bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Greater Himalayan Thrust Belt: Insight Into the Assembly of the Exhumed Himalayan Metamorphic Core, Modi Khola Valley, Central Nepal
Authors: Shrestha Sudip , Larson Kyle P. , Martin Aaron J. , Guilmette Carl , Smit Matthijs A. , Cottle John M. 
Published: August 2020

AbstractStrike‐parallel tectonometamorphic discontinuities within the Himalayan metamorphic core are typically interpreted to reflect thrust‐sense movement. However, there is disagreement on the nature and sense of movement across one such structure in central Nepal. Using an integrated approach, this study characterizes multiple structural breaks in the Modi Khola region. Thermobarometric calculations combined with petrochronological investigation show that rocks across the Sinuwa thrust record similar histories with prograde garnet growth ca. 35 Ma and peak pressures of ~11.0 kbar, anatexis at ca. 28 Ma, and followed by cooling and exhumation between ca. 24 and 15 Ma. Rocks below the structurally lower Bhanuwa fault record similar garnet growth at ca. 35 Ma and pressures of ~11.5 kbar but experienced melting and retrogression after ca. 21 Ma. Finally, rocks in the footwall of the Main Central thrust, the structurally lowest break investigated, record prograde metamorphism ca. 17–13 Ma with peak pressures of ~7.0 kbar. This down‐structural migration of prograde metamorphism, anatexis, and subsequent cooling and exhumation of the footwall is consistent with models of progressive underplating and in‐sequence thrusting. When paired with published cooling ages across the Bhanuwa fault, results from this study are consistent with normal‐sense reactivation of the structure during middle‐late Miocene time. This new data set shows that the final assembly of the Himalayan metamorphic core is a result of progressive deformation and juxtaposition of multiple thrust sheets through a combination of in‐sequence thrusting, out‐of‐sequence thrusting, and normal faulting. We refer to this as the Greater Himalayan thrust belt.
The role of selenium metabolism and selenoproteins in cartilage homeostasis and arthropathies
Authors: Kang Donghyun , Lee Jeeyeon , Wu Cuiyan , Guo Xiong , Lee Byeong Jae , Chun Jang-Soo , Kim Jin-Hong 
Published: August 2020

AbstractAs an essential nutrient and trace element, selenium is required for living organisms and its beneficial roles in human health have been well recognized. The role of selenium is mainly played through selenoproteins synthesized by the selenium metabolic system. Selenoproteins have a wide range of cellular functions including regulation of selenium transport, thyroid hormones, immunity, and redox homeostasis. Selenium deficiency contributes to various diseases, such as cardiovascular disease, cancer, liver disease, and arthropathy—Kashin–Beck disease (KBD) and osteoarthritis (OA). A skeletal developmental disorder, KBD has been reported in low-selenium areas of China, North Korea, and the Siberian region of Russia, and can be alleviated by selenium supplementation. OA, the most common form of arthritis, is a degenerative disease caused by an imbalance in matrix metabolism and is characterized by cartilage destruction. Oxidative stress serves as a major cause of the initiation of OA pathogenesis. Selenium deficiency and dysregulation of selenoproteins are associated with impairments to redox homeostasis in cartilage. We review the recently explored roles of selenium metabolism and selenoproteins in cartilage with an emphasis on two arthropathies, KBD and OA. Moreover, we discuss the potential of therapeutic strategies targeting the biological functions of selenium and selenoproteins for OA treatment.
The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology
Authors: Sims Natalie A. 
Published: August 2020

AbstractBone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation through an IL-6-dependent pathway. In growth plate chondrocytes, STAT3 signaling promotes the normal differentiation process that leads to bone lengthening. Within the osteoblast lineage, STAT3 signaling promotes bone formation in normal physiology and in response to mechanical loading through direct signaling in osteocytes. This activity, particularly that of the IL-6/gp130 family of cytokines, must be suppressed by SOCS3 for the normal formation of cortical bone.
Understanding paraxial mesoderm development and sclerotome specification for skeletal repair
Authors: Tani Shoichiro , Chung Ung-il , Ohba Shinsuke , Hojo Hironori 
Published: August 2020

