bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanoreceptor signal convergence and transformation in the dorsal horn flexibly shape a diversity of outputs to the brain
Authors: Chirila Anda M. , Rankin Genelle , Tseng Shih-Yi , Emanuel Alan J. , Chavez-Martinez Carmine L. , Zhang Dawei , Harvey Christopher D. , Ginty David D. 
Published: May 2022

SummaryThe encoding of touch in the spinal cord dorsal horn (DH) and its influence on tactile representations in the brain are poorly understood. Using a range of mechanical stimuli applied to the skin, large scale in vivo electrophysiological recordings, and genetic manipulations, here we show that neurons in the mouse spinal cord DH receive convergent inputs from both low- and high-threshold mechanoreceptor subtypes and exhibit one of six functionally distinct mechanical response profiles. Genetic disruption of DH feedforward or feedback inhibitory motifs, comprised of interneurons with distinct mechanical response profiles, revealed an extensively interconnected DH network that enables dynamic, flexible tuning of postsynaptic dorsal column (PSDC) output neurons and dictates how neurons in primary somatosensory cortex respond to touch. Thus, mechanoreceptor subtype convergence and nonlinear transformations at the earliest stage of the somatosensory hierarchy shape how touch of the skin is represented in the brain.
Oncogenic KRAS alters splicing factor phosphorylation and alternative splicing in lung cancer
Authors: Lo April , McSharry Maria , Berger Alice 
Published: May 2022

AbstractBackgroundAlternative RNA splicing is widely dysregulated in cancers including lung adenocarcinoma, where aberrant splicing events are frequently caused by somatic splice site mutations or somatic mutations of splicing factor genes. However, the majority of mis-splicing in cancers is unexplained by these known mechanisms. We hypothesize that the aberrant Ras signaling characteristic of lung cancers plays a role in promoting the alternative splicing observed in tumors.MethodsWe recently performed transcriptome and proteome profiling of human lung epithelial cells ectopically expressing oncogenic KRAS and another cancer-associated Ras GTPase, RIT1. Unbiased analysis of phosphoproteome data identified altered splicing factor phosphorylation in KRAS-mutant cells, so we performed differential alternative splicing analysis using rMATS to identify significantly altered isoforms in lung epithelial. To determine whether these isoforms were uniquely regulated by KRAS, we performed a large-scale splicing screen in which we generated over 300 unique RNA sequencing profiles of isogenic A549 lung adenocarcinoma cells ectopically expressing 75 different wild-type or variant alleles across 28 genes implicated in lung cancer.ResultsMass spectrometry data showed widespread downregulation of splicing factor phosphorylation in lung epithelial cells expressing mutant KRAS compared to cells expressing wild-type KRAS. We observed alternative splicing in the same cells, with 2196 and 2416 skipped exon events in KRASG12V and KRASQ61H cells, respectively, 997 of which were shared (p < 0.001 by hypergeometric test). In the high-throughput splicing screen, mutant KRAS induced the greatest number of differential alternative splicing events, second only to the RNA binding protein RBM45 and its mutant allele RBM45M126I. We identified ten high confidence cassette exon events across multiple KRAS variants and cell lines. These included differential splicing of the Myc Associated Zinc Finger (MAZ). As MAZ regulates expression of KRAS, this splice variant may be a mechanism for the cell to modulate wild-type KRAS levels in the presence of oncogenic KRAS.ConclusionProteomic and transcriptomic profiling of lung epithelial cells uncovered splicing factor phosphorylation and mRNA splicing events regulated by oncogenic KRAS. These data suggest that in addition to widespread transcriptional changes, Ras signaling pathways in cancer promote post-transcriptional splicing changes that may contribute to oncogenic processes.
Mutation in the matricellular gene fibulin-4 leads to endothelial dysfunction in resistance arteries
Authors: Lin Michelle , Jones Kara , Brengle Bridget M. , Mecham Robert P. , Halabi Carmen M. 
Published: May 2022

