bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantification of the escape from X chromosome inactivation with the million cell-scale human single-cell omics datasets reveals heterogeneity of escape across cell types and tissues
Authors: Tomofuji Yoshihiko , Edahiro Ryuya , Shirai Yuya , Kock Kian Hong , Sonehara Kyuto , Wang Qingbo S. , Namba Shinichi , Moody Jonathan , Ando Yoshinari , Suzuki Akari , Yata Tomohiro , Ogawa Kotaro , Namkoong Ho , Lin Quy Xiao Xuan , Buyamin Eliora Violain , Tan Le Min , Sonthalia Radhika , Han Kyung Yeon , Tanaka Hiromu , Lee Ho ,   Asian Immune Diversity Atlas Network,   Japan COVID-19 Task Force,   The BioBank Japan Project, Okuno Tatsusada , Liu Boxiang , Matsuda Koichi , Fukunaga Koichi , Mochizuki Hideki , Park Woong-Yang , Yamamoto Kazuhiko , Hon Chung-Chau , Shin Jay W. , Prabhakar Shyam , Kumanogoh Atsushi , Okada Yukinori 
Published: October 2023

AbstractOne of the two X chromosomes of females is silenced through X chromosome inactivation (XCI) to compensate for the difference in the dosage between sexes. Among the X-linked genes, several genes escape from XCI, which could contribute to the differential gene expression between the sexes. However, the differences in the escape across cell types and tissues are still poorly characterized because no methods could directly evaluate the escape under a physiological condition at the cell-cluster resolution with versatile technology. Here, we developed a method,single-cellLevelinactivatedXchromosome mapping (scLinaX), which directly quantifies relative gene expression from the inactivated X chromosome with droplet-based single-cell RNA-sequencing (scRNA-seq) data. The scLinaX and differentially expressed genes analyses with the scRNA-seq datasets of ∼1,000,000 blood cells consistently identified the relatively strong degree of escape in lymphocytes compared to myeloid cells. An extension ofscLinaXformulti-modal datasets,scLinaX-multi, suggested a stronger degree of escape in lymphocytes than myeloid cells at the chromatin-accessibility level with a 10X multiome dataset. The scLinaX analysis with the human multiple-organ scRNA-seq datasets also identified the relatively strong degree of escape from XCI in lymphoid tissues and lymphocytes. Finally, effect size comparisons of genome-wide association studies between sexes identified the larger effect sizes of thePRKXgene locus-lymphocyte counts association in females than males. This could suggest evidence of the underlying impact of escape on the genotype–phenotype association in humans. Overall, scLinaX and the quantified catalog of escape identified the heterogeneity of escape across cell types and tissues and would contribute to expanding the current understanding of the XCI, escape, and sex differences in gene regulation.
Spatial mapping of acoustic impedance of shrimp scale using multiple overlap discrete wavelet transform (moDWT)
Authors: Ojha Shivam , Agarwal Komal , Khan M Sarim Ameed , Shelke Amit , Habib Anowarul 
Published: October 2023

ABSTRACTThere are lots of challenges associated with conventional optical observation of biological tissues, where specimens are typically sliced and stained for better contrast. In contrast, Scanning Acoustic Microscopy (SAM) is a versatile label-free imaging technology widely applied in various domains, including biomedical imaging, non-destructive testing, and material research. It excels in offering precise visualization of both surface and subsurface structures, providing valuable insights through visual inspection and quantitative analysis. Acknowledging the SAM, this paper presents acoustic impedance microscopy of the shrimp scale in a novel manner. The proposed technique aims to image the local distribution of cross-sectional acoustic impedance in biological tissue, which is a parameter closely related to sound speed and potentially valuable for tissue characterization. The study leverages advanced signal processing techniques, maximal overlap discrete wavelet transform (moDWT), to decompose acoustic responses effectively. The moDWT, with its ability to handle signals of various lengths without constraints, is highlighted as a promising approach. To determine shrimp scale impedance, we first establish the accuracy of the proposed algorithm using PVDF as the target and polyimide as reference material. The results indicate an algorithm accuracy exceeding 90%. An impedance map is generated through Gaussian process regression (GPR), which predicts the impedance over the complete domain, addressing spatial variations in biological specimens. The resulting acoustic impedance maps provide in-depth insights into the functional framework and advance our understanding of shrimp biomechanics.
Inferring state-dependent diversification rates using approximate Bayesian computation (ABC)
Authors: Xie Shu , Valente Luis , Etienne Rampal S. 
Published: October 2023

