bluuebunny/crossref_metadata_2025_split huggingface dataset:
PtenandDicer1loss causes poorly-differentiated endometrial adenocarcinoma in mice
Authors: Wang Xiyin , Wendel Jillian R. H. , Emerson Robert E. , Broaddus Russell R. , Creighton Chad , Rusch Douglas B. , Buechlein Aaron , DeMayo Francesco J. , Lydon John P. , Hawkins Shannon M. 
Published: March 2020

AbstractEndometrial cancer remains the most common gynecological malignancy in the United States. While the loss of the tumor suppressor, PTEN (phosphatase and tensin homolog), is well studied in endometrial cancer, recent studies suggest thatDICER1, the endoribonuclease responsible for miRNA genesis, also plays a significant role in endometrial adenocarcinoma. In an endometrial adenocarcinoma mouse model, which has a conditional uterine deletion ofPten, Dicer1was also conditionally deleted. Conditional uterine deletion ofDicer1andPtenresulted in high-penetrance, poorly-differentiated endometrial adenocarcinomas. Poorly-differentiated endometrial adenocarcinomas expressed known markers of clear-cell adenocarcinoma, including Napsin A and HNF1B (hepatocyte nuclear factor 1 homeobox B). Adenocarcinomas were hormone-independent, and treatment with long-term progesterone did not mitigate poorly-differentiated adenocarcinoma, nor did it affect adnexal metastasis. Transcriptomic analyses of uteri or Ishikawa cells with deletion ofDICER1revealed unique transcriptomic profiles and global downregulation of miRNAs. Integration of downregulated miRNAs with upregulated mRNA targets revealed deregulated let-7 and miR-16 target genes, similar to published humanDICER1-mutant endometrial cancers from TCGA (The Cancer Genome Atlas). Importantly, these miRNA-target genes, involved in ephrin-receptor and transforming growth factor-beta signaling, represent potential clinical targets for rare, yet deadly, poorly-differentiated endometrial adenocarcinomas in women. This mouse model represents poorly-differentiated endometrial adenocarcinoma and will allow for the discovery of novel mechanisms of hormone-independent endometrial adenocarcinoma from atrophic endometrium.Significance StatementEndometrial cancer is one of the few cancers with an increasing death rate in the United States. The most significant risk factor associated with death is high tumor grade, which occurs most frequently in postmenopausal women, where it develops within an atrophic endometrium. Here, we present a mouse model with conditional deletion ofDicer1, a key enzyme in miRNA genesis, andPten, a tumor suppressor, that develops poorly-differentiated, steroid hormone-independent, endometrial adenocarcinoma with adnexal metastasis. These high-grade adenocarcinomas develop from an atrophic endometrium and share molecular features withDICER1-mutant human endometrial adenocarcinomas. We anticipate that this preclinical model represents a move toward the discovery of novel mechanisms of hormone-independent development of endometrial adenocarcinoma from atrophic endometrium.
RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation
Authors: Cayre Surya , Faraldo Marisa M. , Bardin Sabine , Miserey-Lenkei Stéphanie , Deugnier Marie-Ange , Goud Bruno 
Published: March 2020

ABSTRACTThe Golgi-associated RAB GTPases, RAB6A and RAB6A’, regulate anterograde and retrograde transport pathways from and to the Golgi.In vitro, RAB6A/A’ have been reported to be involved in several cellular functions, including, in addition to transport, cell division, migration, adhesion and polarity. However, their role remains poorly describedin vivo, in particular in epithelial tissues. Here, we generated BlgCre;Rab6aF/Fmouse presenting a specific deletion ofRab6ain the mammary luminal secretory lineage during gestation and lactation.Rab6aloss severely impaired the differentiation, maturation and maintenance of the secretory tissue, compromising lactation. It led to a decreased activation of STAT5, a key regulator of the lactogenic process primarily governed by prolactin. Data obtained with a human mammary epithelial cell line suggested that defective STAT5 activation might originate from a perturbed transport of the prolactin receptor, altering its membrane expression and signaling cascade. Despite the major functional defects observed uponRab6adeletion, the polarized organization of the mammary epithelial bilayer was preserved. Altogether, our data reveal a crucial role for RAB6A/A’ in the lactogenic function of the mammary gland. They also suggest that the trafficking pathways controlled by RAB6A/A’ depend on cell type specialization and tissue context.SUMMARY STATEMENTThis study reveals a role for the Golgi-associated RAB GTPases, RAB6A/A’, in the lactogenic function of the mammary gland.
An inability to maintain the ribonucleoprotein genomic structure is responsible for host detection of negative-sense RNA viruses
Authors: Blanco-Melo Daniel , Nilsson-Payant Benjamin E. , Uhl Skyler , Escudero-Pèrez Beatriz , Olschewski Silke , Thibault Patricia , Panis Maryline , Rosenthal Maria , Muñoz-Fontela César , Lee Benhur , tenOever Benjamin R. 
Published: March 2020

