bluuebunny/crossref_metadata_2025_split huggingface dataset:
DARTsort: A modular drift tracking spike sorter for high-density multi-electrode probes
Authors: Boussard Julien , Windolf Charlie , Hurwitz Cole , Lee Hyun Dong , Yu Han , Winter Olivier , Paninski Liam 
Published: August 2023

AbstractWith the advent of high-density, multi-electrode probes, there has been a renewed interest in developing robust and scalable algorithms for spike sorting. Current spike sorting approaches, however, struggle to deal with noisy recordings and probe motion (drift). Here we introduce a modular and interpretable spike sorting pipeline,DARTsort (DriftAwareRegistration andTracking), that builds upon recent advances in denoising, spike localization, and drift estimation. DARTsort integrates a precise estimate of probe drift over time into a model of the spiking signal. This allows our method to be robust to drift across a variety of probe geometries. We show that our spike sorting algorithm outperforms a current state-of-the-art spike sorting algorithm, Kilosort 2.5, on simulated datasets with different drift types and noise levels. Open-source code can be found athttps://github.com/cwindolf/dartsort.
Volumetric imaging of an intact organism by a distributed molecular network
Authors: Qian Nianchao , Weinstein Joshua A. 
Published: August 2023

AbstractLymphatic, nervous, and tumoral tissues, among others, exhibit physiology that emerges from three-dimensional interactions between genetically unique cells. A technology capable of volumetrically imaging transcriptomes, genotypes, and morphologies in a single de novo measurement would therefore provide a critical view into the biological complexity of living systems. Here we achieve this by extending DNA microscopy, an imaging modality that encodes a spatio-genetic map of a specimen via a massive distributed network of DNA molecules inside it, to three dimensions and multiple length scales in developing zebrafish embryos.
Linking reduced prefrontal microcircuit inhibition in schizophrenia to EEG biomarkers in silico
Authors: Rosanally Sana , Mazza Frank , Yao Heng Kang , Hay Etay 
Published: August 2023

AbstractReduced cortical inhibition by parvalbumin-expressing (PV) interneurons has been associated with impaired cortical processing in the prefrontal cortex (PFC) and altered EEG signals such as oddball mismatch negativity (MMN) in schizophrenia. However, establishing the link between reduced PV interneuron inhibition and reduced MMN experimentally in humans is currently not possible. To overcome these challenges, we used detailed computational models of human PFC microcircuits, and modeled schizophrenia microcircuits by integrating gene-expression data from schizophrenia patients indicating reduced PV interneuron inhibition output and NMDA input. We simulated spiking activity and EEG in microcircuits with different levels of reduced PV interneuron mechanisms and showed that a double effect of the reduction indicated by gene-expression led to a reduced MMN amplitude within the range seen in Schizophrenia patients, whereas a single effect resulted in a smaller decrease in MMN that matched the magnitude seen in patients at high-risk of schizophrenia. In addition, we showed that simulated resting EEG of schizophrenia microcircuits exhibited a right shift from alpha to beta frequencies. Our study thus links the level of reduced PV interneuron inhibition to distinct EEG biomarkers that can serve to better stratify different severities of schizophrenia and improve the early detection using non-invasive brain signals.
Correlation of two different devices for the evaluation of primary implant stability depending on dental implant length and bone density: an in vitro study
Authors: Lee Jungwon , Lim Young-Jun , Ahn Jin-Soo , Kim Bongju , Baek Yeon-Wha , Lim Bumsoon 
Published: August 2023