AbstractMutations in fibulin-4 (FBLN4), a matricellular gene required for extracellular matrix (ECM) assembly, result in autosomal recessive cutis laxa type 1B (ARCL1B), a syndrome characterized by loose skin, aortic aneurysms, pulmonary emphysema and skeletal abnormalities.Fbln4E57K/E57K mice recapitulated the phenotypes observed in ARCL1B. In particular, they exhibited ascending aortic aneurysms, elastic fiber fragmentation and increased stiffness in large arteries, and systolic hypertension. Surprisingly however, internal elastic laminae of small resistance and muscular arteries were intact. Here, we show that the increased pulsatile flow resulting from the structural abnormalities and increased stiffness of conduit arteries in Fbln4E57K/E57K mice leads to increased shear stress, a highly oxidative environment, and endothelial dysfunction related to reduced nitric oxide bioavailability in resistance mesenteric arteries. These data have significant implications, not only for the basic biology of ECM assembly along the arterial tree, but also for the clinical consequences of large artery stiffness on the microcirculation.
High-throughput, real-time monitoring of engineered skeletal muscle function using magnetic sensing
Authors: Smith Alec S.T. , Luttrell Shawn M. , Dupont Jean-Baptiste , Gray Kevin , Lih Daniel , Fleming Jacob W. , Cunningham Nathan J. , Jepson Sofia , Hesson Jennifer , Mathieu Julie , Maves Lisa , Berry Bonnie J. , Fisher Elliot C. , Sniadecki Nathan J. , Geisse Nicholas A. , Mack David L. 
Published: May 2022

AbstractEngineered muscle tissues represent powerful tools for examining tissue level contractile properties of skeletal muscle. However, limitations in the throughput associated with standard analysis methods limit their utility for longitudinal study, high throughput drug screens, and disease modeling. Here we present a method for integrating 3D engineered skeletal muscles with a magnetic sensing system to facilitate non-invasive, longitudinal analysis of developing contraction kinetics. Using this platform, we show that engineered skeletal muscle tissues derived from both induced pluripotent stem cell and primary sources undergo improvements in contractile output over time in culture. We demonstrate how magnetic sensing of contractility can be employed for simultaneous assessment of multiple tissues subjected to different doses of known skeletal muscle inotropes as well as the stratification of healthy versus diseased functional profiles in normal and dystrophic muscle cells. Based on these data, this combined culture system and magnet-based contractility platform greatly broadens the potential for 3D engineered skeletal muscle tissues to impact the translation of novel therapies from the lab to the clinic.
Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice
Authors: Weber André A. , Yang Xiaojing , Mennillo Elvira , Ding Jeffrey , Watrous Jeramie D. , Jain Mohit , Chen Shujuan , Karin Michael , Tukey Robert H. 
Published: May 2022

ABSTRACTPediatric non-alcoholic fatty liver disease (NAFLD) is escalating in the United States, with a limited mechanistic understanding. Triclosan (TCS) is a high-volume antimicrobial additive that has been detected in human breastmilk and shown in adult mice to cause hepatosteatosis. To examine the effect of TCS presented to neonatal mice through lactation, we exposed pregnant females to TCS in their diet and evaluated its impact on nursing neonates. TCS is efficiently transferred by lactation to newborn mice, causing significant fatty liver (FL) during the suckling period. Lactational delivery stimulated hepatosteatosis, triglyceride accumulation, endoplasmic reticulum (ER) stress, inflammation, and liver fibrosis. These events were mirrored by inhibition of key metabolic regulators, FGF21 and AMPK. De novo lipogenesis (DNL) induced by lactational TCS exposure was blocked in mice deficient in hepatic ATF4 . In primary hepatocytes, siRNA specific inhibition of PERK, an ATF4 upstream activator and initiator of ER stress, blocked TCS induced DNL. Also, in the absence of PPARα, which targets regulation of ATF4, TCS induced triglyceride accumulation and the induction of DNL was blocked. The administration of obeticholic acid (OCA), a potent FXR agonist, as well as activation of intestinal mucosal-regenerative gp130 signaling, led to reduced liver ATF4 expression, PPARα signaling, and DNL when neonates were exposed to TCS. In summary, TCS exposure via lactation leads to early indicators of NAFLD development accompanied by hepatosteatosis that were mediated in a PERK-eIF2α-ATF4-PPARα cascade. These studies indicate that mother to child transmission of environmental toxicants such as TCS may underlie the recent increases in pediatric NAFLD.
Comparative genomic insights into the evolution of Halobacteria-associated “Candidatus Nanohaloarchaeota”
Authors: Zhao Dahe , Zhang Shengjie , Kumar Sumit , Zhou Heng , Xue Qiong , Sun Wurunze , Zhou Jian , Xiang Hua 
Published: May 2022

