics and recover the original system’s statistics. However, encoding all the relevant degrees of freedom in a limited number of CVs is challenging, particularly in large biophysical systems. Another category of techniques, such as parallel tempering, simulates multiple replicas of the system in parallel, with-out requiring CVs. However, these methods may explore less relevant high-energy portions of the phase space and become computationally expensive for large systems. To overcome the limitations of both approaches, we propose a replica exchange method called OneOPES that combines the power of multi-replica simulations and CV-based enhanced sampling. This method efficiently accelerates the phase space sampling without the need for ideal CVs, extensive parameters fine tuning nor the use of a large number of replicas, as demonstrated by its successful applications to protein-ligand binding and protein folding benchmark systems. Our approach shows promise as a new direction in the development of enhanced sampling techniques for molecular dynamics simulations, providing an efficient and robust framework for the study of complex and unexplored problems.Table of Content Graphic
An expanded GCaMP reporter toolkit for functional imaging inC. elegans
Authors: Ding Jimmy , Peng Lucinda , Moon Sihoon , Lee Hyun Jee , Patel Dhaval S. , Lu Hang 
Published: March 2023

AbstractIn living organisms, changes in calcium flux are integral to many different cellular functions and are especially critical for the activity of neurons and myocytes. Genetically encoded calcium indicators (GECIs) have been popular tools for reporting changes in calcium levelsin vivo. In particular, GCaMP, derived from GFP, are the most widely used GECIs and have become an invaluable toolkit for neurophysiological studies. Recently, new variants of GCaMP, which offer a greater variety of temporal dynamics and improved brightness, have been developed. However, these variants are not readily available to theCaenorhabditis elegansresearch community. This work reports a set of GCaMP6 and jGCaMP7 reporters optimized forC. elegansstudies. Our toolkit provides reporters with improved dynamic range, varied kinetics, and targeted subcellular localizations. Besides optimized routine uses, this set of reporters are also well-suited for studies requiring fast imaging speeds and low magnification or low-cost platforms.
Calorie Restriction activates a gastric Notch-FOXO1 pathway to expand Ghrelin cells
Authors: McKimpson Wendy M. , Spiegel Sophia , Mukhanova Maria , Kraakman Michael , Du Wen , Kitamoto Takumi , Yu Junjie , Pajvani Utpal , Accili Domenico 
Published: March 2023

AbstractCalorie restriction increases lifespan. While some tissue-specific protective effects of calorie restriction have been described, the impact of calorie restriction on the gastrointestinal tract remains unclear. We found increased abundance of chromogranin A+, including orexigenic ghrelin+, endocrine cells in the stomach of calorie-restricted mice. This effect coincided with increased Notch target Hes1 and Notch ligand Jag1 and was reversed when Notch signaling was blocked using the γ-secretase inhibitor DAPT. Using primary cultures and genetically-modified reporter mice, we determined that increased endocrine cell abundance was due to altered stem and progenitor proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, calorie restriction triggered nuclear localization of FOXO1, which was sufficient to promote endocrine cell differentiation. Taken together, the data indicate that calorie restriction promotes gastric endocrine cell differentiation triggered by active Notch signaling and regulated by FOXO1.
DNAJB8 oligomerization is mediated by an aromatic-rich motif that is dispensable for substrate activity
Authors: Ryder Bryan D. , Ustyantseva Elizaveta , Boyer David R. , Mendoza-Oliva Ayde , Kuska Mikołaj I. , Wydorski Paweł M. , Macierzynska Paulina , Morgan Nabil , Sawaya Michael R. , Diamond Marc I. , Kampinga Harm H. , Joachimiak Lukasz A. 
Published: March 2023

