bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mathematical Analysis of Left Ventricular Elastance with respect to Afterload Change During Ejection Phase
Authors: Kato Shiro , Himeno Yukiko , Amano Akira 
Published: September 2023

ABSTRACTSince the left ventricle (LV) has pressure (Pιυ) and volume (Vιυ), we can define LV elastance from the ratio betweenPιυandVιυ, termed as “instantaneous elastance.” On the other hand, end-systolic elastance (Emax) is known to be a good index of LV contractility, which is measured by the slope of several end-systolicPιυ-Vιυpoints obtained by using different loads. The wordEmaxoriginates from the assumption that LV elastance increases during the ejection phase and attains its maximum at the end-systole. From this concept, we can define another elastance determined by the slopes of isochronousPιυ-Vιυpoints, that isPιυ-Vιυpoints at a certain time after the ejection onset time by using different loads. We refer to this elastance as “load-dependent elastance.”To reveal the relation between these two elastances, we used a hemodynamic model that included a detailed ventricular myocyte contraction model. From the simulation results, we found that the isochronousPιυ-Vιυpoints lay in one line and that the line slope corresponding to the load-dependent elastance slightly decreased during the ejection phase, which is quite different from the instantaneous elastance.Subsequently, we analyzed the mechanism determining these elastances from the model equations. We found that instantaneous elastance is directly related to contraction force generated by the ventricular myocyte, but the load-dependent elastance is determined by two factors: one is the transient characteristics of the cardiac cell, i.e., the velocity–dependent force drops characteristics in instantaneous shortening. The other is the force–velocity relationship of the cardiac cell. We also found that the linear isochronous pressure–volume relation is based on the approximately linear relation between the temporal differential of the cellular contraction force and the cellular shortening velocity that results from the combined characteristics of LV and aortic compliances.
Enhancing KCC2 function reduces interictal activity and prevents seizures in mesial temporal lobe epilepsy
Authors: Donneger Florian , Zanin Adrien , Besson Jeremy , Kadiri Yoness , Pagan Carla , David Nicolas , Russeau Marion , Bielle Franck , Devaux Bertrand , Mathon Bertrand , Navarro Vincent , Chassoux Francine , Poncer Jean Christophe 
Published: September 2023

AbstractThe neuronal K/Cl cotransporter KCC2 controls intraneuronal chloride and subsequently the efficiency of GABA signaling. In many neurological disorders, including mesial temporal lobe epilepsy (mTLE), reduced KCC2 expression or function may lead to depolarizing GABA signaling, which may then contribute to pathological activity and seizures. Compensating for the dysregulation of chloride transport in the pathology therefore appears to be a promising therapeutic strategy. Two small molecules - prochlorperazine (PCPZ) and CLP-257 - recently identified from library screening as candidate KCC2 enhancers, appear to improve symptoms in animal models of disorders associated with KCC2 extinction. However, their mode of action in cortical neurons and their therapeutic potential in epilepsy remain elusive and even controversial. Here, we show in rat hippocampal neurons that PCPZ and CLP-257 act by increasing KCC2 function and clustering while decreasing its membrane diffusion, independent of phosphorylation of canonical regulatory residues. Consistently, both compounds suppress spontaneous interictal-like discharges in postoperative tissue from patients with mTLE. Chronic administration of PCPZ also reduces seizure frequency and interictal activity in a mouse model of mTLE. These results unravel the mechanism of action of two KCC2 enhancers and validate their therapeutic potential in mesial temporal lobe epilepsy.
A cell-free transcription-translation pipeline for recreating methylation patterns boosts DNA transformation in bacteria
Authors: Vento Justin M. , Durmusoglu Deniz , Li Tianyu , Sullivan Sean , Ttofali Fani , Schaik John van , Yu Yanying , Barquist Lars , Crook Nathan , Beisel Chase L. 
Published: September 2023

ABSTRACTThe bacterial world offers diverse strains for understanding medical and environmental processes and for engineering synthetic-biology chasses. However, genetically manipulating these strains has faced a long-standing bottleneck: how to efficiently transform DNA. Here we report IMPRINT, a generalized, rapid and scalable approach based on cell-free transcription-translation (TXTL) systems to overcome DNA restriction, a prominent barrier to transformation. IMPRINT utilizes TXTL to express DNA methyltransferases from the bacterial host’s restriction-modification systems. The expressed methyltransferases then methylate DNAin vitroto match the host DNA’s methylation pattern, circumventing restriction and enhancing transformation. With IMPRINT, we efficiently multiplex methylation by diverse DNA methyltransferases and enhance plasmid transformation in gram-negative and gram-positive bacteria. We also developed a high-throughput pipeline that identifies the most consequential methyltransferases, and we apply IMPRINT to facilitate a library screen for translational rules in a hard-to-transform Bifidobacterium. Overall, IMPRINT can enhance DNA transformation, enabling use of increasingly sophisticated genetic manipulation tools across the bacterial world.
HLA-Based Banking of Human Induced Pluripotent Stem Cells in Saudi Arabia
Authors: Alowaysi Maryam , Lehmann Robert , Al-Shehri Mohammad , Baadheim Moayad , Alzahrani Hajar , Aboalola Doaa , Zia Asima , Malibari Dalal , Daghestani Mustafa , Alghamdi Khaled , Haneef Ali , Jawdat Dunia , Hakami Fahad , Gomez-Cabrero David , Tegner Jesper , Alsayegh Khaled 
Published: September 2023