AbstractNon-invasive objective implant stability measurements are needed to determine the appropriate timing of prosthetic fitting after implant placement. We compared the early implant stability results obtained using resonance frequency analysis (RFA) and damping capacity analysis (DCA) depending on the implant length and bone density. Total 60, 4.0 mm diameter implants of various lengths (7.3 mm, 10 mm, and 13 mm) were used. Group I and Group II had implants placed in an artificial bone model with a uniform density of 15 PCF (0.24 g/cm3) and 30 PCF (0.48 g/cm3), respectively. RFA was performed using an Osstell® Beacon+; DCA was performed using Anycheck®. Measurements were repeated five times for each implant. Statistical significance was set atP<0.05. In Group I, bone density and primary implant stability were positively correlated, while implant length and primary implant stability were positively correlated. In Group II, the implant stability quotient (ISQ) and implant stability test (IST) values in did not change significantly above a certain length. Primary implant stability was positively correlated with bone density and improved with increasing implant length at low bone densities. Compared with the Osstell® Beacon+, the simplicity of Anycheck® was easy to use and accessible.
A frog adaptive radiation: Ecomorphological evolution in Old-World shrub frogs (Rhacophoridae:Pseudophilautus)
Authors: Meegaskumbura Madhava , Ellepola Gajaba , Senevirathne Gayani , Manamendra-Arachchi Kelum , Wijayathillaka Nayana , Pie Marcio , Sun Dan , Pethiyagoda Rohan , Schneider Christopher J. 
Published: August 2023

AbstractEcomorphs result from divergent natural selection, leading to species-rich adaptive radiations. Identifying ecomorphs and the resulting adaptive radiations in frogs is challenging due to conserved morphology and high species diversity. In this study, we demonstrate the ecological and climate specializations that have driven the diversification of shrub frogs of the genusPseudophilautusin Sri Lanka, a tropical continental island. We use a time-calibrated phylogeny, morphometric analyses, and climate-niche evolution, and identify five ecomorphological categories, including Tree-shrub, Rock-boulder, Leaf-litter, Habitat Generalists, and Canopy forms, and describe their evolution. Body size is the primary factor separating species, and specific body features correlate with habitat type. Ecomorphs likely evolved multiple times in disparate lineages, and in different regions and altitudes, during cold climatic periods owing to monsoon cycles resulting from the Himalayan-Tibetan orogeny. The common ancestor was a medium-sized, wet-adapted, tree-shrub habitat specialist which originated in the late Oligocene. Extreme size classes (diminutive leaf litter forms and large canopy forms) evolved recently and suggest that morphological disparity arose late in diversification, possibly aided by favorable climates. This work will facilitate understanding of adaptive radiations in frogs, which possibly will help uncover the prevalence of subtle adaptive radiations in frogs, just as in tailed-vertebrates.
A vast repertoire of secondary metabolites influences community dynamics and biogeochemical processes in cold seeps
Authors: Dong Xiyang , Zhang Tianxueyu , Wu Weichao , Peng Yongyi , Liu Xinyue , Han Yingchun , Chen Xiangwei , Gao Zhizeng , Xia Jinmei , Shao Zongze , Greening Chris 
Published: August 2023

AbstractIn deep sea cold seeps, diverse microbial communities thrive on the geological seepage of hydrocarbons and inorganic compounds. These chemosynthetically-driven communities are unique in composition, ecology, and biogeochemical activities compared to photosynthetically-driven ecosystems. However, their biosynthetic capabilities remain largely unexplored. Here, we analyzed 81 metagenomes, 33 metatranscriptomes, and seven metabolomes derived from nine globally distributed areas of cold seeps to investigate the secondary metabolites produced by cold seep microbiomes. Cold seep microbiomes encode diverse, abundant, and novel biosynthetic gene clusters (BGCs). Most BGCs are affiliated with understudied bacteria and archaea, including key mediators of methane and sulfur cycling, and multiple candidate phyla. The BGCs encode diverse antimicrobial compounds (e.g. NRPS, PKSs, RiPPs) that potentially shape community dynamics, as well as compounds predicted to influence biogeochemical cycling, such as phosphonates, iron-acquiring siderophores, nitrogenase-protecting glycolipids, and methyl-CoM reductase-modifying proteins. BGCs from key players in cold seeps are widely distributed and highly expressed, with their abundance and expression levels varying with different sediment depths. Numerous unique natural products were detected through untargeted sediment metabolomics, demonstrating a vast, unexplored chemical space and validatingin situexpression of the BGCs in cold seep sediments. Overall, these results demonstrate cold seep sediments potentially serve as a reservoir of hidden natural products and provide insights into microbial adaptation in chemosynthetically-driven ecosystems.
Two-way feedback between chromatin compaction and histone modification state explainsS. cerevisiaeheterochromatin bistability
Authors: Movilla Miangolarra Ander , Saxton Daniel S , Yan Zhi , Rine Jasper , Howard Martin 
Published: August 2023