SUMMARYJ-domain protein (JDP) molecular chaperones have emerged as central players that maintain a healthy proteome. The diverse members of the JDP family function as monomers/dimers and a small subset assemble into micron-sized oligomers. The oligomeric JDP members have eluded structural characterization due to their low-complexity, intrinsically disordered middle domains. This in turn, obscures the biological significance of these larger oligomers in protein folding processes. Here, we identified a short, aromatic motif within DNAJB8, that drives self-assembly through ν-ν stacking and determined its X-ray structure. We show that mutations in the motif disrupt DNAJB8 oligomerizationin vitroand in cells. DNAJB8 variants that are unable to assemble bind to misfolded tau seeds more specifically and retain capacity to reduce protein aggregationin vitroand in cells. We propose a new model for DNAJB8 function in which the sequences in the low-complexity domains play distinct roles in assembly and substrate activity.HIGHLIGHTSDNAJB8 oligomerization is mediated by a short phenylalanine-based motif in the S/T domainMutation of a single phenylalanine yields a monomeric form of DNAJB8Monomeric DNABJ8 binds to an aggregation-prone substrateMonomeric DNAJB8 retains substrate aggregation prevention activity
Whole genome analyses reveal weak signatures of population structure and environmentally associated local adaptation in an important North American pollinator, the bumble beeBombus vosnesenskii
Authors: Heraghty Sam D. , Jackson Jason M. , Lozier Jeffrey D. 
Published: March 2023

AbstractStudies of species that experience environmental heterogeneity across their distributions have become an important tool for understanding mechanisms of adaptation and predicting responses to climate change. We examine population structure, demographic history, and environmentally associated genomic variation inBombus vosnesenskii, a common bumble bee in the western U.S.A., using whole genome resequencing of populations distributed across a broad range of latitudes and elevations. We find thatB. vosnesenskiiexhibits minimal population structure and weak isolation by distance, confirming results from previous studies using other molecular marker types. Similarly, demographic analyses with Sequentially Markovian Coalescent (SMC) models suggest that minimal population structure may have persisted since the last interglacial period, with genomes from different parts of the species range showing similar historical effective population size (Ne) trajectories and relatively small fluctuations through time. Redundancy analysis revealed a small amount of genomic variation explained by bioclimatic variables, and environmental association analysis with latent factor mixed modeling (LFMM2) identified few outlier loci that were sparsely distributed throughout the genome. Some outlier loci were in genes with known regulatory relationships, suggesting the possibility of weak selection, although compared to other species examined with similar approaches, evidence for extensive local adaptation signatures in the genome was relatively weak. Overall, results indicateBombus vosnesenskiiis an example of a generalist with a high degree of flexibility in its environmental requirements that may ultimately benefit the species under periods of climate change.
QuaC: A Pipeline Implementing Quality Control Best Practices for Genome Sequencing and Exome Sequencing Data
Authors: Gajapathy Manavalan , Wilk Brandon M. , Worthey Elizabeth A. 
Published: March 2023

SummaryQuality Control (QC) of human genome sequencing and exome sequencing data is necessary to ensure they are of sufficient quality for downstream analyses. While several QC tools are available to measure quality parameters at various levels post-sequencing, their output needs to be reviewed and interpreted in a very manual and time-consuming process. Such manual review is a major challenge towards standardization and consistency, as the process can be subjective depending on the reviewer. To address these difficulties, we have developed QuaC, which implements, integrates, and standardizes QC best practices at our Center. It performs three major steps: (1) runs several QC tools using data produced by the read alignment (BAM) and small variant calling (VCF) as input and optionally accepts QC output for raw sequencing reads (FASTQ); (2) executes QuaC-Watch to perform QC checkup based on the expected thresholds for quality metrics; and (3) aggregates QC metrics produced by all the QC tools as well as QuaC-Watch results into single, self-contained MultiQC report, both at the per-sample and across-project levels. This report provides aggregate summaries for all samples within a project/cohort for efficient comprehensive review while still allowing for granular review down to individual metrics for a single sample. Finally, we have developed a “Sample QC review system” schema to standardize QC reviewer’s logging of results and simplify downstream users’ interpretation of the reviewers finding.
Orthogonal coupling of a 3D cytoskeletal scaffold coordinates cell morphogenesis and maintains tissue organization in the Drosophila pupal retina
Authors: Sun Xiao , Decker Jacob , Sanchez-Luege Nicelio , Rebay Ilaria 
Published: March 2023

