bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benzyl isothiocyanate induces cardiomyocyte proliferation and heart regeneration
Authors: Sakaguchi Akane , Kawasaki Miwa , Saito Yuichi , Murata Kozue , Masumoto Hidetoshi , Kimura Wataru 
Published: September 2021

AbstractCardiomyocyte proliferation is an evolutionarily conserved mechanism that supports cardiac regeneration in vertebrates. Mammalian cardiomyocytes are arrested from the cell cycle shortly after birth, and therefore mammals lose the ability to regenerate injured myocardium for the rest of their lives. Pharmacological induction of cardiomyocyte proliferation has gained a lot of interest in recent years, as researchers strive to achieve heart tissue regeneration. Here we show that a small chemical, benzyl isothiocyanate (BITC), induced cardiomyocyte proliferation through activation of the cyclin-dependent kinase (CDK) pathway. BITC treatment also allowed heart regeneration in the infarcted neonatal heart, even after the regeneration period in mice. Furthermore, administration of BITC to adult mice in parallel with mild hypoxia (10% O2) induced cell cycle reentry and tissue regeneration in the adult heart. Our findings thus suggest that pharmacological activation of the CDK pathway using BITC, concurrently with the activation of hypoxia-related signaling pathways, may be a promising approach to inducing cardiac regeneration in patients with heart disease.
Polycomb group protein CBX7 represses cardiomyocyte proliferation via modulation of the TARDBP/Rbm38 axis
Authors: Cho Kyu-Won , Andrade Mark , Bae Seongho , Kim Sangsung , Kim Jin Eyun , Jang Er Yearn , Husain Ahsan , Sutliff Roy L. , Calvert John W. , Park Changwon , Yoon Young-sup 
Published: September 2021

SummaryCardiomyocyte (CM) proliferation notably decreases during the perinatal period. At present, regulatory mechanisms for this loss of proliferative capacity is poorly understood. CBX7, a polycomb group (PcG) protein, regulates the cell cycle but its role in CM proliferation is unknown. Here, we report that CBX7 inhibits proliferation of perinatal CMs by controlling TARDBP/Rbm38 pathway. Gene expression profiling demonstrated that CBX7 expression in the heart was low during the prenatal period, abruptly increased during the perinatal period, and sustained constantly throughout the adulthood. CBX7, when overexpressed via adenoviral transduction in neonatal CMs, reduced proliferation and promoted multinucleation of the CMs. Mutant mice carrying targeted inhibition of CBX7 in CMs exhibited cardiomegaly with increased proliferation of CMs at postnatal stages. Mechanistically, CBX7 interacted with TAR DNA-binding protein 43 (TARDBP) and positively regulated its downstream target, RNA Binding Motif Protein 38 (RBM38). Rbm38 was upregulated in the postnatal hearts and overexpression of RBM38 reduced proliferation of neonatal CMs. Together, this study provides a novel insight into the role of CBX7 in regulation of CM proliferation during the perinatal period.
Interleukin-6 Signaling Mediates Cartilage Degradation and Pain in Post-Traumatic Osteoarthritis
Authors: Liao Yihan , Ren Yinshi , Luo Xin , Long Jason T. , Mirando Anthony J. , Leinroth Abigail P. , Ji Ru-Rong , Hilton Matthew J. 
Published: September 2021

