bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional connectivity between the amygdala and prefrontal cortex underlies processing of emotion ambiguity
Authors: Sun Sai , Yu Hongbo , Yu Rongjun , Wang Shuo 
Published: January 2023

AbstractProcessing facial expressions of emotion draws on a distributed brain network. In particular, judging ambiguous facial emotions involves coordination between multiple brain areas. Here, we applied multimodal functional connectivity analysis to achieve network-level understanding of the neural mechanisms underlying perceptual ambiguity in facial expressions. We found directional effective connectivity between the amygdala, dorsomedial prefrontal cortex (dmPFC), and ventromedial PFC, supporting both bottom-up affective processes for ambiguity representation/perception and top-down cognitive processes for ambiguity resolution/decision. Direct recordings from the human neurosurgical patients showed that the responses of amygdala and dmPFC neurons were modulated by the level of emotion ambiguity, and amygdala neurons responded earlier than dmPFC neurons, reflecting the bottom-up process for ambiguity processing. We further found parietal-frontal coherence and delta-alpha cross-frequency coupling involved in encoding emotion ambiguity. We replicated the EEG coherence result using independent experiments and further showed modulation of the coherence. EEG source connectivity revealed that the dmPFC top-down regulated the activities in other brain regions. Lastly, we showed altered behavioral responses in neuropsychiatric patients who may have dysfunctions in amygdala-PFC functional connectivity. Together, using multimodal experimental and analytical approaches, we have delineated a neural network that underlies processing of emotion ambiguity.Significance StatementA large number of different brain regions participate in emotion processing. However, it remains elusive how these brain regions interact and coordinate with each other and collectively encode emotions, especially when the task requires orchestration between different brain areas. In this study, we employed multimodal approaches that well complemented each other to comprehensively study the neural mechanisms of emotion ambiguity. Our results provided a systematic understanding of the amygdala-PFC network underlying emotion ambiguity with fMRI-based connectivity, EEG coordination of cortical regions, synchronization of brain rhythms, directed information flow of the source signals, and latency of single-neuron responses. Our results further shed light on neuropsychiatric patients who have abnormal amygdala-PFC connectivity.
Increased Ca2+signaling through CaV1.2 induces tendon hypertrophy with increased collagen fibrillogenesis and biomechanical properties
Authors: Li Haiyin , Korcari Antonion , Ciufo David , Mendias Christopher L. , Rodeo Scott A. , Buckley Mark R. , Loiselle Alayna E. , Pitt Geoffrey S. , Cao Chike 
Published: January 2023

AbstractTendons are tension-bearing tissues transmitting force from muscle to bone for body movement. This mechanical loading is essential for tendon development, homeostasis, and healing after injury. While Ca2+signaling has been studied extensively for its roles in mechanotransduction, regulating muscle, bone and cartilage development and homeostasis, knowledge about Ca2+signaling and the source of Ca2+signals in tendon fibroblast biology are largely unknown. Here, we investigated the function of Ca2+signaling through CaV1.2 voltage-gated Ca2+channel in tendon formation. Using a reporter mouse, we found that CaV1.2 is highly expressed in tendon during development and downregulated in adult homeostasis. To assess its function, we generatedScxCre;CaV1.2TSmice that express a gain-of-function mutant CaV1.2 channel (CaV1.2TS) in tendon. We found that tendons in the mutant mice were approximately 2/3 larger and had more tendon fibroblasts, but the cell density of the mutant mice decreased by around 22%. TEM analyses demonstrated increased collagen fibrillogenesis in the hypertrophic tendon. Biomechanical testing revealed that the hypertrophic Achilles tendons display higher peak load and stiffness, with no changes in peak stress and elastic modulus. Proteomics analysis reveals no significant difference in the abundance of major extracellular matrix (ECM) type I and III collagens, but mutant mice had about 2-fold increase in other ECM proteins such as tenascin C, tenomodulin, periostin, type XIV and type VIII collagens, around 11-fold increase in the growth factor of TGF-β family myostatin, and significant elevation of matrix remodeling proteins including Mmp14, Mmp2 and cathepsin K. Taken together, these data highlight roles for increased Ca2+signaling through CaV1.2 on regulating expression of myostatin growth factor and ECM proteins for tendon collagen fibrillogenesis during tendon formation.
Metabolically Primed Multipotent Hematopoietic Progenitors Fuel Innate Immunity
Authors: Cosgrove Jason , Lyne Anne-Marie , Rodriguez Ildefonso , Cabeli Vincent , Conrad Cecile , Tenreira-Bento Sabrina , Tubeuf Emilie , Russo Erica , Tabarin Fanny , Belloucif Yannis , Maleki-Toyserkani Shayda , Reed Sophie , Monaco Federica , Ager Ann , Lobry Camille , Bousso Philippe , Fernández-Marcos Pablo Jose , Isambert Herve , Argüello Rafael J. , Perié Leïla 
Published: January 2023