AbstractPluripotent stem cells (PSCs) are attractive regenerative therapy tools for skeletal tissues. However, a deep understanding of skeletal development is required in order to model this development with PSCs, and for the application of PSCs in clinical settings. Skeletal tissues originate from three types of cell populations: the paraxial mesoderm, lateral plate mesoderm, and neural crest. The paraxial mesoderm gives rise to the sclerotome mainly through somitogenesis. In this process, key developmental processes, including initiation of the segmentation clock, formation of the determination front, and the mesenchymal–epithelial transition, are sequentially coordinated. The sclerotome further forms vertebral columns and contributes to various other tissues, such as tendons, vessels (including the dorsal aorta), and even meninges. To understand the molecular mechanisms underlying these developmental processes, extensive studies have been conducted. These studies have demonstrated that a gradient of activities involving multiple signaling pathways specify the embryonic axis and induce cell-type-specific master transcription factors in a spatiotemporal manner. Moreover, applying the knowledge of mesoderm development, researchers have attempted to recapitulate the in vivo development processes in in vitro settings, using mouse and human PSCs. In this review, we summarize the state-of-the-art understanding of mesoderm development and in vitro modeling of mesoderm development using PSCs. We also discuss future perspectives on the use of PSCs to generate skeletal tissues for basic research and clinical applications.
Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment
Authors: Keute Marius , Miller Meghan T. , Krishnan Michelle L. , Sadhwani Anjali , Chamberlain Stormy , Thibert Ronald L. , Tan Wen-Hann , Bird Lynne M. , Hipp Joerg F. 
Published: August 2020

AbstractAngelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11–q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.
Interpretation of psychiatric genome-wide association studies with multispecies heterogeneous functional genomic data integration
Authors: Reynolds Timothy , Johnson Emma C. , Huggett Spencer B. , Bubier Jason A. , Palmer Rohan H. C. , Agrawal Arpana , Baker Erich J. , Chesler Elissa J. 
Published: August 2020

AbstractGenome-wide association studies and other discovery genetics methods provide a means to identify previously unknown biological mechanisms underlying behavioral disorders that may point to new therapeutic avenues, augment diagnostic tools, and yield a deeper understanding of the biology of psychiatric conditions. Recent advances in psychiatric genetics have been made possible through large-scale collaborative efforts. These studies have begun to unearth many novel genetic variants associated with psychiatric disorders and behavioral traits in human populations. Significant challenges remain in characterizing the resulting disease-associated genetic variants and prioritizing functional follow-up to make them useful for mechanistic understanding and development of therapeutics. Model organism research has generated extensive genomic data that can provide insight into the neurobiological mechanisms of variant action, but a cohesive effort must be made to establish which aspects of the biological modulation of behavioral traits are evolutionarily conserved across species. Scalable computing, new data integration strategies, and advanced analysis methods outlined in this review provide a framework to efficiently harness model organism data in support of clinically relevant psychiatric phenotypes.
Empirical validation of a touchscreen probabilistic reward task in rats
Authors: Kangas Brian D. , Wooldridge Lisa M. , Luc Oanh T. , Bergman Jack , Pizzagalli Diego A. 
Published: August 2020

AbstractAnhedonia, the loss of pleasure from previously rewarding activities, is implicated in several neuropsychiatric conditions, including major depressive disorder (MDD). In order to accelerate drug development for mood disorders, quantitative approaches are needed to objectively measure responsiveness to reward as a means to identify deficits. One such approach, the probabilistic reward task (PRT), uses visual discrimination methodology to quantify reward learning. In this computerized task, humans make visual discriminations, and probabilistic contingencies are arranged such that correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Healthy participants consistently develop a response bias in favor of the rich alternative. However, participants with MDD typically exhibit lower response biases, and this blunting correlates with current and future anhedonia. The present studies validated a touchscreen-based PRT in rodents with formal and functional similarity to the human task. First, rats were trained to discriminate between two lines that differed in length. Next, parametric manipulations of probabilistic contingencies, line-length stimuli, and drug treatment (amphetamine, 0.32–3.2 mg/kg; scopolamine, 0.1–1.0 mg/kg; oxycodone, 0.1–1.0 mg/kg) on response bias were evaluated. Results demonstrated orderly shifts in bias and discriminability that varied as a function of, respectively, the asymmetry of rich/lean probabilities and disparity in line lengths. Drugs that enhance reward responsiveness (amphetamine and scopolamine, but not oxycodone) increased bias, verifying pharmacological task sensitivity. Finally, performance outcomes under optimized conditions were replicated in female rats. Collectively, the touchscreen-based rodent PRT appears to have high preclinical value as a quantitative assay of reward learning.
Mex3a interacts with LAMA2 to promote lung adenocarcinoma metastasis via PI3K/AKT pathway
Authors: Liang Jinghui , Li Haixia , Han Jingyi , Jiang Jin , Wang Jiang , Li Yongmeng , Feng Zitong , Zhao Renchang , Sun Zhenguo , Lv Bin , Tian Hui 
Published: August 2020