AbstractHuman iPSCs’ derivation and use in clinical studies are transforming medicine. Yet, there is a high cost and long waiting time for autologous iPS-based cellular therapy, and the genetic engineering of hypo-immunogenic iPS cell lines is hampered with numerous hurdles. Therefore, it is increasingly interesting to create cell stocks based on HLA haplotype distribution in a given population. In this study, we assessed the potential of HLA-based iPS banking for the Saudi population. First, we analyzed the HLA database of the Saudi Stem Cell Donor Registry (SSCDR), which contains high-resolution HLA genotype data of 64,315 registered Saudi donors at the time of analysis. We found that only 13 iPS lines would be required to cover 30% of the Saudi population, 39 iPS lines would offer 50% coverage and 596 for more than 90% coverage.Next, As a proof-of-concept, we launched the first HLA-based banking of iPSCs in Saudi Arabia. Using clinically relevant methods, we generated the first iPSC line from a homozygous donor for the most common HLA haplotype in Saudi. The two generated clones expressed pluripotency markers, could be differentiated into all three germ layers, beating cardiomyocytes and neuronal progenitors. To ensure that our reprogramming method generates genetically stable iPSCs, we assessed the mutational burden in the generated clones and the original blood sample from which the iPSCs were derived using whole-genome sequencing. All detected variants were found in the original donor sample and were classified as benign according to current guidelines of the American College of Medical Genetics and Genomics (ACMG).This study sets a road map for introducing iPS-based cell therapy in the Kingdom of Saudi Arabia.
CXCR3-CXCL11 signaling restricts angiogenesis and promotes pericyte recruitment
Authors: Goeckel Megan E. , Lee Jihui , Levitas Allison , Colijn Sarah , Mun Geonyoung , Burton Zarek , Chintalapati Bharadwaj , Yin Ying , Abello Javier , Stratman Amber 
Published: September 2023

ABSTRACTEndothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces, yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs—the chemokine receptor, CXCR3, and one of its ligands, CXCL11—that delimits EC angiogenic potential and suppresses pericyte recruitment during development through regulation ofpdgfbexpression in ECs.In vitromodeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes.In vivo, phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with and expansion of the vasculature in zebrafish treated with the Cxcr3 inhibitor AMG487. We also demonstrate using flow modeling platforms that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared to their control counterparts. Together these data suggest that CXCR3 signaling in ECs drives vascular stabilization events during development.
Outer membrane proteins inMycobacterium tuberculosisand its potential role in small molecule permeation
Authors: Palande Aseem , Patil Saniya , Veeram Anjali , Sahoo Soumya Swastik , Balaji M , Chugh Jeetender , Mukherjee Raju 
Published: September 2023

AbstractIncreased resistance to current anti-mycobacterial and a potential bias towards relatively hydrophobic chemical entities highlight an urgent need to understand how current anti-TB drugs enter the tubercle bacilli. While inner membrane proteins are well-studied, how small molecules cross the impenetrable outer membrane remains unknown. Here we employed mass spectrometry-based proteomics to show that octyl-β-glucopyranoside selectively extracts the outer membrane proteins ofMycobacterium tuberculosis. Differentially expressed proteins between nutrient replete and depleted conditions were enriched to identify proteins involved in nutrient uptake. We demonstrate cell surface localization of seven new proteins using immunofluorescence and show that overexpression of the proteins LpqY and ProX leads to hypersensitivity towards streptomycin, while expression of SubI, FecB2, and Rv0999 exhibited higher membrane permeability, assessed through EtBr accumulation assay. Further, proton NMR metabolomics suggests the role of four outer membrane proteins in glycerol uptake. This study identifies several outer membrane proteins that are involved in the permeation of small hydrophilic molecules and are potential targets for enhancing uptake and efficacy of anti-TB drugs.
Interaction between task-evoked and spontaneous brain activities: Insights from two event-related fMRI studies
Authors: Nayak Siddharth , Hojjati Seyed Hani , Ozoria-Blake Sindy , Feiz Farnia , Shteingart Jacob , Guerrero Antonio Fernandez , Razlighi Qolamreza R 
Published: September 2023