SUMMARYFollowing infection, hematopoietic stem and progenitor cells (HSPCs) support immunity by increasing the rate of innate immune cell production but the metabolic cues that guide this process are unknown. To address this question, we developed MetaFate, a method to trace the metabolic expression state and developmental fate of single cellsin vivo. Using MetaFate we identified a gene expression program of metabolic enzymes and transporters that confers differences in myeloid differentiation potential in a subset of HSPCs that express CD62L. Using single-cell metabolic profiling, we confirmed that CD62Lhighmyeloid-biased HSPCs have an increased dependency on oxidative phosphorylation and glucose metabolism. Importantly, metabolism actively regulates immune-cell production, with overexpression of the glucose-6-phosphate dehydrogenase enzyme of the pentose phosphate pathway skewing MPP output from B-lymphocytes towards the myeloid lineages, and expansion of CD62LhighHSPCs occurring to support emergency myelopoiesis. Collectively, our data reveal the metabolic cues that instruct innate immune cell development, highlighting a key role for the pentose phosphate pathway. More broadly, our results show that HSPC metabolism can be manipulated to alter the cellular composition of the immune system.
Non-alcoholic steatohepatitis disrupts diurnal liver transcriptome rhythms in mice
Authors: de Assis Leonardo Vinicius Monteiro , Demir Münevver , Oster Henrik 
Published: January 2023

ABSTRACTBackground & AimsThe liver ensures organismal homeostasis through modulation of physiological functions over the course of the day. How liver diseases such as non-alcoholic steatohepatitis (NASH) affects daily transcriptome rhythms in the liver remains elusive. To start closing this gap, we evaluated the impact of NASH on the diurnal regulation of the liver transcriptome in mice. Along this, we investigated how stringent consideration of circadian rhythmicity affects the outcomes of NASH transcriptome analyses.Approach & ResultsComparative rhythm analysis of the liver transcriptome from diet-induced NASH and control mice revealed an almost 3h phase advance in global gene expression rhythms. Rhythmically expressed genes associated with DNA repair and cell cycle regulation showed increased overall expression and circadian amplitude. In contrast, lipid and glucose metabolism associated genes showed loss of circadian amplitude, reduced overall expression, and phase advances in NASH livers. Comparison of NASH-induced liver transcriptome responses between published studies revealed little overlap (12%) in differentially expressed genes (DEGs). However, by controlling for sampling time and using circadian analytical tools, a 7-fold increase in DEG detection was achieved compared to methods without time control.ConclusionsNASH had a strong effect on circadian liver transcriptome rhythms with phase- and amplitude-specific effects for key metabolic and cell repair pathways, respectively. Accounting for circadian rhythms in NASH transcriptome studies markedly improves DEGs detection and enhances reproducibility.
Recurrence and propagation of past functions through mineral facilitated horizontal gene transfer
Authors: Verma Taru , Hendiani Saghar , Moral Carlota Carbajo , Andersen Sandra B. , Hammarlund Emma , Burmølle Mette , Sand Karina K. 
Published: January 2023