AbstractLung adenocarcinoma (LUAD) is the main subtype of lung cancer. In this study, we found that RBP Mex3a was significantly upregulated in LUAD tissues and elevated Mex3a expression was associated with poor LUAD prognosis and metastasis. Furthermore, we demonstrated that Mex3a knockdown significantly inhibited LUAD cell migration and invasion in vitro and metastasis in nude mice. Transcriptome sequencing indicated that Mex3a affected gene expression linked to ECM-receptor interactions, including laminin subunit alpha 2(LAMA2). RNA immunoprecipitation (RIP) assay revealed Mex3a directly bound to LAMA2 mRNA and Mex3a increased the instability of LAMA2 mRNA in LUAD cells. Furthermore, we discovered that LAMA2 was surprisingly downregulated in LUAD and inhibited LUAD metastasis. LAMA2 knockdown partially reverse the decrease of cell migration and invasion caused by Mex3a knockdown. In addition, we found that both Mex3a and LAMA2 could influence PI3K-AKT pathway, which are downstream effectors of the ECM-receptor pathway. Moreover, the reduced activation of PI3K-AKT pathway in caused by Mex3a depletion was rescued by LAMA2 knockdown. In conclusion, we demonstrated that Mex3a downregulates LAMA2 expression to exert a prometastatic role in LUAD. Our study revealed the prognostic and prometastatic effects of Mex3a in LUAD, suggesting that Mex3a can serve as a prognostic biomarker and a target for metastatic therapy.
Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma
Authors: Zheng Yang , Song An , Wang Chundi , Zhang Wei , Liang Dong , Ding Xu , Li Gang , Zhang Hongchuang , Zhang Wei , Du Yifei , Zhou Junbo , Wu Heming , Wu Yunong , Song Xiaomeng 
Published: August 2020

AbstractOur group previously identified that the NOTCH1 Abruptex domain contains the most mutations in Chinese OSCC patients, including a hotspot mutation (C1133Y). FBXW7 is an E3 ubiquitin ligase that regulates a network of proteins, including NOTCH1, via degradation. In this study, we first described the co-localization of isoform specific FBXW7-FBXW7β and NOTCH1C1133Y mutation in the same cytoplasmic sites. Gain- and loss-of-function assays were performed to examine the tumor suppressor role of FBXW7β in the proliferation and invasion of OSCC cells. The co-expression of NOTCH1C1133Y and FBXW7β significantly attenuated tumor growth. Meanwhile, FBXW7β reversed the oncogenic phenotype and the activation of the AKT/ERK/NFκB pathway induced by NOTCH1C1133Y mutation. FBXW7β downregulated the stability of NOTCH1C1133Y protein and promoted protein ubiquitination. This was the first time that we selected a NOTCH1 hotspot mutation detected in clinical samples and identified the function of FBXW7β that mediated NOTCH1 mutation degradation in OSCC. The newly identified interaction between FBXW7β and NOTCH1C1133Y protein provides new insights into the progression of OSCC, especially regarding Abruptex domain mutations, and represents a valuable target for OSCC therapy.
PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance
Authors: Montaudon Elodie , Nikitorowicz-Buniak Joanna , Sourd Laura , Morisset Ludivine , El Botty Rania , Huguet Léa , Dahmani Ahmed , Painsec Pierre , Nemati Fariba , Vacher Sophie , Chemlali Walid , Masliah-Planchon Julien , Château-Joubert Sophie , Rega Camilla , Leal Mariana Ferreira , Simigdala Nikiana , Pancholi Sunil , Ribas Ricardo , Nicolas André , Meseure Didier , Vincent-Salomon Anne , Reyes Cécile , Rapinat Audrey , Gentien David , Larcher Thibaut , Bohec Mylène , Baulande Sylvain , Bernard Virginie , Decaudin Didier , Coussy Florence , Le Romancer Muriel , Dutertre Guillaume , Tariq Zakia , Cottu Paul , Driouch Keltouma , Bièche Ivan , Martin Lesley-Ann , Marangoni Elisabetta 
Published: August 2020

AbstractA significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1-driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1-driven BC, including patients progressing on palbociclib treatment.
Engineering regulatory networks for complex phenotypes in E. coli
Authors: Liu Rongming , Liang Liya , Freed Emily F. , Choudhury Alaksh , Eckert Carrie A. , Gill Ryan T. 
Published: August 2020