AbstractThe phylum “Candidatus Nanohaloarchaeota” is a representative halophilic lineage within DPANN superphylum. They are characterized by their nanosized cells and symbiotic lifestyle with Halobacteria. However, the development of the symbiosis remains unclear for the lack of genomes located at the transition stage. Here, we performed a comparative genomic analysis of “Ca. Nanohaloarchaeota”. We propose a novel family “Candidatus Nanoanaerosalinaceae” represented by five de-replicated metagenome-assembled genomes obtained from hypersaline sediments and the enrichment cultures of soda-saline lakes. Phylogeny analysis reveals that the novel family are placed at the root of the family “Candidatus Nanosalinaceae” including the well-researched taxa. Most members of “Ca. Nanoanaerosalinaceae” contain lower proportion of putative horizontal gene transfers from Halobacteria than “Ca. Nanosalinaceae”, while they maintain moderately acidic proteomes for hypersaline adaptation of “salt-in” strategy, suggesting that “Ca. Nanoanaerosalinaceae” have not established an intimate association with Halobacteria, and may descend from an intermediate stage. Functional prediction discloses that they exhibit divergent potentials in carbohydrate and organic acids metabolism, and environmental responses. Historical events reconstruction illustrates that the involved genes acquired at the putative ancestors possibly drive the evolutionary and symbiotic divergences. Globally, this research on the new family “Ca. Nanoanaerosalinaceae” enriches the taxonomic and functional diversity of “Ca. Nanohaloarchaeota”, and provides insights into the evolutionary process of “Ca. Nanohaloarchaeota” and their Halobacteria-associated symbiosis.ImportanceDPANN superphylum is a group of archaea widely distributing in various habitats. They generally have small cells, and perform a symbiotic lifestyle with other archaea. The archaeal symbiotic interaction is important to understand microbial community. However, the formation and evolution of the symbiosis between the DPANN lineages and other diverse archaea remain unclear. Based on phylogeny, hypersaline adaptation, functional potentials, and historical events of “Ca. Nanohaloarchaeota”, a representative phylum within the DPANN superphylum, we report a novel family descending from an intermediate stage, and we illustrate the evolutionary process of “Ca. Nanohaloarchaeota” and their Halobacteria-associated symbiosis. Furthermore, we find the acquired genes involved in carbohydrate and organic acids metabolism and environmental responses possibly drive the evolutionary and symbiotic divergences. Altogether, this research helps in understanding the evolution of the archaeal symbiosis, and provides a model for the evolution of the other DPANN lineages.
The efficacy of coenzyme Q10treatment in alleviating the symptoms of primary coenzyme Q10deficiency: a systematic review
Authors: Wang Ying , Hekimi Siegfried 
Published: May 2022

AbstractCoenzyme Q10(CoQ10) is necessary for mitochondrial electron transport. Mutations in CoQ10biosynthetic genes cause primary CoQ10deficiency (PCoQD) and manifest as mitochondrial disorders. It is often stated that PCoQD patients can be treated by oral CoQ10supplementation. To test this, we compiled all studies describing PCoQD patients up to May 2022. We excluded studies with no data on CoQ10treatment, or with insufficient description of effectiveness. Out of 303 PCoQD patients identified, we retained 89 cases, of which 24 reported improvements after CoQ10treatment (27.0%). In five cases, the patient’s condition was reported to deteriorate after halting of CoQ10treatment. 12 cases reported improvement in the severity of ataxia, and 5 cases in the severity of proteinuria. Only a subjective description of improvement was reported for four patients described as responding. All reported responses were partial improvements of only some symptoms. For PCoQD patients, CoQ10supplementation is replacement therapy. Yet, there is only very weak evidence for the efficacy of the treatment. Our findings thus suggest a need for caution when seeking to justify the widespread use of CoQ10for the treatment of any disease or as dietary supplement.HighlightsOnly 27% of primary CoQ10deficiency patients benefited from CoQ10supplementation.Studies of the effects of supplementation necessarily lacked controls and blinding.All reported positive responses to treatment only partially improved few symptoms.CoQ10supplementation for the treatment of any disease should be questioned.Firm evidence of benefits requires randomize, controlled trials of CoQ10therapy.Graphic Abstract
Nucleoli and the nucleoli-centromere association are dynamic during normal development and in cancer
Authors: Rodrigues Aaron , MacQuarrie Kyle L. , Freeman Emma , Leano Kurt , Willis Alexander B , Xu Zhaofa , Alvarez Angel A , Kosak Steven , Ma Yongchao , Perez White Bethany E , Foltz Daniel R , Huang Sui 
Published: May 2022