ABSTRACTHorizontal gene transfer is one of the most important drivers of bacterial evolution. Transformation by uptake of extracellular DNA is traditionally not considered to be an effective mode of gene acquisition, simply because extracellular DNA is degraded in a matter of days when it is suspended in e.g. seawater. Mineral surfaces are, however, known to preserve DNA in the environment, and sedimentary ancient DNA studies have solidified that there are considerable amounts of fragmented DNA stored in sediments world-wide. Recently the age span of stored DNA was increased to at least 2 Ma. Here, we highlight that fragmented ancient DNA can be fueling the evolution of contemporary bacteria and advocate to consider this route for genetic variation in evolutionary history. We show thatAcinetobacter baylyican incorporate 60 bp DNA fragments adsorbed to a wide range of common sedimentary minerals and that the transformation frequencies scale with the mineral surface properties. Further, our results point to interfacial geochemical and sedimentologic processes as facilitators of evolutionary innovation where DNA-molecules are specific to the environment and the processes providing new DNA molecules may also provide the need to evolve. In contrast to heritable stochastic mutations as proposed by Darwin, the access by which bacteria acquire new genomic material at times with increased stress and also needs, would indicate a non-random mechanism that may propel evolution in a non-stochastic manner.
Telomerase reactivation induces progression of mouse BrafV600E-driven thyroid cancers without telomere lengthening
Authors: Landa Iñigo , Thornton Caitlin EM , Xu Bin , Haase Jacob , Krishnamoorthy Gnana P. , Hao Jingzhu , Knauf Jeffrey A , Herbert Zachary T , Blasco María A , Ghossein Ronald , Fagin James A 
Published: January 2023

ABSTRACTMutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the paradigm of a cross-cancer alteration in a non-coding region.TERTpromoter mutations (TPMs) are biomarkers of poor prognosis in several tumors, including thyroid cancers. TPMs enhanceTERTtranscription, which is otherwise silenced in adult tissues, thus reactivating abona fideoncoprotein. To studyTERTderegulation and its downstream consequences, we generated aTertmutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalentlocus(Tert-123C>T) and crossed it with thyroid-specific BrafV600E-mutant mice. We also employed an alternative model ofTertoverexpression (K5-Tert). Whereas all BrafV600Eanimals developed well-differentiated papillary thyroid tumors, 29% and 36% of BrafV600E+Tert-123C>Tand BrafV600E+K5-Tert mice progressed to poorly differentiated thyroid cancers at week 20, respectively. Braf+Tert tumors showed increased mitosis and necrosis in areas of solid growth, and older animals from these cohorts displayed anaplastic-like features, i.e., spindle cells and macrophage infiltration. MurineTertpromoter mutation increasedTerttranscriptionin vitroandin vivo, but temporal and intra-tumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine and chemokine signaling, were overactivated. Braf+Tert animals remained responsive to MAPK pathway inhibitors. These models constitute useful pre-clinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs.
Healthy aging and cognitive impairment alter EEG functional connectivity in distinct frequency bands
Authors: Kumar Wupadrasta Santosh , Ray Supratim 
Published: January 2023

AbstractFunctional connectivity (FC) indicates the interdependencies between brain signals recorded from spatially distinct locations in different frequency bands, which is modulated by cognitive tasks and is known to change with aging and cognitive disorders. Recently, the power of narrow-band gamma oscillations induced by visual gratings has been shown to reduce with both healthy aging and in subjects with mild cognitive impairment (MCI). However, the impact of aging/MCI on stimulus-induced gamma FC has not been well studied. We recorded electroencephalogram (EEG) from a large cohort (N=229) of elderly subjects (>49 years) while they viewed large cartesian gratings to induce gamma oscillations and studied changes in alpha and gamma FC with healthy aging (N=218) and MCI (N=11). Surprisingly, we found that aging and disease changed power and FC in different ways. With healthy aging, alpha power did not change but FC decreased significantly. MCI reduced gamma but not alpha FC significantly compared with age and gender matched controls, even when power was matched between the two groups. Overall, our results show distinct effects of aging and disease on EEG power and FC, suggesting different mechanisms and the potential to use EEG stimulus-induced FC along with power for early diagnosis of Alzheimer’s Disease.
Circadian oscillation in primary cilium length by clock genes regulate fibroblast cell migration
Authors: Nakazato Ryota , Matsuda Yuki , Ijaz Faryal , Ikegami Koji 
Published: January 2023