AbstractCompact chromatin is closely linked with gene silencing in part by sterically masking access to promoters, inhibiting transcription factor binding and preventing polymerase from efficiently transcribing a gene. Here, we propose a broader view: chromatin compaction can be both a cause and a consequence of the histone modification state, and this tight bidirectional interaction can underpin bistable transcriptional states. To test this theory, we developed a mathematical model for the dynamics of the HMR locus inS. cerevisiae, that incorporates activating histone modifications, silencing proteins and a dynamic, acetylation-dependent, three-dimensional locus size. Chromatin compaction enhances silencer protein binding, which in turn feeds back to remove activating histone modifications, leading to further compaction. The bistable output of the model was in good agreement with prior quantitative data, including switching rates from expressed to silent states, and vice versa, and protein binding levels within the locus. We then tested the model by predicting changes in switching rates as the genetic length of the locus was increased, which were then experimentally verified. This bidirectional feedback between chromatin compaction and the histone modification state may be an important regulatory mechanism at many loci.SignificanceChromatin is the complex formed by proteins, including histones, and DNA to form chromosomes. Specific chromatin structures and states are thought to be key factors regulating transcription. A common view proposes that histone modifications activate or inhibit transcription either via specific activation or inhibition of RNA polymerase binding/elongation at a locus, or by expanding/compacting the locus, thereby modulating its accessibility to many macromolecules. In this work, we elucidated a broader hypothesis that chromatin compaction may both inhibit transcription, and feedback via silencing proteins to remove histone modifications that further control chromatin compaction and correlate with gene activity. We developed a model incorporating these ideas and showed that it explains quantitative experimental data for a silent locus in budding yeast.
Hyaluronan Hydrogel “Safety Nets” for 3D Cell Culture Applications
Authors: Wilson Russell T. , Bonteanu Andrei , Harrington Daniel A. 
Published: August 2023

AbstractPolymeric hydrogels can mimic features of native extracellular matrix (ECM), and their facile production and characterization enable customizable cell encapsulation and 3-dimensional (3D) culture. These have applications relevant to dentistry such as soft tissue engineering, cancer modeling, and drug screening. Hyaluronan (HA), a biologically-derived polymer found in native ECM, offers an optimal platform for this use, as it can be modified covalently with adhesive ligands, enzyme-degradable crosslinkers, and other biorelevant moieties, yielding tailored physical properties and biological response. Cell-directed degradation of these encapsulating matrices can be a prerequisite for phenotype preservation, but degradation kinetics may not match desired timelines for drug screening applications. This study focused on optimizing hydrogel composition, network structure, and gelation kinetics to preserve z-distribution of physiologically relevant cells within high-throughput microfluidic plates. Hydrogels were formed from aqueous solutions of thiolated HA (HA-SH), bifunctional acrylated poly(ethylene glycol)-peptide crosslinkers, and pendant acrylated peptides (RGD or YIGSR sequences) to support cell adhesion. By varying the absolute crosslinker concentration and relative proportions of high:low crosslinker degradation kinetics, hydrogels could be tuned to desired moduli (G’: ∼10-120 Pa) and enzymatic degradation rate. Ratios of high:low degradable crosslinkers, at equivalent total crosslinker concentration, minimally impacted final modulus or gelation rate. Similarly, pendant adhesive ligands were swapped easily with negligible impact on hydrogel physical properties. Hydrogels with a 50:50 ratio of high:low degradable crosslinkers provided a “safety net” that preserved z-distribution of encapsulated bone marrow-derived fibroblasts, while maintaining expected phenotype. A comparable system supported the 3D co-culture of primary human salivary epithelial and mesenchymal cells within a perfusable microfluidic multiwell plate. This customizable bottom-up construction reduced confounding factors encountered in hybridoma-derived protein matrices, enabling modular customization of physiologically relevant, yet reproducible matrices to replicate native ECM. Our optimized model demonstrates workflows to improve future pharmaceutical screens, and tailor tissue engineering applications.
Nonlinear Parameter and State Estimation Approach for Intradialytic Measurement of Absolute Blood Volume
Authors: Abohtyra Rammah , Vincent Tyrone , Schneditz Daniel 
Published: August 2023

