bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiac overexpression of microRNA-7 is associated with adverse cardiac remodeling
Authors: Gupta Manveen K , Sahu Anita , Wang Xi , Martelli Elizabeth E. , Stenson Kate , Witherow Conner , Naga Prasad Sathyamangla V. 
Published: September 2020

AbstractRole of microRNA-7 (miRNA-7) in targeting Epidermal growth factor receptor (EGFR/ERBB) family is known in dividing cancer cells while less is known about its role in terminally differentiated cardiac cells. We generated transgenic (Tg) mice with cardiomyocyte-specific overexpression of miRNA-7 to determine its role in regulating cardiac function. Despite similar survival, expression of miRNA-7 results in cardiac dilation as measured by echocardiography, instead of age-based cardiac hypertrophy observed in littermate controls. In contrast to the classical adaptive hypertrophy in response to TAC, miRNA-7 Tg mice directly undergo cardiac dilation post-TAC that is associated with increased fibrosis. Interestingly, significant loss in ERBB2 expression was observed in cardiomyocytes with no changes in ERBB1 (EGFR). Gene ontology and cellular component analysis using the cardiac proteomics data showed significant reduction in mitochondrial membrane integrity reflecting the differential enrichment/loss of proteins in miRNA-7 Tg mice compared to littermate controls. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized and rounded mitochondrial morphology indicating mitochondrial dysfunction. These findings show that expression of miRNA-7 uniquely results in cardiac dilation instead of adaptive hypertrophic response to cardiac stress providing insights on adverse remodeling in physiology and pathology.
YY1 cistrome analysis uncovers an essential requirement of the YY1:BRD4-PFKP regulatory axis for promoting tumorigenesis of castration-resistant prostate cancer
Authors: Xu Chenxi , Tsai Yi-Hsuan , Galbo Phillip , Gong Weida , Storey Aaron J. , Xu Yuemei , Byrum Stephanie D. , Whang Young E. , Parker Joel S. , Mackintosh Samuel G. , Edmondson Ricky D. , Tackett Alan J. , Huang Jiaoti , Zheng Deyou , Earp H. Shelton , Wang Gang Greg , Cai Ling 
Published: September 2020

AbstractCastration-resistant prostate cancer (CRPC) is a terminal disease, demanding a better understanding of its pathogenesis. Targeted therapy needs to be developed for CRPC due to its heterogeneity and resistance to current treatments. Here, through cistrome study of YY1, a transcription factor significantly overexpressed during prostate cancer progression, we identify a YY1-PFKP axis to be essential for CRPC tumorigenesis. Depletion of YY1 in independent CRPC models dramatically reduced tumor cell growthin vitroand delayed oncogenic progressionin vivo. Importantly, YY1 functions as a master regulator of prostate tumor metabolism including the Warburg effect and mitochondria respiration. Loss-of-function and rescue studies further reveals a mechanistic underpinning in which YY1 directly binds and trans-activatesPFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced oncogenic phenotypes such as enhanced tumor cell glycolysis and malignant growth. Additionally, a vast majority of gene-regulatory element in advanced prostate cancer cells are bound by YY1, lending a support for its role as a master regulator of prostate cancer progression. YY1 interactome studies point to bromodomain-containing coactivators in prostate cancer, which act as functional partners of YY1 to potentiate YY1-related target gene activation. Altogether, this study unveils an unexplored YY1:BRD4-PFKP oncogenic axis operating in advanced prostate cancer with implications for therapy.
Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors
Authors: Kačar Dina , Cañedo Librada M , Rodríguez Pilar , Gonzalez Elena , Galán Beatriz , Schleissner Carmen , Leopold-Messer Stefan , Piel Jörn , Cuevas Carmen , de la Calle Fernando , García José L. 
Published: September 2020

AbstractGlutaramide-containing polyketides are known as potent antitumoral and antimetastatic agents. However, the associated gene clusters have only been identified and studied in a fewStreptomycesproducers and soleBurkholderia gladiolisymbiont. The new glutaramide-family polyketides, denominated sesbanimides D, E and F along with the previously known sesbanimide A and C, were isolated from two marine alphaproteobacteriaStappia indicaPHM037 andLabrenzia aggregataPHM038. Structures of the isolated compounds were elucidated based on 1D and 2D homo and heteronuclear NMR analyses and ESI-MS spectrometry. All compounds exhibited strong antitumor activity in lung, breast and colorectal cancer cell lines. Subsequent whole genome sequencing and genome mining revealed the presence of thetrans-AT PKS gene cluster responsible for the sesbanimide biosynthesis, described assbncluster, and the sesbanimide modular assembly is proposed. Interestingly, numerous homologous orphan gene clusters were localized in distantly related bacteria and used as comparative genomic assets for a more global characterization ofsbnlike-clusters. Strikingly, the modular architecture of downstream mixed type PKS/NRPS, SbnQ, revealed high similarity to PedH in pederin and Lab13 in labrenzin gene clusters, although those clusters are responsible for the production of structurally completely different molecules. The unexpected presence of SbnQ homologs in unrelated polyketide gene clusters across phylogenetically distant bacteria, raises intriguing questions about the evolutionary relationship between glutaramide-like and pederin-like pathways, as well as the functionality of their synthetic products.SignificanceGlutaramide-containing polyketides are still a largely understudied group of polyketides, produced mainly by the generaStreptomyces, with a great potential for antitumor drug production. Here, we describe genomes of two cultivable marine bacteria,Stappia indicaPHM037 andLabrenzia aggregataPHM038, producers of the cytotoxic glutaramide-family polyketides sesbanimide A and C with chemical elucidation of newly identified analogs D, E and F. Genome mining revealedtrans-AT PKS gene cluster responsible for sesbanimide biosynthesis. Although there are numerous homologous gene clusters present in remarkably different bacteria, this is the first time that the biosynthesis product has been reported. The comparative genome analysis reveals stunning, cryptic evolutionary relationship between sesbanimides, glutaramides fromStreptomycesspp. and the pederin-family gene clusters.
Graph representation forecasting of patient’s medical conditions: towards a digital twin
Authors: Barbiero Pietro , Viñas Torné Ramon , Lió Pietro 
Published: September 2020