ABSTRACTHuman brain activities measured by fMRI can be categorized into at least two distinct categories; 1) spontaneous: slow (< 0.1 Hz) but inter-regionally coherent fluctuations in MR signal, and 2) task-evoked: change in the MR signal due to external stimulation. To date, there is no consensus in the field about the roles of spontaneous brain activity and whether it interacts with task-evoked activity. This is mainly because direct measurements of spontaneous activity during task performance is challenging, if not impossible. Here for the first time, we used a data-driven approach to obtain the time course of the spontaneous brain activity in two of the well-studied brain networks; 1) the Default mode network (DMN), where the strongest task-evoked negative BOLD response is also observed and 2) the dorsal attention network (DAN), where some of the strongest task-evoked positive BOLD response is observed. Voxel-wise multiple regression analysis is used to model fMRI timeseries with anticipated task-evoked BOLD response, the obtain time course of the spontaneous activity, and their interaction at each participant. Using 46 young and cognitively normal participants performing an event-related perceptual speed task inside the fMRI scanner, we showed that there is no significant interaction between the spontaneous and the task-evoked activity either as negative BOLD response in the DMN or as positive BOLD response in the DAN. We replicate our findings in a separate dataset with 24 young and cognitively normal participants performing a different event-related task inside another fMRI scanner. Our results suggest that the presence or absence of coherent spontaneous activity in the DMN, or DAN has negligible effect on the magnitude of the BOLD response and vice versa, which consequently means that the fMRI signal is a linear superposition of spontaneous and task evoked activity.
Large scale spatio-temporal study on European hake depicts sensitivity to sea bottom temperature, sea bottom oxygen concentration and sea surface temperature
Authors: Paradinas Iosu , Chust Guillem , Garcia Dorleta , Ibaibarriaga Leire 
Published: September 2023

AbstractEuropean hake (Merluccius merluccius) is a commercially important fish species that is known to have a marked bathymetric preference. No other environmental variable has yet been identified to drive the distribution of hake. This study looked into different climatic variables at different depths and identified sea bottom temperature, sea bottom dissolved oxygen concentration and chlorophyll concentration to affect the distribution of both juvenile and adult hake distributions.
ZeptoCTC - Sensitive Protein Analysis of True Single Cell Lysates using Reverse Phase Protein Arrays (RPPA)
Authors: Rivandi Mahdi , Franken André , Yang Liwen , Abramova Anna , Stamm Nadia , Eberhardt Jens , Gierke Berthold , Beer Meike , Fehm Tanja , Niederacher Dieter , Pawlak Michael , Neubauer Hans 
Published: September 2023

AbstractCirculating Tumor Cells (CTCs) are commonly analyzed through genomic profiling, which does not capture posttranslational and functional alterations of encoded proteins. To address this limitation, we developed ZeptoCTC, a single-cell protein analysis workflow that combines established technologies for single-cell isolation and sensitive Reverse Phase Protein Array (RPPA) analysis to assess multiple protein expression and activation in individual CTCs. The workflow involves single cell labeling, isolation, lysis, and printing of the true single cell lysates onto a ZeptoChip using a modified micromanipulator CellCelectorTM. Subsequently, the printed lysates undergo fluorescence immunoassay RPPA protein detection using a ZeptoReader followed by signal quantification with Image J software. ZeptoCTC was successfully optimized, beginning with the measurement of EpCAM protein expression—a standard marker for CTC detection. As expected, mean fluorescence signals for EpCAM levels were significantly higher in single MCF-7 cells compared to MDA-MB-231 cells. Next, Capivasertib-treated MCF-7 cells exhibited an approximately 2-fold increase in the pAkt/Akt ratio compared to non-treated control cells. This finding was consistent with a co-performed western blot analysis of pooled MCF-7 cells. Application of ZeptoCTC to the analysis of single CTCs derived from a metastasized breast cancer (MBC) patient indicated a significantly higher level of pAkt, accompanied by a corresponding increase in pErk level when compared to patient-matched WBC. Finally, the current workflow successfully indicated the detectable pAkt and Akt signal difference in CTCs from two MBC patients: one with an Akt1 wild-type genotype, and the other harboring approximately 80% Akt1(E17K) mutated CTCs. The mutated CTCs revealed clearly elevated pAkt levels (1.8-fold), along with an even more strongly elevated total Akt (3.4-fold) when compared to the respective signals measured in wild-type CTCs. In conclusion, ZeptoCTC is a highly sensitive method for measuring the expression and phosphorylation of treatment-relevant proteins in key cancer-driving signaling pathways from true single cell samples.
Ectopic assembly of an auxin efflux control machinery shifts developmental trajectories
Authors: Aliaga Fandino Ana Cecilia , Jelinkova Adriana , Marhava Petra , Petrasek Jan , Hardtke Christian S. 
Published: September 2023