AbstractVarious mammalian cells have autonomous cellular clocks that are produced by the transcriptional cycle of clock genes. Cellular clocks provide circadian rhythms for cellular functions via transcriptional and cytoskeletal regulation. The vast majority of mammalian cells possess a primary cilium, an organelle protruding from the cell surface. Here, we investigated the little-known relationship between circadian rhythm and primary cilia. The length and number of primary cilia showed circadian dynamics both in vitro and in vivo. The circadian rhythm of primary cilium length was abolished by SR9011 and Bmal1 knockout. A centrosomal protein, pericentrin, transiently accumulates in centriolar satellites, the base of primary cilia at the shortest cilia phase, and induces elongation of primary cilia at the longest cilia phase in the circadian rhythm of primary cilia. In addition, rhythmic cell migration during wound healing depends on the length of primary cilia and affects the rate of wound healing. Our findings demonstrate that the circadian dynamics of primary cilia length by clock genes control fibroblast migration and could provide new insights into chronobiology.
USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC
Authors: Zheng Jingyi , Wu Shasha , Tang Mao , Xi Shaoyan , Wang Yanchen , Ren Jun , Luo Hao , Hu Pengchao , Sun Liangzhan , Du Yuyang , Yang Hui , Wang Fenfen , Gao Han , Dai Ziwei , Ou Xijun , Li Yan 
Published: January 2023

AbstractAbnormal alternative splicing (AS) caused by alterations in spliceosomal factors is implicated in cancers. Standard models posit that splice site selection is mainly determined by early spliceosomal U1, U2 snRNPs. Whether and how other mid/late-acting spliceosome components such as USP39 modulate tumorigenic splice site choice remain largely elusive. We observed that hepatocyte-specific knock-in of USP39 promoted hepatocarcinogenesis and potently regulated splice site selection. In human liver cancer cells, USP39 promoted tumor proliferation in a spliceosome-dependent manner. USP39 depletion deregulated hundreds of AS events, including the oncogenic splice-switching of KANK2. Mechanistically, we developed a novel RBP-motif enrichment analysis and found that USP39 modulated exon inclusion/exclusion by interacting with SRSF6/HNRNPC in both humans and mice. Our data represent a paradigm for the control of splice site selection by mid/late-acting spliceosome proteins and their interacting RBPs. USP39 and possibly other mid/late-acting spliceosome proteins may represent potential prognostic biomarkers and targets for cancer therapy.Graphic Abstract
Towards Analyzing the Reclassification Dynamics of ClinVar Variants
Authors: Ruscheinski Andreas , Reimler Anna Lena , Ewald Roland , Uhrmacher Adelinde M. 
Published: January 2023

AbstractClinVar aggregates information about genetic variants and their relation to human diseases and forms a valuable resource for clinical diagnostics. The assessment of variants, e.g., as being benign or pathogenetic, changes over time. We collected variant classification histories of ClinVar releases and used those to derive discrete-time Markov chains to investigate the reclassification dynamics of variants in ClinVar in terms of transition probabilities between ClinVar releases and reclassifications.
Transformation of primary murine peritoneal mast cells by constitutive KIT activation as a result of lostCdkn2a/Arfexpression
Authors: Capellmann Sandro , Sonntag Roland , Schüler Herdit , Meurer Steffen K , Gan Lin , Kauffmann Marlies , Horn Katharina , Königs-Werner Hiltrud , Weiskirchen Ralf , Liedtke Christian , Huber Michael 
Published: January 2023