AbstractState-dependent speciation and extinction (SSE) models provide a framework for quantifying whether species traits have an impact on evolutionary rates and how this shapes the variation in species richness among clades in a phylogeny. However, SSE models are becoming increasingly complex, limiting the application of likelihood-based inference methods. Approximate Bayesian computation (ABC), a likelihood-free approach, is a potentially powerful alternative for estimating parameters. One of the key challenges in using ABC is the selection of efficient summary statistics, which can greatly affect the accuracy and precision of the parameter estimates. In state-dependent diversification models, summary statistics need to capture the complex relationships between rates of diversification and species traits. Here, we develop an ABC framework to estimate state-dependent speciation, extinction and transition rates in the BiSSE (binary state dependent speciation and extinction) model. Using different sets of candidate summary statistics, we then compare the inference ability of ABC with that of using likelihood-based maximum likelihood (ML) and Markov chain Monte Carlo (MCMC) methods. Our results show the ABC algorithm can accurately estimate state-dependent diversification rates for most of the model parameter sets we explored. The inference error of the parameters associated with the species-poor state is larger with ABC than in the likelihood estimations only when the speciation rate is highly asymmetric between the two states (λ1/λ0= 5). Furthermore, we find that the combination of normalized lineage-through-time (nLTT) statistics and phylogenetic signal in binary traits (Fitz and Purvis’sD) constitute efficient summary statistics for the ABC method. By providing insights into the selection of suitable summary statistics, our work aims to contribute to the use of the ABC approach in the development of complex state-dependent diversification models, for which a likelihood is not available.
Minimally Sufficient Experimental Design using Identifiability Analysis
Authors: Gevertz Jana L. , Kareva Irina 
Published: October 2023

ABSTRACTMathematical models are increasingly being developed and calibrated in tandem with data collection, empowering scientists to intervene in real time based on quantitative model predictions. Well-designed experiments can help augment the predictive power of a mathematical model but the question of when to collect data to maximize its utility for a model is non-trivial. Here we define data as model-informative if it results in a unique parametrization, assessed through the lens of practical identifiability. The framework we propose identifies an optimal experimental design (how much data to collect and when to collect it) that ensures parameter identifiability (permitting confidence in model predictions), while minimizing experimental time and costs. We demonstrate the power of the method by applying it to a modified version of a classic site-of-action pharmacokinetic/pharmacodynamic model that describes distribution of a drug into the tumor microenvironment (TME), where its efficacy is dependent on the level of target occupancy in the TME. In this context, we identify a minimal set of time points when data needs to be collected that robustly ensures practical identifiability of model parameters. The proposed methodology can be applied broadly to any mathematical model, allowing for the identification of a minimally sufficient experimental design that collects the most informative data.
Enhanced KNa1.1 Channel Underlies Cortical Hyperexcitability and Seizure Susceptibility after Traumatic Brain Injury
Authors: Liu Ru , Sun Lei , Du Le , Guo Xi , Jia Meng , Wang Qun , Wu Jianping 
Published: October 2023