AbstractOsteoarthritis (OA) and post-traumatic OA (PTOA) are prevalent joint disorders and leading causes of chronic pain. The disease pathology of OA/PTOA is caused by imbalanced catabolic and anabolic responses and pro-inflammatory changes; however, their connection to pain is not well studied. Since IL-6 is involved in cartilage degradation and conditions of inflammatory pain, we set out to identify whether IL-6 and IL-6 signaling mechanisms contribute to both PTOA-associated cartilage degradation and pain. We performed a modified destabilization of the medial meniscus (DMM) surgery, a model of PTOA, on conventional IL-6 KO and control mice and assessed both cartilage degradation and pain-associated phenotypes. Genetic removal ofIl6in males attenuates PTOA-associated cartilage catabolism, decreases innervation of soft tissues associated with the knee joint, and reduces nociceptive pain signaling, without improving subchondral bone sclerosis or chondrocyte apoptosis. We further demonstrate that specific downstream mediators of IL-6 signaling, the Janus kinases (JAKs), are critical in regulating both cartilage catabolism and pain signaling. We identified STAT3 as a key regulator of cartilage catabolism downstream of JAK; however, inhibition of STAT3 decreases cartilage anabolism while enhancing pain signals. ERK was found to be important for neurite outgrowth and pain signaling; however, inhibition of ERK was less effective in reducing cartilage catabolism. Therefore, our data demonstrate that IL-6 mediates both PTOA-associated cartilage degradation and pain, and provides critical details regarding the downstream mediators of IL-6 signaling as therapeutic targets for disease-modifying osteoarthritis drugs.Single Sentence SummaryIL-6 mediates PTOA-associated cartilage degradation and pain via specific downstream signaling mechanisms in a gender specific manner.
Mct11 deficiency alters hepatic glucose metabolism and energy homeostasis
Authors: Ainbinder Alina , Zhao Liping , Glover Patricia , Gelinas-Roa Karen , Rusu Victor , Harney Alycen , Hoch Eitan , Deik Amy A. , Pierce Kerry A. , Bullock Kevin , Dennis Courtney , Jeanfavre Sarah , Krejci Jesse , Choi Jinyoung , Hollenberg Anthony N. , Centeno-Cruz Federico , Barajas-Olmos Francisco , Zerrweck Carlos , Orozco Lorena , Clish Clary B. , Lander Eric S. , Florez Jose C. , Jacobs Suzanne B. R. 
Published: September 2021

SUMMARYGenetic variation at the SLC16A11 locus contributes to the disproportionate impact of type 2 diabetes (T2D) on Latino populations. We recently demonstrated that T2D risk variants reduce SLC16A11 liver expression and function of MCT11, the monocarboxylate transporter encoded by the SLC16A11 gene. Here, we show that SLC16A11 expression within the liver is primarily localized to the low oxygen pericentral region, and that T2D risk variants disrupt oxygen-regulated SLC16A11 expression in human hepatocytes. Under physiologic oxygen conditions, MCT11 deficiency alters hepatocyte glucose metabolism, resulting in elevated intracellular lactate and a metabolic shift toward triacylglycerol accumulation. We also demonstrate an impact of Mct11 deficiency on glucose and lipid metabolism in Slc16a11 knockout mice, which display physiological changes that are observed in individuals with T2D. Our findings provide mechanistic insight into how SLC16A11 disruption impacts hepatic energy metabolism and T2D risk, and highlight MCT11-mediated regulation of lactate levels as a potential therapeutic target.
Large dataset of octocoral mitochondrial genomes provides new insights into mt-mutS evolution and function
Authors: Muthye Viraj , Mackereth Cameron D. , Stewart James B. , Lavrov Dennis V. 
Published: September 2021

AbstractAll studied octocoral mitochondrial genomes contain a gene from the MutS family, whose members code for proteins involved in DNA mismatch repair, other types of DNA repair, meiotic recombination, and other functions. Although mutS homologues are found in all domains of life as well as viruses, octocoral mt-mutS is the only such gene encoded in an organellar genome. While the function of mtMutS is not known, its domain architecture, conserved sequence, and presence of some characteristic residues suggest its involvement in mitochondrial DNA repair. This inference is supported by exceptionally low rates of mt-sequence evolution observed in octocorals. Previous studies of mt-mutS have been limited by the small number of octocoral mt-genomes available. We utilized sequence-capture data from the recent Quattrini et al. study to assemble complete mitochondrial genomes for 97 species of octocorals. Combined with sequences publicly available in GenBank, this resulted in a dataset of 184 complete mitochondrial genomes, which we used to re-analyze the conservation and evolution of mt-mutS. We discovered the first case of mt-mutS loss among octocorals in one of the two Pseudoanthomastus sp. assembled from Quattrini et al. data. This species displayed accelerated rate and and changed patterns of nucleotide substitutions in mt-genome, which we argue provide additional evidence for the role of mtMutS in DNA repair. In addition, we found accelerated mt-sequence evolution in the presence of mt-mutS in several octocoral lineages. This accelerated evolution did not appear to be the result of relaxed selection pressure and did not entail changes in patterns of nucleotide substitutions. Overall, our results support previously reported patterns of conservation in mt-mutS and suggest that mtMutS is involved in DNA repair in octocoral mitochondria. They also indicate that the presence of mt-mutS contributes to, but does not fully explain, the low rates of sequence evolution in octocorals
Identification and characterization ofBotrylloides(Styelidae) species from Aotearoa New Zealand coasts
Authors: Temiz Berivan , Clarke Rebecca M. , Page Mike , Lamare Miles , Wilson Megan J. 
Published: September 2021