AbstractHow complex three-dimensional (3D) organs coordinate cellular morphogenetic events to achieve the correct final form is a central question in development. The question is uniquely tractable in the lateDrosophilapupal retina where cells maintain stereotyped contacts as they elaborate the specialized cytoskeletal structures that pattern the apical, basal and longitudinal planes of the epithelium. In this study, we combined cell type-specific genetic manipulation of the cytoskeletal regulator Abelson (Abl) with 3D imaging to explore how the distinct cellular morphogenetic programs of photoreceptors and interommatidial pigment cells coordinately organize tissue pattern to support retinal integrity. Our experiments revealed an unanticipated intercellular feedback mechanism whereby correct cellular differentiation of either cell type can non-autonomously induce cytoskeletal remodeling in the otherAblmutant cell type, restoring retinal pattern and integrity. We propose that genetic regulation of specialized cellular differentiation programs combined with inter-plane mechanical feedback confers spatial coordination to achieve robust 3D tissue morphogenesis.
Promoting diversity in ecological systems through toxin production
Authors: Lui Ga Ching , Goyal Sidhartha 
Published: March 2023

AbstractToxin production is generally thought as a mechanism to increase competitiveness of the toxin producers over other strains, thus driving down the diversity in the system. However, the production of toxin would also incur costs to the producer, and thus the overall effect may not be one-sided. In this work, we investigate the regime in which the presence of toxins is required to maintain high diversity, either at steady state or at persistence where the strain abundances shows oscillations or chaotic behaviors. Complementary to cross-feeding, which is one of several mechanisms previously proposed to resolve the paradox of plankton, we suggest the regulation of toxin production could play a role in increasing diversity above the upper bound given by the competitive exclusion principle.
Regulation of Traction Force through the Direct Binding of Basigin and Calpain 4
Authors: Hao Bingqing , Beningo Karen A. 
Published: March 2023

ABSTRACTTraction force and mechanosensing (the ability to sense mechanical attributes of the environment) are two important factors used by a cell to modify behavior during migration. Previously it was determined that the calpain small subunit, calpain 4, regulates the production of traction force independent of its proteolytic holoenzyme. A proteolytic enzyme is formed by calpain4 binding to either of its catalytic partners, calpain 1 and 2. To further understand how calpain 4 regulates traction force, we used two-hybrid analysis to identify more components of the traction pathway. We discovered that basigin, an integral membrane protein and a documented matrix-metalloprotease (MMP) inducer binds to calpain 4 in two-hybrid and pull-down assays. Traction force was deficient when basigin was silenced in MEF cells, and defective in substrate adhesion strength. Consistent with Capn4-/-MEF cells, the cells deficient in basigin responded to localized stimuli. Together these results implicate basigin in the pathway in which calpain 4 regulates traction force independent of the catalytic large subunits.
The fingering patterns in the epithelial layer control the gap closure rate via curvature-mediated force
Authors: Jeong Hyuntae , Yeo Jinwook , Ryu Seunghwa , Shin Jennifer Hyunjong 
Published: March 2023

AbstractClosing gaps in cellular monolayers is a fundamental aspect of both morphogenesis and wound healing. This closure can be achieved through leader cell crawling or actomyosin-based contraction, depending on the size of the gap. Here, we focus on wounds whose closure is driven by interfacial instabilities, featuring both leader cell-driven fingers and actin-mediated contraction. Our proposed model predicts a positive correlation between the frequency of fingering and the overall speed of boundary closure. This fingering frequency is precisely regulated through the orchestration of cell density-driven pressure, cell-cell repulsions, and the initial curvature of the wound boundary. Our findings demonstrate an inverse correlation between fingering frequency and boundary curvatures, indicating a “self-control” mechanism for closure rates independent of the initial curvatures of the wound periphery. Notably, changes in curvature caused by fingering formation generate force that aids in the healing process.
A multiscale functional map of somatic mutations in cancer integrating protein structure and network topology
Authors: Zhang Yingying , Leung Alden K. , Kang Jin Joo , Sun Yu , Wu Guanxi , Li Le , Sun Jiayang , Cheng Lily , Qiu Tian , Zhang Junke , Wierbowski Shayne , Gupta Shagun , Booth James , Yu Haiyuan 
Published: March 2023