AbstractPathogenic variants of the sodium-activated potassium channel KNa1.1, have been reported in multiple epileptic disorders. However, whether and how KNa1.1 channel is involved in epileptogenesis after traumatic brain injury (TBI) remains unknown. Firstly, we used behavioral monitoring and EEG recording to examine physiological property, spontaneous seizure activity, and seizure susceptibility after TBI. We explored the changes of KNa1.1 channel following TBI, including changes of subcellular distribution and expression pattern. Meanwhile, we performed patch-clamp recording to detect the neuronal excitability. Furthermore, we built TBI model usingkcnt1−/−mice and compared seizure activity with those on wild- type mice. We found severity-dependent seizure susceptibility in different degree of injured mice. Meanwhile, increased neuronal expression of KNa1.1 channel, especially in inhibitory neurons, around the lesion was also observed following TBI with increased neuronal excitability including reduced firing rate of interneurons and imbalanced excitation and inhibition (E/I). Although the maximum frequency of action potential ofkcnt1−/−neurons was increased,kcnt1−/−mice displayed decreased seizure susceptibility to the pentylenetetrazole (PTZ) after TBI. Taken together, this study suggests that pathologically enhanced expression and abnormally distributed KNa1.1 channel after TBI contribute to disputed E/I and seizure susceptibility, which might provide a potential therapeutic target on the epileptogenesis after TBI.
Multi-omics profiling reveals ethylene signalling as a key pathway underlying both genetic and epigenetic responses to low-dose ionizing radiation inArabidopsis
Authors: Newman Jeremy R B , Zhou Mingqi , Pires J. Chris , Bacher Rhonda L , Kladde Michael , Concannon Patrick 
Published: October 2023

AbstractThere is increasing interest in the effects of low-dose ionizing radiation (IR) on plants as might occur during spaceflight, or as a consequence of human activities, such as nuclear power generation, that may result in the release of radioactive materials into the environment. High IR doses have long been used for the induction of mutations in plants with the goal of generating desirable traits for agribusiness. Less is known about the responses of plants to acute low doses of IR exposure. Here, we take a multi-omics approach to characterize the response to low dose IR inArabidopsis thaliana. We adapt the Methyltransferase Accessibility Protocol for individual templates (MAPit) technique for use in plants allowing us to assay the epigenetic response to acute low-dose IR (10 cGy and 100 cGy) 72 hr after exposure, and, in parallel, use RNA sequencing to profile the transcription response at 1, 3, 24 and 72 hr after exposure. IR exposures as low as 10 cGy elicit robust genetic responses inA. thalianadetectable as early as 1 hr after exposure. Further examination revealed dose-dependent changes in gene expression, chromatin accessibility and DNA methylation that implicate the ethylene signalling pathway and abiotic stress response as underlying the transcriptional and epigenetic changes associated with IR. These changes are observable up to 72 hr post-exposure, suggesting that they are maintained well after the initial acute exposure. Our findings indicate thatA. thalianaexecutes a multi-modal response to low-dose IR through induction and regulation of the ethylene response pathway.
Assessing the potential for genome-assisted breeding in red perilla using quantitative trait locus analysis and genomic prediction
Authors: Kinoshita Sei , Sakurai Kengo , Hamazaki Kosuke , Tsusaka Takahiro , Sakurai Miki , Kurosawa Terue , Aoki Youichi , Shirasawa Kenta , Isobe Sachiko , Iwata Hiroyoshi 
Published: October 2023

AbstractRed perilla is an important medicinal plant used in Kampo medicine, and the development of elite varieties of this species is urgently necessary. Medicinal compounds are generally considered target traits in medicinal plant breeding; however, selection based on the phenotypes of the compounds (i.e., conventional selection) is expensive and time-consuming. Here, we proposed genomic selection (GS) and marker-assisted selection (MAS) as suitable selection methods for medicinal plants, and evaluated the effectiveness of GS and MAS in red perilla breeding. Three breeding populations generated from crosses between one red and three green perilla genotypes were used to elucidate the genetic mechanisms underlying the production of major medicinal compounds using quantitative trait locus analysis and to evaluate the accuracy of genomic prediction (GP). We found that GP had sufficiently high accuracy for all traits, confirming that GS was an effective method for perilla breeding. Moreover, the three populations showed varying degrees of segregation, suggesting that use of these populations in breeding may yield simultaneous enhancements of different target traits. This study can contribute to research on the genetic mechanisms of the major medicinal compounds of red perilla as well as the breeding efficiency of this medicinal plant.
Development of covalent chemogenetic K2Pchannel activators
Authors: Deal Parker E. , Lee Haerim , Mondal Abhisek , Lolicato Marco , de Mendonca Philipe Ribeiro Furtado , Black Holly , El-Hilali Xochina , Bryant Clifford , Isacoff Ehud Y. , Renslo Adam R. , Minor Daniel L. 
Published: October 2023