SUMMARYCellular biology has a uniformity not shared amongst viruses. This is perhaps best exemplified by negative-sense RNA viruses that encode their genetic material as a ribonucleoprotein complex composed of genome, RNA-dependent RNA polymerase, and the nucleoprotein. Here we demonstrate that limiting nucleoprotein availability not only universally culminates in a replicative catastrophe for negative-sense RNA viruses, but it results in the production of aberrant genomic material and induction of the interferon-based host defenses. This dynamic illustrates the tremendous stress imposed on negative-sense RNA viruses during replication as genomic products accumulate in an environment that requires an increasing demand on nucleoprotein availability. We show that limiting NP by RNA interference or drug targeting blocks replication and primes neighboring cells through the production of interferon. Together, these results demonstrate that the nucleoprotein represents the Achilles heel of the entire phylum of negative-sense RNA viruses. Here we establish this principle for a diverse collection of human pathogens and propose that the nucleoprotein should be a primary target for the development of future antiviral drugs.HIGHLIGHTSLimited levels of NP result in production of defective viral genomesDefective viral genomes and viral antagonists are key determinants of the host antiviral responseThe host response and defective viral genome generation further exasperate NP availabilityNP is an optimal drug target for the whole phylum of negative-sense RNA viruses
Tumor Necrosis Factor Receptor Signaling Modulates Carcinogenesis in a Mouse Model of Breast Cancer
Authors: He Ling , Bhat Kruttika , Duhacheck-Muggy Sara , Ioannidis Angeliki , Zhang Le , Nguyen Nhan T. , Moatamed Neda A. , Pajonk Frank 
Published: March 2020

AbstractProinflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both, obesity and in the response of tissues to radiation, two known risk factors for the development of breast cancer. Using the MMTV-Wnt1 mouse model for spontaneous breast cancer and knockout mice for TNFR1 and TNFR2 we report that loss of a TNFR2 allele leads to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal endbuds. Furthermore, that loss of one TNFR2 allele increases the incidence of breast cancers in MMTV-Wnt1 mice and results in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-κB signaling pathways and autocrine production of TNFα. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression.We conclude, that imbalances in TNFR signaling promote the development and progression of breast cancer, indicating that selective agonists of TNFR2 could potentially modulate the risk for breast cancer in high-risk populations.Significance StatementOver the past four decades the treatment results for patients suffering from breast cancer have constantly improved, leaving breast cancer prevention as an important frontier against the second leading cause of cancer death in the United States. Obesity has become a national health crisis and is a known proinflammatory risk factor for breast cancer. Our study describes a previously unknown aspect of proinflammatory signaling on breast cancer development and progression, thus suggesting novel potential targets to modulate the incidence of the disease.
Global impact of phosphorylation on protein endurance
Authors: Wu Chongde , Ba Qian , Li Wenxue , Salovska Barbora , Hou Pingfu , Mueller Torsten , Rosenberger George , Gao Erli , Di Yi , Liu Yansheng 
Published: March 2020