ABSTRACTAscidians are marine filter feeder primitive chordates.Botrylloidesascidians possess diverse biological abilities like whole-body regeneration (WBR), hibernation/aestivation, blastogenesis, metamorphosis, and natural chimerism. However, the absence of distinctive morphological features often makes identification problematic.Botrylloides diegensisis an ascidian that has been misidentified in previous studies and is recorded in GenBank asBotrylloides leachiidue to the high morphological similarity between the sister species. More available sequences and strategies around identification would help resolve some of the confusion currently surrounding its ambiguous nature. We collected severalBotrylloidessamples from 7 locations around New Zealand - Dunedin, Christchurch, Picton, Nelson, Whangateau, New Plymouth and Invercargill - and barcoded the species based on Cytochrome Oxidase I, Histone 3, 18S, and 28S ribosomal RNA markers. Network and Bayesian trees confirmed the presence of threeBotrylloidesspecies:B. diegensis, B. jacksonianum, andB. aff. anceps. Additionally, morphotypes of three species were investigated regarding zooid size, area, tentacle numbers and colonial arrangement.
Genome sequencing and analysis of two early-flowering cherry (Cerasus × kanzakura) varieties, ‘Kawazu-zakura’ and ‘Atami-zakura’
Authors: Shirasawa Kenta , Itai Akihiro , Isobe Sachiko 
Published: September 2021

AbstractTo gain genetic insights into the early-flowering phenotype of ornamental cherry, also known as sakura, we determined the genome sequences of two early-flowering cherry (Cerasus × kanzakura) varieties, ‘Kawazu-zakura’ and ‘Atami-zakura’. Since the two varieties are interspecific hybrids, likely derived from crosses between Cerasus campanulata (early-flowering species) and Cerasus speciosa, we employed the haplotype-resolved sequence assembly strategy. Genome sequence reads obtained from each variety by single molecule real-time sequencing (SMRT) were split into two subsets, based on the genome sequence information of the two probable ancestors, and assembled to obtain haplotype-phased genome sequences. The resultant genome assembly of ‘Kawazu-zakura’ spanned 519.8 Mb with 1,544 contigs and an N50 value of 1,220.5 kb, while that of ‘Atami-zakura’ totaled 509.6 Mb with 2,180 contigs and an N50 value of 709.1 kb. A total of 72,702 and 72,528 potential protein-coding genes were predicted in the genome assemblies of ‘Kawazu-zakura’ and ‘Atami-zakura’, respectively. Gene clustering analysis identified 2,634 clusters uniquely presented in the C. campanulata haplotype sequences, which might contribute to its early-flowering phenotype. Genome sequences determined in this study provide fundamental information for elucidating the molecular and genetic mechanisms underlying the early-flowering phenotype of ornamental cherry tree varieties and their relatives.
Developing an ethanol utilisation pathway based NADH regeneration system in Escherichia coli
Authors: Ng Wenfa 
Published: September 2021