AbstractK2Ppotassium channels regulate excitability by affecting cellular resting membrane potential in the brain, cardiovascular system, immune cells, and sensory organs. Despite their important roles in anesthesia, arrhythmia, pain, hypertension, sleep, and migraine, the ability to control K2Pfunction remains limited. Here, we describe a chemogenetic strategy termed CATKLAMP (CovalentActivation ofTREK familyK+channels to cLAmpMembranePotential) that leverages the discovery of a site in the K2Pmodulator pocket that reacts with electrophile-bearing derivatives of a TREK subfamily small molecule activator, ML335, to activate the channel irreversibly. We show that the CATKLAMP strategy can be used to probe fundamental aspects of K2Pfunction, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members. Together, our findings exemplify a new means to alter K2Pchannel activity that should facilitate studies both molecular and systems level studies of K2Pfunction and enable the search for new K2Pmodulators.
Keratinocytes Drive the Epithelial Hyperplasia Key to Sea Lice Resistance in Coho Salmon
Authors: Salisbury S.J. , Daniels R. Ruiz , Monaghan S.J. , Bron J.E. , Villamayor P.R. , Gervais O. , Fast M.D. , Sveen L. , Houston R.D. , Robinson N. , Robledo D. 
Published: October 2023

ABSTRACTBackgroundSalmonid species have followed markedly divergent evolutionary trajectories in their interactions with sea lice. While sea lice parasitism poses significant economic, environmental, and animal welfare challenges for Atlantic salmon (Salmo salar) aquaculture, coho salmon (Oncorhynchus kisutch) exhibit near-complete resistance to sea lice, achieved through a potent epithelial hyperplasia response leading to rapid louse detachment. The molecular mechanisms underlying these divergent responses to sea lice are unknown.ResultsWe characterised the cellular and molecular responses of Atlantic salmon and coho salmon to sea lice using single-nuclei RNA sequencing. Juvenile fish were exposed to copepodid sea lice (Lepeophtheirus salmonis), and lice-attached pelvic fin and skin samples were collected 12h, 24h, 36h, 48h, and 60h after exposure, along with control samples. Comparative analysis of control and treatment samples revealed an immune and wound-healing response that was common to both species, but attenuated in Atlantic salmon, potentially reflecting greater sea louse immunomodulation. Our results revealed unique but complementary roles of three layers of keratinocytes in the epithelial hyperplasia response leading to rapid sea lice rejection in coho salmon. Our results suggest that basal keratinocytes direct the expansion and mobility of intermediate and, especially, superficial keratinocytes, which eventually encapsulate the parasite.ConclusionOur results highlight the key role of keratinocytes to coho salmon’s sea lice resistance, and the diverged biological response of the two salmonid host species when interacting with this parasite. This study has identified key pathways and candidate genes that could be manipulated using various biotechnological solutions to improve Atlantic salmon sea lice resistance.
Chemical proteomics reveals that the anticancer drug everolimus affects ubiquitin-proteasome system
Authors: Lobas Anna A. , Saei Amir Ata , Lyu Hezheng , Zubarev Roman A. , Gorshkov Mikhail V. 
Published: October 2023

AbstractRapamycin is a natural antifungal, immunosuppressive, and antiproliferative compound allosterically inhibiting mTOR complex 1. The ubiquitin-proteasome system (UPS) responsible for protein turnover is usually not listed among the pathways affected by mTOR signaling; however, a number of reports indicated the interplay between UPS and mTOR. It is also reported that rapamycin and analogs can allosterically inhibit the proteasome itself. We studied the molecular effect of rapamycin and its analogs (rapalogs), everolimus, and temsirolimus by expression chemical proteomics on A549 cell line. The analysis revealed that the cellular response to everolimus differs dramatically from that of rapamycin and temsirolimus. In cluster analysis the effect of everolimus was similar to that of bortezomib, a well-established proteasome inhibitor. UPS-related pathways were enriched in the cluster of proteins specifically up-regulated upon everolimus and bortezomib treatments, suggesting that both compounds have similar proteasome inhibition effects. In particular, the total amount of ubiquitin was significantly elevated in the samples treated with everolimus and bortezomib, and the analysis of the polyubiquitination patterns revealed elevated intensities of the ubiquitin peptide with a GG modification at K48 residue, consistent with a bottleneck in the proteasomal protein degradation. Moreover, everolimus treatment resulted in both ubiquitin phosphorylation and a significant amount of semi-tryptic peptides illustrating the induction of protease activity. These observations suggest that everolimus affects the ubiquitin-proteasome system in a unique way and its mechanism of action is strikingly different from that of its close chemical analogs, rapamycin and temsirolimus. Data are available via ProteomeXchange with identifier PXD045774.
Multi-omics Identification and Route-Specific Characterization of Metastasis-specific EMT Genes and Their Microenvironmental Interactions
Authors: Kim Ki Tae , Lee Jae Eun , Cheong Jae-Ho , Cho In , Choi Yoon Young 
Published: October 2023