AbstractMast cells (MCs) are immune cells of the myeloid lineage distributed in tissues throughout the body. Phenotypically, they are a heterogeneous group characterized by different protease repertoires stored in secretory granules and differential presence of receptors. To adequately address aspects of MC biology either primary MCs isolated from human or mouse tissue or different human MC lines, like HMC-1.1 and -1.2, or rodent MC lines like L138.8A or RBL-2H3 are frequently used. Nevertheless, cellular systems to study MC functions are very limited. We have generated a murine connective tissue-like MC line, termed PMC-306, derived from primary peritoneal MCs (PMCs), which spontaneously transformed. We analyzed PMC-306 cells regarding MC surface receptor expression, effector functions and respective signaling pathways, and found that the cells reacted very similar to primary wildtype (WT) PMCs. In this regard, stimulation with MAS-related G-protein-coupled receptor member B2 (MRGPRB2) ligands induced respective signaling and effector functions. Furthermore, PMC-306 cells revealed significantly accelerated cell cycle progression, which however was still dependent on IL-3 and stem cell factor (SCF). Phenotypically, PMC-306 cells adopted an immature connective tissue-like MCs appearance. The reason for immortalization most likely is the loss of the two critical cell cycle regulatorsCdkn2a/INK4A andArf/p19, respectively. The loss ofCdkn2aandArfexpression could be mimicked in primary bone marrow-derived mast cells (BMMCs) by SCF supplementation strongly arguing for an involvement of KIT activation in the transformation process. Hence, this new cell line might be a useful tool to study further aspects of PMC function and to address tumorigenic processes associated with MC leukemia.
From breast cancer cell homing to the onset of early bone metastasis: dynamic bone (re)modeling as a driver of metastasis
Authors: Young Sarah A. E. , Heller Anna-Dorothea , Garske Daniela S. , Rummler Maximilian , Qian Victoria , Ellinghaus Agnes , Duda Georg N. , Willie Bettina M. , Grüneboom Anika , Cipitria Amaia 
Published: January 2023

AbstractBreast cancer often metastasizes to bone causing osteolytic lesions. Structural and biophysical changes are rarely studied, yet are hypothesized to influence metastatic progression. Here, we developed a mouse model of early bone metastasis and multimodal 3D imaging to quantify cancer cell homing, dynamic bone (re)modeling and onset of bone metastasis. Using 3D light sheet fluorescence microscopy, we show eGFP+cancer cells and small clusters in 3D (intact) bones. We detect early bone lesions using time-lapsein vivomicroCT and reveal altered bone (re)modeling in absence of detectable lesions. With a new microCT image analysis tool, we detect and track the growth of early bone lesions over time. We show that cancer cells home in all bone compartments, while osteolytic lesions are only detected in the metaphysis, a region of high (re)modeling. Our study provides novel insights of dynamic bone (re)modeling as a driver during the early phase of metastasis.
Contribution of protein conformational heterogeneity to NMR lineshapes at cryogenic temperatures
Authors: Yi Xu , Fritzsching Keith J. , Rogawski Rivkah , Xu Yunyao , McDermott Ann E. 
Published: January 2023

AbstractWhile low temperature NMR holds great promise for the analysis of unstable samples and for sensitizing NMR detection, spectral broadening in frozen protein samples is a common experimental challenge. One hypothesis explaining the additional linewidth is that a variety of conformations are in rapid equilibrium at room temperature and become frozen, creating an inhomogeneous distribution at cryogenic temperatures. Here we investigate conformational heterogeneity by measuring the backbone torsion angle (Ψ) inE. coliDHFR at 105K. Motivated by the particularly broad N chemical shift distribution in this and other examples, we modified an established NCCN Ψ experiment to correlate the chemical shift of Ni+1to Ψi. With selective15N and13C enrichment of Ile, only the unique I60-I61 pair was expected to be detected in13C’-15N correlation spectrum. For this unique amide we detected three different conformation basins based on dispersed chemical shifts. Backbone torsion angles Ψ were determined for each basin 114 ± 7 for the major peak, and 150 ± 8 and 164 ± 16° for the minor peak as contrasted with 118 for the X-ray crystal structure (and 118-130 for various previously reported structures). These studies support the hypothesis that inhomogeneous distributions of protein backbone torsion angles contribute to the lineshape broadening in low temperature NMR spectra.Significance StatementUnderstanding protein conformational flexibility is essential for insights into the molecular basis of protein function and the thermodynamics of proteins. Here we investigate the ensemble of protein backbone conformations in a frozen protein freezing, which is likely a close representation for the ensemble in rapid equilibrium at room temperature. Various conformers are spectrally resolved due to the exquisite sensitivity of NMR shifts to local conformations, and NMR methods allow us to directly probe the torsion angles corresponding to each band of chemical shifts.