AbstractMany industrially relevant biotransformation in whole-cells are dependent on cofactors such as NADH or NADPH. Cofactor regeneration is an established approach for providing a cheap source of cofactors in support of the main biotransformation reaction in biocatalysis. In essence, cofactor regeneration uses a sacrificial substrate to help regenerate a cofactor consumed by the main biotransformation reaction. Enzymatic in nature, alternative cofactor regeneration systems with high efficiency and which utilises low cost sacrificial substrate are of interest. Glucose dehydrogenase system has been dominant in NADH regeneration. But, in its current incarnation, glucose dehydrogenase system is relatively inefficient in regenerating NADH with theoretical yield of one NADH per glucose molecule. This work sought to explore the utility of a two-gene ethanol utilisation pathway in NADH regeneration. Comprising the first step that takes ethanol to acetaldehyde, and a second step that converts acetaldehyde to acetyl-CoA, NADH from both steps could be mined for supporting biotransformation reaction in cofactor regeneration mode. Theoretically, ethanol utilisation pathway (EUP) affords a higher NADH yield of two NADH per ethanol molecule, and is therefore more efficient than glucose dehydrogenase (GDH) system. In this project, the EUP pathway was coupled to a cpsADH (an alcohol dehydrogenase from Candida parapsilosis) mediated ketone to alcohol anaerobic biotransformation with concentration of alcohol product as marker for efficiency of cofactor regeneration. Experiment tests showed that EUP was more efficient than GDH. Further, EUP could support biotransformation of both butanone and acetophenone in single and two-phase biotransformation, respectively. Additional work conducted to improve biotransformation efficiency revealed that ethanol provision positively correlated with biotransformation efficiency. Growing cell biotransformation was also found to improve biotransformation efficiency compared to resting cell due largely to the driving force generated by cell growth. Tests of a growth medium effect also found that cells cultivated in M9 ethanol medium delivered higher biotransformation efficiency compared to those cultivated in LB medium. This could arise due to the lower expression of NADH dependent enzymes during growth in M9 ethanol medium compared to LB medium that allowed more NADH to be diverted to support ketone biotransformation. However, a persistent problem with the experimental system is the relatively poor consumption of ethanol that points to need for further engineering of the system. Collectively, pathway-based NADH regeneration is possible with ethanol utilisation, with biotransformation efficiency dependent on mode of biotransformation (resting cell versus growing cell) and growth medium used.
Horizontal orientation facilitates pollinator attraction and rain avoidance in radially symmetrical flowers
Authors: Nakata Taichi , Rin Ishii , Yaida Yuki A , Ushimaru Atushi 
Published: September 2021

AbstractPremiseFloral angle, such as upward, horizontal, and downward orientation are known to evolve under both biotic and abiotic agents to enhance pollination success in zoophilious plants. Adaptive significance of horizontal orientation in radially symmetrical (actinomorphic) flowers under biotic and abiotic selection pressures were largely unknown, although those in bilaterally symmetrical flowers have been well studied.MethodsUsing experimentally angle changed flowers, we examined the effects of flower angle on pollinator behaviors, pollination success and rain avoidance in a population of insect-pollinatedPlatycodon grandiflorus. We further investigated the frequency and amount of precipitation in the flowering season and pollen damage by water in this species.Main results: Horizontally oriented flowers received more visitations and pollen grains on the stigma in male and/or female phases than downward and/or upward oriented flowers and avoided pollen damage by rainfall compared to upward oriented flowers. The pollen germination experiment showed that approximately 30% of pollen grains burst in distilled water, thus pollen damage by rainfall was potentially serious inP. garndiflorus.ConclusionIn this study, our field experiments revealed that upward flowers cannot avoid damage from rainfall during the flowering period whereas both upward and downward flowers suffered from pollinator limitation in female success. Thus, horizontal flower orientation is suggested to be adaptive in this insect-pollinated actinomorphic species which blooms in the rainy season.
The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling
Authors: Ding Yanyan , Li Yuzhe , Zhang Qiangfeng Cliff , Liu Feng 
Published: September 2021