AbstractBackgroundManaging blood and fluid volumes in chronic kidney disease (CKD) patients plays an essential role in dialysis therapy to replace kidney function.ObjectiveThis study aims to develop an estimation approach to provide predictable information on blood and fluid volumes during a regular dialysis routine.MethodsThe method utilizes a non-linear fluid volume model, an optimization technique, and the Unscented Kalman Filter (UKF). This method does not rely on specific ultrafiltration and dilution protocols and uses the Fisher information matrix to quantify the estimation error.ResultsThe method was applied to 21 data sets of ten patients. A significant moderate correlation was obtained when estimated blood volumes were compared to a different method applied to the same data set. Average specific blood volumes were plausible and in the range of 78.7 and 75.9 mL/kg at the end of the high ultrafiltration rate pulse and above the critical level of 65 mL/kg. Critical blood volumes were only observed in four studies done on three patients.ConclusionThe absolute blood volume estimated at the beginning and during every dialysis session offers the opportunity to detect critical blood volumes and to improve fluid management in CKD patients significantly.
Multi-omic stratification of the missense variant cysteinome
Authors: Desai Heta , Ofori Samuel , Boatner Lisa , Yu Fengchao , Villanueva Miranda , Ung Nicholas , Nesvizhskii Alexey I. , Backus Keriann 
Published: August 2023

ABSTRACTCancer genomes are rife with genetic variants; one key outcome of this variation is gain-of-cysteine, which is the most frequently acquired amino acid due to missense variants in COSMIC. Acquired cysteines are both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all acquired cysteines remain uncharacterized. Here, we pair cysteine chemoproteomics—a technique that enables proteome-wide pinpointing of functional, redox sensitive, and potentially druggable residues—with genomics to reveal the hidden landscape of cysteine acquisition. For both cancer and healthy genomes, we find that cysteine acquisition is a ubiquitous consequence of genetic variation that is further elevated in the context of decreased DNA repair. Our chemoproteogenomics platform integrates chemoproteomic, whole exome, and RNA-seq data, with a customized 2-stage false discovery rate (FDR) error controlled proteomic search, further enhanced with a user-friendly FragPipe interface. Integration of CADD predictions of deleteriousness revealed marked enrichment for likely damaging variants that result in acquisition of cysteine. By deploying chemoproteogenomics across eleven cell lines, we identify 116 gain-of-cysteines, of which 10 were liganded by electrophilic druglike molecules. Reference cysteines proximal to missense variants were also found to be pervasive, 791 in total, supporting heretofore untapped opportunities for proteoform-specific chemical probe development campaigns. As chemoproteogenomics is further distinguished by sample-matched combinatorial variant databases and compatible with redox proteomics and small molecule screening, we expect widespread utility in guiding proteoform-specific biology and therapeutic discovery.
Lymphatic vessel development in human embryos
Authors: Yamaguchi Shoichiro , Minamide Natsuki , Imai Hiroshi , Ikeda Tomoaki , Watanabe Masatoshi , Imanaka-Yoshida Kyoko , Maruyama Kazuaki 
Published: August 2023