AbstractCentromeres are known to cluster around nucleoli in drosophila and mammalian cells. However, the functional significance of nucleoli-centromere interaction remains underexplored. We hypothesize that if this conserved interaction is functionally important, it should be dynamic under different physiological and pathological conditions. We examined the nucleolar structure and centromeres at various differentiation stages using cell culture models. The results show dynamic changes of nucleolar number, area, and nucleoli-centromere interactions at differentiation stages and in cancer cells. Embryonic stem cells usually have a single large nucleolus, which associates with a high percentage of centromeres. As cells differentiate into intermediate states, the nucleolar number increases and the association with centromeres decreases. In terminally differentiated cells, including myotubes, neurons and keratinocytes, the number of nucleoli and their association with centromeres are at the lowest. Cancer cells demonstrate the pattern of nucleoli number and nucleoli-centromere association that is akin to proliferative less differentiated cell types, suggesting that nucleolar reorganization and changes in nucleoli-centromere interactions may help facilitate malignant transformation. This idea is supported in a case of pediatric rhabdomyosarcoma, in which induced differentiation inhibits cell proliferation and reduces nucleolar number and centromere association. These findings suggest active roles of nucleolar structure in centromere function and genome organization critical for cellular function in both normal development and cancer.
Time Lagged Multidimensional Pattern Connectivity (TL MDPC): An EEG/MEG Pattern Transformation Based Functional Connectivity Metric
Authors: Rahimi Setareh , Jackson Rebecca , Farahibozorg Seyedeh-Rezvan , Hauk Olaf 
Published: May 2022

AbstractFunctional and effective connectivity methods are essential to study the complex information flow in brain networks underlying human cognition. Only recently have connectivity methods begun to emerge that make use of the full multidimensional information contained in patterns of brain activation, rather than univariate summary measures of these patterns. To date, these methods have mostly been applied to fMRI data, and no method allows vertex-vertex transformation with the temporal specificity of EEG/MEG data. Here, we introduce time-lagged multidimensional pattern connectivity (TL-MDPC) as a novel bivariate functional connectivity metric for EEG/MEG research. TL-MDPC estimates the vertex-to-vertex transformations among multiple brain regions and across different latency ranges. It determines how well patterns in ROI X at time point tx can linearly predict patterns of ROI Y at time point ty. In the present study, we use simulations to demonstrate TL-MDPC’s increased sensitivity to multidimensional effects compared to a univariate approach across realistic choices of number of trials and signal-to-noise ratio. We applied TL-MDPC, as well as its univariate counterpart, to an existing dataset varying the depth of semantic processing of visually presented words by contrasting a semantic decision and a lexical decision task. TL-MDPC detected significant effects beginning very early on, and showed stronger task modulations than the univariate approach, suggesting that it is capable of capturing more information. With TL-MDPC only, we observed rich connectivity between core semantic representation (left and right anterior temporal lobes) and semantic control (inferior frontal gyrus and posterior temporal cortex) areas with greater semantic demands. TL-MDPC is a promising approach to identify multidimensional connectivity patterns, typically missed by univariate approaches.HighlightsTL-MDPC is a multidimensional functional connectivity method for event-related EMEGTL-MDPC captures both univariate and multidimensional connectivityTL-MDPC yields both zero-lag and time-lagged dependenciesTL-MDPC produced richer connectivity than univariate approaches in a semantic taskTL-MDPC identified connectivity between the ATL hubs and semantic control regions
Development of fluoroquinolone resistance through antibiotic tolerance in Campylobacter jejuni
Authors: Park Myungseo , Kim Jinshil , Feinstein Jill , Lang Kevin S. , Ryu Sangryeol , Jeon Byeonghwa 
Published: May 2022