AbstractBackgroundGastric cancer (GC) constitute a significant cause of cancer-related mortality worldwide, with metastatic patterns including hematogenous, peritoneal, and ovarian routes. Although GC gene expression patterns have been extensively researched, the metastasis-specific gene expression landscape remains largely unexplored.MethodsWe undertook a whole transcriptome sequencing analysis of 66 paired primary and metastatic (hematogenous, peritoneal, or ovarian) GC tumors from 14 patients. Public databases including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) was used for validation. Single-cell RNA sequencing (scRNA-seq) of four ascites from serosa positive GC patients and five primary tumors by layer (superficial and deep) were analyzed.ResultsThrough differential expression analysis between paired primary and metastatic tumors by routes identified 122 unique metastasis-specific epithelial-mesenchymal transition (msEMT) genes. These genes demonstrated varying expression patterns depending on the metastatic route, suggesting route-specific molecular mechanisms in GC metastasis. High expression of msEMT genes in primary tumors was associated with more frequentCDH1mutations, the genomically stable subtype, and poor prognosis in TCGA GC cohort. This association was further corroborated by poor prognosis and high predictive performance for peritoneal/ovarian recurrence in two independent cohorts (GSE66229; n=300, GSE84437; n=433). scRNA-seq analysis of five primary tumors (GSE167297) and four independent ascites samples from GC patients revealed that msEMT genes were predominantly expressed in diverse fibroblast sub-populations, rather than cancer cells.ConclusionsThis study illuminates the route-specific mechanisms and underlines the significance of msEMT genes and cancer-associated fibroblasts in peritoneal metastasis of GC.
Methylphenidate modulates motor cortical dynamics and behavior
Authors: Verhein Jessica R. , Vyas Saurabh , Shenoy Krishna V. 
Published: October 2023

AbstractMethylphenidate (MPH, brand: Ritalin) is a common stimulant used both medically and non-medically. Though typically prescribed for its cognitive effects, MPH also affects movement. While it is known that MPH noncompetitively blocks the reuptake of catecholamines through inhibition of dopamine and norepinephrine transporters, a critical step in exploring how it affects behavior is to understand how MPH directly affects neural activity. This would establish an electrophysiological mechanism of action for MPH. Since we now have biologically-grounded network-level hypotheses regarding how populations of motor cortical neurons plan and execute movements, there is a unique opportunity to make testable predictions regarding how systemic MPH administration – a pharmacological perturbation – might affect neural activity in motor cortex. To that end, we administered clinically-relevant doses of MPH to Rhesus monkeys as they performed an instructed-delay reaching task. Concomitantly, we measured neural activity from dorsal premotor and primary motor cortex. Consistent with our predictions, we found dose-dependent and significant effects on reaction time, trial-by-trial variability, and movement speed. We confirmed our hypotheses that changes in reaction time and variability were accompanied by previously established population-level changes in motor cortical preparatory activity and the condition-independent signal that precedes movements. We expected changes in speed to be a result of changes in the amplitude of motor cortical dynamics and/or a translation of those dynamics in activity space. Instead, our data are consistent with a mechanism whereby the neuromodulatory effect of MPH is to increase the gain and/or the signal-to-noise of motor cortical dynamics during reaching. Continued work in this domain to better understand the brain-wide electrophysiological mechanism of action of MPH and other psychoactive drugs could facilitate more targeted treatments for a host of cognitive-motor disorders.