AbstractAlthough thrombosis has been extensively studied using various animal models, however, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that smarca5-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus that mimics venous thrombosis. We further used the anti-thrombosis drugs to treat smarca5zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5zko1049a and their siblings and found that both the chromatin accessibility at the keap1a promoter and expression of keap1a were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of hmox1a, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon smarca5 deletion. Importantly, overexpression of keap1a or knockdown of hmox1a partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the venous thrombosis-like phenotypes in smarca5 mutants. Together, our study using zebrafish smarca5 mutants not only characterizes a novel role for smarca5 in blood clot formation, but also provides a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.
Modeling single-cell phenotypes links yeast stress acclimation to transcriptional repression and pre-stress cellular states
Authors: Bergen Andrew C. , Kocik Rachel A. , Hose James , McClean Megan N. , Gasch Audrey P. 
Published: September 2021

AbstractStress defense and cell growth are inversely related in bulk culture analyses; however, these studies miss substantial cell-to-cell heterogeneity, thus obscuring true phenotypic relationships. Here, we devised a microfluidics system to characterize multiple phenotypes in single yeast cells over time before, during, and after salt stress. The system measured cell and colony size, growth rate, and cell-cycle phase along with nuclear trans-localization of two transcription factors: stress-activated Msn2 that regulates defense genes and Dot6 that represses ribosome biogenesis genes during an active stress response. By tracking cells dynamically, we discovered unexpected discordance between Msn2 and Dot6 behavior that revealed subpopulations of cells with distinct growth properties. Surprisingly, post-stress growth recovery was positively corelated with activation of the Dot6 repressor. In contrast, cells lacking Dot6 displayed slower growth acclimation, even though they grow normally in the absence of stress. We show that wild-type cells with a larger Dot6 response display faster production of Msn2-regulated Ctt1 protein, separable from the contribution of Msn2. These results are consistent with the model that transcriptional repression during acute stress in yeast provides a protective response, likely by redirecting translational capacity to induced transcripts.
Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo
Authors: Benetti Natalia , Gouil Quentin , del Fierro Andres Tapia , Beck Tamara , Breslin Kelsey , Keniry Andrew , McGlinn Edwina , Blewitt Marnie E. 
Published: September 2021

AbstractParents transmit genetic and epigenetic information to their offspring. Maternal effect genes regulate the offspring epigenome to ensure normal development. Here we report that the epigenetic regulator SMCHD1 has a maternal effect on Hox gene expression and skeletal patterning. Maternal SMCHD1, present in the oocyte and preimplantation embryo, prevents precocious activation of Hox genes postimplantation. Without maternal SMCHD1, highly penetrant posterior homeotic transformations occur in the embryo. Hox genes are decorated with Polycomb marks H2AK119ub and H3K27me3 from the oocyte throughout early embryonic development; however, loss of maternal SMCHD1 does not alter these marks. Therefore, we propose maternal SMCHD1 acts downstream of Polycomb marks to establish a chromatin state necessary for persistent epigenetic silencing and appropriate Hox gene expression later in the developing embryo. This is a striking role for maternal SMCHD1 in long-lived epigenetic effects impacting offspring phenotype.
Distinct proteostasis states drive pharmacologic chaperone susceptibility for Cystic Fibrosis Transmembrane Conductance Regulator misfolding mutants
Authors: McDonald Eli Fritz , Sabusap Carleen Mae P. , Kim Minsoo , Plate Lars 
Published: September 2021

ABSTRACTPharmacological chaperones represent a class of therapeutic compounds for treating protein misfolding diseases. One of the most prominent examples is the FDA-approved pharmacological chaperone lumacaftor (VX-809), which has transformed cystic fibrosis (CF) therapy. CF is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). VX-809 corrects folding of F508del CFTR, the most common patient mutation, yet F508del exhibits only mild VX-809 response. In contrast, rarer mutations P67L and L206W are hyper-responsive to VX-809, while G85E is non-responsive. Despite the clinical success of VX-809, the mechanistic origin for the distinct susceptibility of mutants remains unclear. Here, we use interactomics to characterize the impact of VX-809 on proteostasis interactions of P67L and L206W and compare these to F508del and G85E. We determine hyper-responsive mutations P67L and L206W exhibit decreased interactions with proteasomal, and autophagy degradation machinery compared to F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response, and inhibiting the lysosome attenuates F508del VX-809 response. Our data suggests a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.