AbstractRegulatory networks describe the hierarchical relationship between transcription factors, associated proteins, and their target genes. Regulatory networks respond to environmental and genetic perturbations by reprogramming cellular metabolism. Here we design, construct, and map a comprehensive regulatory network library containing 110,120 specific mutations in 82 regulators expected to perturb metabolism. We screen the library for different targeted phenotypes, and identify mutants that confer strong resistance to various inhibitors, and/or enhanced production of target compounds. These improvements are identified in a single round of selection, showing that the regulatory network library is universally applicable and is convenient and effective for engineering targeted phenotypes. The facile construction and mapping of the regulatory network library provides a path for developing a more detailed understanding of global regulation in E. coli, with potential for adaptation and use in less-understood organisms, expanding toolkits for future strain engineering, synthetic biology, and broader efforts.
Engineering designer beta cells with a CRISPR-Cas9 conjugation platform
Authors: Lim Donghyun , Sreekanth Vedagopuram , Cox Kurt J. , Law Benjamin K. , Wagner Bridget K. , Karp Jeffrey M. , Choudhary Amit 
Published: August 2020

AbstractGenetically fusing protein domains to Cas9 has yielded several transformative technologies; however, the genetic modifications are limited to natural polypeptide chains at the Cas9 termini, which excludes a diverse array of molecules useful for gene editing. Here, we report chemical modifications that allow site-specific and multiple-site conjugation of a wide assortment of molecules on both the termini and internal sites of Cas9, creating a platform for endowing Cas9 with diverse functions. Using this platform, Cas9 can be modified to more precisely incorporate exogenously supplied single-stranded oligonucleotide donor (ssODN) at the DNA break site. We demonstrate that the multiple-site conjugation of ssODN to Cas9 significantly increases the efficiency of precision genome editing, and such a platform is compatible with ssODNs of diverse lengths. By leveraging the conjugation platform, we successfully engineer INS-1E, a β-cell line, to repurpose the insulin secretion machinery, which enables the glucose-dependent secretion of protective immunomodulatory factor interleukin-10.
Clearance of HIV infection by selective elimination of host cells capable of producing HIV
Authors: Li Min , Liu Wei , Bauch Tonya , Graviss Edward A. , Arduino Roberto C. , Kimata Jason T. , Chen Min , Wang Jin 
Published: August 2020

AbstractThe RNA genome of the human immunodeficiency virus (HIV) is reverse-transcribed into DNA and integrated into the host genome, resulting in latent infections that are difficult to clear. Here we show an approach to eradicate HIV infections by selective elimination of host cells harboring replication-competent HIV (SECH), which includes viral reactivation, induction of cell death, inhibition of autophagy and the blocking of new infections. Viral reactivation triggers cell death specifically in HIV-1-infected T cells, which is promoted by agents that induce apoptosis and inhibit autophagy. SECH treatments can clear HIV-1 in >50% mice reconstituted with a human immune system, as demonstrated by the lack of viral rebound after withdrawal of treatments, and by adoptive transfer of treated lymphocytes into uninfected humanized mice. Moreover, SECH clears HIV-1 in blood samples from HIV-1-infected patients. Our results suggest a strategy to eradicate HIV infections by selectively eliminating host cells capable of producing HIV.
Optogenetic control of protein binding using light-switchable nanobodies
Authors: Gil Agnieszka A. , Carrasco-López César , Zhu Liyuan , Zhao Evan M. , Ravindran Pavithran T. , Wilson Maxwell Z. , Goglia Alexander G. , Avalos José L. , Toettcher Jared E. 
Published: August 2020

AbstractA growing number of optogenetic tools have been developed to reversibly control binding between two engineered protein domains. In contrast, relatively few tools confer light-switchable binding to a generic target protein of interest. Such a capability would offer substantial advantages, enabling photoswitchable binding to endogenous target proteins in cells or light-based protein purification in vitro. Here, we report the development of opto-nanobodies (OptoNBs), a versatile class of chimeric photoswitchable proteins whose binding to proteins of interest can be enhanced or inhibited upon blue light illumination. We find that OptoNBs are suitable for a range of applications including reversibly binding to endogenous intracellular targets, modulating signaling pathway activity, and controlling binding to purified protein targets in vitro. This work represents a step towards programmable photoswitchable regulation of a wide variety of target proteins.