AbstractPost-translational modifications such as phosphorylation can have profound effects on the physicochemical and biological properties of proteins. However, high-throughput and systematic approaches have not yet been developed to assess the effects of specific modification types and sites on protein lifetime, which represents a key parameter for understanding signaling rewiring and drug development. Here we describe a proteomic method, DeltaSILAC, to quantify the impact of site-specific phosphorylation on the endurance of thousands of proteins in live cells. Being configured on the reproducible data-independent acquisition mass spectrometry (DIA-MS), the pulse labeling approach using stable isotope-labeled amino acids in cells (SILAC), together with a novel peptide-level matching strategy, this multiplexed assay revealed the global delaying effect of phosphorylation on protein turnover in growing cancer cells. Further, we identified local sequence and structural features in proximity to the phosphorylated sites that could be associated with protein endurance alterations. We found that phosphorylated sites accelerating protein turnover are functionally selected for cell fitness and evolutionarily conserved. DeltaSILAC provides a generalizable approach for prioritizing the effects of phosphorylation sites on protein lifetime in the context of cell signaling and disease biology, which is highly complementary to existing methods. Finally, DeltaSILAC is widely applicable to diverse post-translational modification types and different cell systems.
Serial sarcomere number is substantially decreased within the paretic biceps brachii in individuals with chronic hemiparetic stroke
Authors: Adkins Amy N. , Dewald Julius P.A. , Garmirian Lindsay , Nelson Christa M. , Murray Wendy M. 
Published: March 2020

ABSTRACTA muscle’s structure, or architecture, is indicative of its function and is plastic; changes in input to or use of the muscle alter its architecture. Stroke-induced neural deficits substantially alter both input to and usage of individual muscles. Here, we combined novelin vivoimaging methods (second harmonic generation microendoscopy, extended field-of-view ultrasound, and fat-supression MRI) to quantify functionally meaningful muscle architecture parameters in the biceps brachii of both limbs of individuals with chronic hemiparetic stroke and in age-matched, unimpaired controls. Specifically, serial sarcomere number and physiological cross-sectional area were calculated from data collected at three anatomical scales: sarcomere length, fascicle length, and muscle volume. Our data indicate that the paretic biceps brachii had ~8,500 fewer serial sarcomeres compared to the contralateral limb (p=0.0044). In the single joint posture tested, the decreased serial sarcomere number was manifested by significantly shorter fascicles (10.7cm vs 13.6cm; p<0.0001) without significant differences in sarcomere lengths (3.58μm vs. 3.54μm; p=0.6787) in the paretic compared to the contralateral biceps. No interlimb differences were observed in unimpaired controls, suggesting we observed muscle adaptations associated with stroke rather than natural interlimb variability. This study provides the first direct evidence of the loss of serial sarcomeres in human muscle, observed in a population with neural impairments that lead to disuse and chronically place the affected muscle at a shortened position. This adaptation is consistent with functional consequences (increased passive resistance to elbow extension) that would amplify already problematic, neurally driven motor impairments.SIGNIFICANCE STATEMENTSerial sarcomere number determines a muscle’s length during maximum force production and its available length range for active force generation. Skeletal muscle length adapts to functional demands; for example, animal studies demonstrate that chronically shortened muscles decrease length by losing serial sarcomeres. This phenomenon has never been demonstrated in humans. Integrating multi-scale imaging techniques, including two photon microendoscopy, an innovative advance from traditional, invasive measurement methods at the sarcomere scale, we establish that chronic impairments that place a muscle in a shortened position are associated with the loss of serial sarcomeres in humans. Understanding how muscle adapts following impairment is critical to the design of more effective clinical interventions to mitigate such adaptations and to improve function following motor impairments.
RNA binding domains of heterologous viral proteins substituted for basic residues in the RSV Gag NC domain restore specific packaging of genomic RNA
Authors: Rice Breanna L. , Lochmann Timothy L. , Parent Leslie J. 
Published: March 2020

AbstractThe Rous sarcoma virus Gag polyprotein transiently traffics through the nucleus, which is required for efficient incorporation of the viral genomic RNA (gRNA) into virus particles. Packaging of gRNA is mediated by two zinc knuckles and basic residues located in the nucleocapsid (NC) domain in Gag. To further examine the role of basic residues located downstream of the zinc knuckles in gRNA encapsidation, we used a gain-of-function approach. We replaced a basic residue cluster essential for gRNA packaging with heterologous basic residue motif (BR) with RNA binding activity from either the HIV-1 Rev protein (Rev BR) or the HSV ICP27 protein (ICP27 BR). Compared to wild type Gag, the mutant ICP27 BR and Rev BR Gag proteins were much more strongly localized to the nucleus and released significantly lower levels of virus particles. Surprisingly, both the ICP27 BR and Rev BR mutants packaged normal levels of gRNA per virus particle when examined in the context of a proviral vector, yet both mutants were noninfectious. These results support the hypothesis that basic residues located in the C-terminal region of NC are required for selective gRNA packaging, potentially via initial electrostatic interactions that facilitate specific binding.
The Carbon Dioxide-induced Bioluminescence Increase inArachnocampaLarvae
Authors: Charlton Hamish Richard , Merritt David John 
Published: March 2020