AbstractPolar auxin transport in the Arabidopsis root tip maintains high auxin levels around the stem cell niche that gradually decrease in dividing cells but increase again once they transition towards differentiation. Protophloem differentiates earlier than other proximal tissues and employs a unique auxin ‘canalization’ machinery that is thought to balance auxin efflux with retention. It consists of a proposed activator of PIN auxin efflux carriers, the AGC kinase PAX; its inhibitor, BRX; and PIP5K enzymes, which promote polar PAX and BRX localization. Because of dynamic PAX-BRX-PIP5K interplay, the net cellular output of this machinery remains unclear. Here we deciphered the dosage-sensitive regulatory interactions between PAX, BRX and PIP5K by their ectopic expression in developing xylem vessels. The data suggest that the dominant collective output of the PAX-BRX-PIP5K module is a localized reduction in PIN abundance. This requires PAX-stimulated clathrin-mediated PIN endocytosis by site-specific phosphorylation, which distinguishes PAX from other AGC kinases. Importantly, ectopic assembly of the PAX-BRX-PIP5K module is sufficient to cause cellular auxin retention and affects root growth vigor by accelerating the trajectory of xylem vessel development. Our data thus provide direct evidence that local manipulation of auxin efflux alters the timing of cellular differentiation in the root.
RIDGE, a tool tailored to detect gene flow barriers across species pairs
Authors: Burban Ewen , Tenaillon Maud I. , Glémin Sylvain 
Published: September 2023

AbstractCharacterizing the processes underlying reproductive isolation between diverging lineages is central to understanding speciation. Here, we present RIDGE – Reproductive Isolation Detection using Genomic polymorphisms – a tool tailored for quantifying gene flow barrier proportions and identifying the corresponding genomic regions. RIDGE relies on an Approximate Bayesian Computation with a model-averaging approach to accommodate diverse scenarios of lineage divergence. It captures heterogeneity in effective migration rate along the genome while accounting for variation in linked selection and recombination. The barrier detection test relies on numerous summary statistics to compute a Bayes factor, offering a robust statistical framework that facilitates cross-species comparisons. Simulations revealed that RIDGE is particularly efficient both at capturing signals of ongoing migration and at identifying barrier loci, including for recent divergence times (~0.1 2Negenerations). Applying RIDGE to four published crow datasets, we validated our tool by identifying a well-known large genomic region associated with mate choice patterns. We identified additional barrier loci between species pairs, which have shown, on the one hand, that depending on the biological, demographic, and selection contexts, different combinations of summary statistics are informative for the detection of signals. On the other hand, these analyses also highlight the value of our newly developed outlier statistics in challenging detection conditions.
Conformational dynamics of a nicotinic receptor neurotransmitter site
Authors: Singh Mrityunjay , Indurthi Dinesh C. , Mittal Lovika , Auerbach Anthony , Asthana Shailendra 
Published: September 2023

AbstractAgonists increase receptor activity by providing net-favorable binding energy to active versus resting conformations of their target sites. We used molecular dynamics (MD) simulations to explore dynamics of the low-to-high affinity conformational change (L→H) at theTorpedoα–δ nicotinic acetylcholine receptor neurotransmitter site, using 4 agonists. Alternative conformations were identified in trajectories generated from a single starting structure by matching approximate binding energies calculatedin silicowith exact values measured experimentallyin vitro. In all simulations, the L→H transition started with a rotation of the agonist about its cationic center (’flip’), followed by a staged downward displacement of loop C (’flop’) and the formation of a compact, hydrophobic and stable high-affinity pocket (’fix’). Agonist rotation and a transient intermediate state are only in simulations but can be confirmed or refuted, for example by time-resolved structures.
Quantitative Learning of Cellular Features From Single-cell Transcriptomics Data Facilitates Effective Drug Repurposing
Authors: Zhong Jianmei , Yang Junyao , Song Yinghui , Zhang Zhihua , Wang Chunming , Tong Renyang , Li Chenglong , Yu Nanhui , Zou Lianhong , Liu Sulai , Pu Jun , Lin Wei 
Published: September 2023

AbstractIn this study, we have devised a computational framework SuperFeat that allows for the training of a machine learning model and evaluate the canonical cellular states/features in pathological tissues that underlie the progression of disease. This framework also enables the identification of potential drugs that target the presumed detrimental cellular features. This framework was constructed on the basis of an artificial neural network with the gene expression profiles serving as input nodes. The training data comprised single-cell RNA-seq datasets that encompassed the specific cell lineage during the developmental progression of cell features. A few models of the canonical cancer-involved cellular states/features were tested by such framework. Finally, we have illustrated the drug repurposing pipeline, utilizing the training parameters derived from the adverse cellular states/features, which has yielded successful validation results bothin vitroandin vivo. SuperFeat is accessible athttps://github.com/weilin-genomics/rSuperFeat.