AbstractLymphatic vessel development has been a subject of research for about 120 years. Studies employing mice and zebrafish models have elucidated that lymphatic endothelial cells (LECs) predominantly differentiate from venous endothelial cells via the expression of transcription factor Prospero homeobox protein 1 (Prox1), a master regulator of lymphatic vessel development. On the other hand, it has been found that LECs can also be generated from undifferentiated mesodermal or hemogenic endothelial cells, suggesting potential diversity in their origins depending on the organ or anatomical location. However, knowledge of human lymphatic vessel development remains limited. Here, we examined early lymphatic development in humans by analyzing 31 embryos and three 9-week old fetuses. We found that human embryos produce Prox1-expressing LECs in and around the cardinal veins, which converged to form initial lymph sacs. Furthermore, we also examined lymphatic vessel development in the heart, lungs, lower jaw, mesentery, intestines and kidneys. Lymphatic vessels appeared to develop at different rates in each organ and to display temporal differences in marker expression. These observation showed the possibility that there could exist different patterns of lymphatic vessel development across organs, which may reflect different cellular origins or developmental signaling in each organ.Our research clarifies the early development of human lymphatic vessels, contributing to a better understanding of the evolution and phylogenetic relationships of lymphatic systems, and enriching our knowledge of the role of lymphatics in various human diseases.Significance StatementLymphatic vessel development has been a focus of research for over a century. Recent studies across a variety of species have demonstrated that lymphatic endothelial cells originate from embryonic veins, and undifferentiated mesodermal cells. However, whether these findings are applicable to human has yet to be determined. In this study, we explored lymphatic vessel development in humans. Our analysis demonstrated that lymphatic endothelial cells in human embryos initially derived from embryonic veins. Notably, we found that lymphatic vessels in different organs displayed distinct developmental and marker expression patterns, suggesting a diversity in lymphatic vessel development across organs. Our research revealed the human lymphatic vessel development, contributing to the understanding of phylogenetics of lymphatic vessels and lymph-related diseases.
Engineered BCL6 BTB Domain of the Bcl-2 Protein Family shows Dynamic Structural Behavior: Insights from Molecular Dynamics Simulations
Authors: Saddam Md. , Habib Mohammad Ahsan , Fahim Md. Abrar , Mimi Afsana , Islam Saiful , Uddin Helal Md Mostofa 
Published: August 2023

AbstractApoptosis is crucially regulated by the Bcl-6 protein, and mutations in this protein can have a significant impact on many malignancies. In this study, we used molecular dynamics simulations to examine the effects of specific mutations (Q8C, R67C, and N84C) in the crystal structure of the BCL6 BTB domain in a compound with pyrazole-pyrimidine ligand. We concentrated on comprehending the dynamics of these alterations and their possible effects on the emergence of cancer. To explore the structural and dynamic changes induced by these mutations, we performed in silico simulations using the GROMACS software suite (version 5.2, 2020.1) on Google Colab’s Tesla T4 GPU. The crystal structure of the BCL6 BTB domain in complex with the pyrazole-pyrimidine ligand (PDB ID: 5N20) served as the wild-type reference structure. Mutations were imposed using the Rotamer functions of Chimera. The simulations were carried out for a total duration of 20 ns using a time step of 2 femtoseconds (0.002 ps). The Trajectory profiles of the BCL6 BTB domain protein and its three mutations, Q8C, R67C and N84C, were shown to differ from each other. Based on the analysis of RMSD, RMSF, and Rg, it was determined that the mutant 2 (R67C) protein exhibited increased instability and greater flexibility. In contrast, mutant 3 (N84C) demonstrates a heightened level of compactness and greater stability compared to the remaining protein mutant. PCA also provides information regarding the structural dynamics of these mutants. In addition, the SASA and SASA autocorrelation provides a distinct view of the solvent accessibility of these proteins.
Structure and function of the human mitochondrial MRS2 channel
Authors: He Zhihui , Tu Yung-Chi , Tsai Chen-Wei , Mount Jonathan , Zhang Jingying , Tsai Ming-Feng , Yuan Peng 
Published: August 2023

AbstractThe human Mitochondrial RNA Splicing 2 protein (MRS2) has been implicated in Mg2+transport across mitochondrial inner membranes, thus playing an important role in Mg2+homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here, we present structural and functional investigation of MRS2. Cryo-electron microscopy structures in various ionic conditions reveal a pentameric channel architecture and the molecular basis of ion permeation and potential regulation mechanisms. Electrophysiological analyses demonstrate that MRS2 is a Ca2+-regulated, non-selective channel permeable to Mg2+, Ca2+, Na+and K+, which contrasts with its prokaryotic ortholog, CorA, operating as a Mg2+-gated Mg2+channel. Moreover, a conserved arginine ring within the pore of MRS2 functions to restrict cation movements, likely preventing the channel from collapsing the proton motive force that drives mitochondrial ATP synthesis. Together, our results provide a molecular framework for further understanding MRS2 in mitochondrial function and disease.