AbstractArachnocampalarvae utilise bioluminescence to lure small arthropod prey into their web-like silk snares. The luciferin-luciferase light-producing reaction occurs in a specialised light organ composed of Malpighian tubule cells in association with a tracheal mass. The accepted model for bioluminescence regulation is that light is actively repressed during the non-glowing period and released when glowing through the night. The model is based upon foregoing observations that carbon dioxide (CO2) – a commonly-used insect anaesthetic – produces elevated light output in whole, live larvae as well as isolated light organs. Alternative anaesthetics were reported to have a similar light-releasing effect. We set out to test this model inArachnocampa flavalarvae by exposing them to a range of anaesthetics and gas mixtures. The anaesthetics isoflurane, ethyl acetate, and diethyl ether did not produce high bioluminescence responses in the same way as CO2. Ligation and dissection experiments localised the CO2response to the light organ rather than it being a response to general anaesthesia. Exposure to hypoxia through the introduction of nitrogen gas combined with CO2exposures highlighted that continuity between the longitudinal tracheal trunks and the light organ tracheal mass is necessary for recovery of the CO2-induced light response. The physiological basis of the CO2-induced bioluminescence increase remains unresolved but is most likely related to access of oxygen to the photocytes. The results suggest that the repression model for bioluminescence control can be rejected. An alternative is proposed based on neural upregulation modulating bioluminescence intensity.Summary StatementCO2was thought to act as an anaesthetic producing elevated bioluminescence inArachnocampa. Here we show it acts directly on the light organ and does not act as an anaesthetic.
Lipogenesis and innate immunity in hepatocellular carcinoma cells reprogrammed by an isoenzyme switch of hexokinases
Authors: Perrin-Cocon Laure , Vidalain Pierre-Olivier , Jacquemin Clémence , Aublin-Gex Anne , Olmstead Keedrian , Panthu Baptiste , Rautureau Gilles J. P. , André Patrice , Nyczka Piotr , Hütt Marc-Thorsten , Amoedo Nivea , Rossignol Rodrigue , Filipp Fabian Volker , Lotteau Vincent , Diaz Olivier 
Published: March 2020

AbstractDuring the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). The transcriptomic analysis of HCC tumors shows that highest expression level ofHK2in tumor lesions is inversely correlated toGCKexpression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis,HK2was knocked-out in the HCC cell line Huh7 and replaced byGCK, to generate the Huh7-GCK+/HK2−cell line. HK2 knockdown and GCK expression rewired central carbon metabolism, stimulated mitochondrial respiration and restored essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion, glycogen storage. It also reactivated innate immune responses and sensitivity to natural killer cells, showing that consequences of the HK switch extend beyond metabolic reprogramming.
Synchronised oscillations in growing cell populations are explained by demographic noise
Authors: Gavagnin Enrico , Vittadello Sean T. , Gunasingh Gency , Haass Nikolas K. , Simpson Matthew J. , Rogers Tim , Yates Christian A. 
Published: March 2020