AbstractAntibiotic tolerance not only enables bacteria to survive under acute antibiotic exposures but also provides bacteria with a window of time to develop antibiotic resistance. Campylobacter jejuni is increasingly resistant to clinically important antibiotics, particularly fluoroquinolones (FQs). Currently, little is known about antibiotic tolerance and its effects on resistance development in C. jejuni. Here, we show that exposure to ciprofloxacin and tetracycline at concentrations 10 and 100 times higher than the minimum inhibitory concentration (MIC) induce antibiotic tolerance in C. jejuni, whereas gentamicin and erythromycin treatment cause cell death. Interestingly, FQ resistance is rapidly developed in C. jejuni after tolerance induction by ciprofloxacin and tetracycline. Furthermore, alkyl hydroperoxide reductase plays a critical role in preventing FQ resistance development in C. jejuni during antibiotic tolerance by alleviating oxidative stress. Together, these results demonstrate that exposure of C. jejuni to antibiotics used to treat campylobacteriosis can induce antibiotic tolerance and that FQ-resistant (FQR) C. jejuni rapidly emerges through tolerance induction by FQs and non-FQ antibiotics. Work presented in this study shows mechanisms underlying the high prevalence of FQRC. jejuni and provides an insight into the effects of antibiotic tolerance on resistance development.ImportanceAntibiotic tolerance compromises the efficacy of antibiotic treatment by extending bacterial survival and developing mutations associated with antibiotic resistance. Despite growing public health concerns about antibiotic resistance in C. jejuni, antibiotic tolerance has not yet been investigated in this important zoonotic pathogen. Here, our results show that exposure of C. jejuni to ciprofloxacin and tetracycline, a common agricultural antibiotic, develops antibiotic tolerance, which subsequently facilitates the emergence of FQRC. jejuni. Since antibiotic-resistant C. jejuni is transmitted primarily from animals to humans, our study suggests that non-FQ drugs, such as tetracycline, used for animals can also promote FQ resistance development by inducing antibiotic tolerance in C. jejuni. Overall, the findings in this study help us understand mechanisms of resistance development through the induction of antibiotic tolerance.
Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation
Authors: Alexander Desi C , Corman Tanya , Mendoza Mariel , Glass Andrew , Belity Tal , Campbell Riane R , Han Joseph , Keiser Ashley A , Winkler Jeffrey , Wood Marcelo A , Kim Thomas , Garcia Benjamin A , Cohen Hagit , Mews Philipp , Egervari Gabor , Berger Shelley L 
Published: May 2022

ABSTRACTHistone acetylation is a key component in the consolidation of long-term fear memories. Epigenetic enzymes involved in histone acetylation, including histone acetyltransferases and deacetylases, have been put forward as potential pharmacological targets in the treatment of pathological fear memories, such as those that underlie post-traumatic stress disorder (PTSD). However, these enzymes typically play a ubiquitous role in gene regulation, which precludes the clinical use of systemic manipulations. Recently, we have found that a nuclear-localized metabolic enzyme, Acetyl-coA synthetase 2 (Acss2), modulates histone acetylation during learning and memory. Loss of Acss2 is well-tolerated in mice, with no impact on general health or baseline behavior. Here, we show that an Acss2 null mouse model shows reduced acquisition of long-term fear memories in assays of contextual and cued fear conditioning. We find that loss of Acss2 leads to consolidation-specific reductions in both histone acetylation and the expression of critical learning and memory-related genes in the dorsal hippocampus. Further, we show that systemic administration of blood-brain-barrier (BBB)-permeable Acss2 inhibitors during the consolidation window reduces fear memory formation in mice and rats, and also reduces anxiety in a predator-scent-stress (PSS) paradigm. Our findings suggest that Acss2 plays a critical role in the formation of fear memories, and represents a potential pharmacological target in the treatment of PTSD.