AbstractA major goal of cancer biology is to understand the mechanisms underlying tumorigenesis driven by somatically acquired mutations. Two distinct types of computational methodologies have emerged: one focuses on analyzing clustering of mutations within protein sequences and 3D structures, while the other characterizes mutations by leveraging the topology of protein-protein interaction network. Their insights are largely non-overlapping, offering complementary strengths. Here, we established a unified, end-to-end 3D structurally-informed protein interaction network propagation framework, NetFlow3D, that systematically maps the multiscale mechanistic effects of somatic mutations in cancer. The establishment of NetFlow3D hinges upon the Human Protein Structurome, a comprehensive repository we compiled that incorporates the 3D structures of every single protein as well as the binding interfaces of all known protein interactions in humans. NetFlow3D leverages the Structurome to integrate information across atomic, residue, protein and network levels: It conducts 3D clustering of mutations across atomic and residue levels on protein structures to identify potential driver mutations. It then anisotropically propagates their impacts across the protein interaction network, with propagation guided by the specific 3D structural interfaces involved, to identify significantly interconnected network “modules”, thereby uncovering key biological processes underlying disease etiology. Applied to 1,038,899 somatic protein-altering mutations in 9,946 TCGA tumors across 33 cancer types, NetFlow3D identified 1,4444 significant 3D clusters throughout the Human Protein Structurome, of which ~55% would not have been found if using only experimentally-determined structures. It then identified 26 significantly interconnected modules that encompass ~8-fold more proteins than applying standard network analyses. NetFlow3D and our pan-cancer results can be accessed fromhttp://netflow3d.yulab.org.
Computational investigation of Scutellarein derivatives as an inhibitor against triple-negative breast cancer by Quantum calculation, and drug-designed approaches
Authors: Akash Shopnil , Aovi Farjana Islam , Azad Md. A.K , Kumer Ajoy , Chakma Unesco , Islam Md Rezaul , Mukerjee Nobendu , Rahman Md. Mominur , Bayıl Imren , Rashid Summya , Sharma Rohit 
Published: March 2023

AbstractTriple-negative breast cancer accounts for 10-15% of all breast tumors (TNBC). Triple-negative breast cancer lacks either estrogen or progesterone receptors (ER or PR), producing either too little or too much HER2. (All three tests result in “negative” results for the cells.) These cancers are more common in women under 40 who are Black or have the BRCA1 mutation. TNBC differs from other types of invasive breast cancer in that it has fewer treatment options, a worse prognosis, and grows and spreads more quickly (outcome). So, first of all, the protein of triple-negative breast cancer was collected from the PDB database having the most stable configuration, and a natural bioactive molecule, Scutellarein, was selected. Scutellarein is well-known to possess anti-cancer properties, so its derivatives were chosen to design anticancer drugs through computational tools. In this case, the functional group has applied and modified structural activity relationship methods. Then, the pass prediction score was taken, which indicates the probability of active (Pa) and the probability of inactive (Pi). After that, otherin-silcoapproaches, such as the ADMET parameter, and quantum calculation by Density Functional Theory (DFT), have been conducted. Finally, molecular docking and dynamics have been evaluated against TNBC to determine the binding affinity and stability. Scutellarein derivatives (DM03 at -10.7 kcal/mol, DM04 at -11.0 kcal/mol) have been reported to have a maximum tendency for binding against TNBC. Besides, the molecular dynamic simulation was performed at 100ns and described by root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF), which are much more stable compounds. The pharmacokinetics specifications for a suitable therapeutic candidate were satisfied by these molecules, like as non-carcinogenic, minimal to aquatic and non-aquatic toxicity. Almost all the molecules are highly soluble in the aqueous system. These all-computational data suggested that they might be suitable as a medication for the inhibition of TNBC, and further experimental studies should be carried out.