AbstractUnderstanding synchrony in growing populations is important for applications as diverse as epidemiology and cancer treatment. Recent experiments employing fluorescent reporters in melanoma cell lines have uncovered growing subpopulations exhibiting sustained oscillations, with nearby cells appearing to synchronise their cycles. In this study we demonstrate that the behaviour observed is consistent with long-lasting transient phenomenon initiated, and amplified by the finite-sample effects and demographic noise. We present a novel mathematical analysis of a multi-stage model of cell growth which accurately reproduces the synchronised oscillations. As part of the analysis, we elucidate the transient and asymptotic phases of the dynamics and derive an analytical formula to quantify the effect of demographic noise in the appearance of the oscillations. The implications of these findings are broad, such as providing insight into experimental protocols that are used to study the growth of asynchronous populations and, in particular, those investigations relating to anti-cancer drug discovery.Statement of SignificanceRecent experiments have reported strong evidence of periodic oscillations in the proportion of young and old melanoma cells. The biological mechanism generating this synchronisation and the potential impact that can have on commonly used experimental protocols is still unclear. Here we studied a population of melanoma cells for which we found oscillations in the proportions of cells in each phase of the cell cycle. We demonstrate that these observations may be triggered by intrinsic demographic noise alone, rather than any active synchronisation mechanism requiring cell-cell communication. Our findings may have implications for typical experimental protocols which aim to produce asynchronous cell populations.
Phosphorylation of the Anaphase Promoting Complex activator CDH1/FZR regulates the transition from Meiosis I to Meiosis II in mouse male germ cell
Authors: Tanno Nobuhiro , Kuninaka Shinji , Fujimura Sayoko , Okamura Kaho , Takemoto Kazumasa , Araki Kimi , Araki Masatake , Saya Hideyuki , Ishiguro Kei-ichiro 
Published: March 2020

SummaryCDH1/FZR is an activator of Anaphase promoting complex/Cyclosome (APC/C), best known for its role as E3 ubiquitin ligase that drives the cell cycle. APC/C activity is regulated by CDK-mediated phosphorylation of CDH1 during mitotic cell cycle. Although the critical role of CDH1 phosphorylation has been shown mainly in yeast andin vitrocell culture studies, its biological significance in mammalian tissuesin vivoremained elusive. Here, we examined thein vivorole of CDH1 phosphorylation using a mouse model, in which non-phosphorylatable substitutions were introduced in the putative CDK-phosphorylation sites of CDH1. Although ablation of CDH1 phosphorylation did not show substantial consequences in mouse somatic tissues, it led to severe testicular defects resulting in male infertility. In the absence of CDH1 phosphorylation, male juvenile germ cells entered meiosis normally but skipped meiosis II producing diploid spermatid-like cells. In aged testis, male germ cells were overall abolished, showing Sertoli cell-only phenotype. The present study demonstrated that phosphorylation of CDH1 is required for temporal regulation of APC/C activity at the transition from meiosis I to meiosis II, and for spermatoginial stem cell maintenance, which raised an insight into the sexual dimorphism of CDH1-regulation in germ cells.
Biodiverse food plants in the semiarid region of Brazil have unknown potential: A systematic review
Authors: Jacob Michelle Cristine Medeiros , Medeiros Maria Fernanda Araujo , Albuquerque Ulysses Paulino 
Published: March 2020

AbstractFood biodiversity presents one of the most significant opportunities to enhance food and nutrition security today. The lack of data on many plants, however, limits our understanding of their potential and the possibility of building a research agenda focused on them. Our objective with this systematic review was to identify biodiverse food plants occurring in the Caatinga biome, Brazil, strategic for the promotion of food and nutrition security. We selected studies from the following databases: Web of Science, Medline/PubMed (via the National Library of Medicine), Scopus and Embrapa Agricultural Research Databases (BDPA). Eligible were original articles, published since 2008, studying food plants occurring in the Caatinga. We assessed the methodological quality of the studies we selected. We reviewed a total of fifteen studies in which 65 plants that met our inclusion criteria were mentioned. Of this amount, 17 species, including varieties, subspecies, and different parts of plants, had data on chemical composition, in addition to being mentioned as food consumed by rural communities in observational ethnobotanical studies. From the energy and protein data associated with these plants, we produced a ranking of strategic species. The plants with values higher than the average of the set were:Dioclea grandifloraMart. ex Benth (mucunã),Hymenaea courbarilL. (jatobá),Syagrus cearensisNoblick (coco-catolé),Libidibia ferrea(Mart. ex Tul.) L.P.Queiroz (jucá),Sideroxylon obtusifolium(Roem. & Schult.) T.D.Penn. (quixabeira). We suggest that the scientific community concentrates research efforts on tree legumes, due to their resilience and physiological, nutritional, and culinary qualities.