AbstractObjectiveModern medicine needs to shift from a wait and react, curative discipline to a preventative, interdisciplinary science aiming at providing personalised, systemic and precise treatment plans to patients. The aim of this work is to present how the integration of machine learning approaches with mechanistic computational modelling could yield a reliable infrastructure to run probabilistic simulations where the entire organism is considered as a whole.MethodsWe propose a general framework that composes advanced AI approaches and integrates mathematical modelling in order to provide a panoramic view over current and future physiological conditions. The proposed architecture is based on a graph neural network (GNNs) forecasting clinically relevant endpoints (such as blood pressure) and a generative adversarial network (GANs) providing a proof of concept of transcriptomic integrability.ResultsWe show the results of the investigation of pathological effects of overexpression of ACE2 across different signalling pathways in multiple tissues on cardiovascular functions. We provide a proof of concept of integrating a large set of composable clinical models using molecular data to drive local and global clinical parameters and derive future trajectories representing the evolution of the physiological state of the patient.SignificanceWe argue that the graph representation of a computational patient has potential to solve important technological challenges in integrating multiscale computational modelling with AI. We believe that this work represents a step forward towards a healthcare digital twin.
Shared residual risk of childhood undernutrition indicators in Malawi. An application of shared spatial component model
Authors: Ngwira Alfred 
Published: September 2020

AbstractMany studies have looked at the residual risk of the specific child undenutrition indicators. This study aimed at mapping the shared risk of two of the undernutrition indicators. The shared spatial component model was fitted to two of the child undernutrition indicators using 5066 child records of the 2015 Malawi demographic health survey data. The spatial components were modelled by the convolution prior, with the structured components being assigned the conditional autoregressive distribution. The southern region is at the greatest risk of having stunting and wasting, wasting and underweight, as compared to the central and northern region. The shared risk of stunting and underweight is randomly distributed. Interventions to reduce the shared risk of child undernutrition should focus on the southern region and a little bit in the central region, and attention should be on addressing the issue of overpopulation and effects of climate change.
Msp1/ATAD1 restores mitochondrial function in Zellweger Spectrum Disease
Authors: Nuebel Esther , Morgan Jeffrey T , Fogarty Sarah , Winter Jacob M , Lettlova Sandra , Berg Jordan A , Chen Yu-Chan , Kidwell Chelsea U , Maschek J Alan , Clowers Katie J , Argyriou Catherine , Chen Lingxiao , Wittig Ilka , Cox James E , Roh-Johnson Minna , Braverman Nancy , Steinberg Steven J , Gygi Steven P , Rutter Jared 
Published: September 2020

AbstractPeroxisomal Biogenesis Disorders (PBDs) are a class of inherited metabolic disorders with profound neurological and other phenotypes. The most severe PBDs are caused by mutations in peroxin genes, which result in nonfunctional peroxisomes typically through impaired protein import. In order to better understand the molecular causes of Zellweger Spectrum Disease (ZSD) -the most severe PBDs -, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that loss of peroxisomal import has no effect on peroxin mRNA expression or translational efficiency. Instead, peroxin proteins—still produced at high levels— aberrantly accumulate on the mitochondrial membrane, impairing respiration and ATP generation. Finally, we rescued mitochondrial function in fibroblasts derived from human patients with ZSD by overexpressing ATAD1, an AAA-ATPase that functions in mitochondrial quality control. These findings might provide a new focus of PBD therapies in supporting quality control pathways that protect mitochondrial function.
Design of Biologically Active Binary Protein 2D Materials
Authors: Ben-Sasson Ariel J. , Watson Joseph , Sheffler William , Johnson Matthew Camp , Bittleston Alice , Somasundaram Logeshwaran , Decarreau Justin , Jiao Fang , Chen Jiajun , Drabek Andrew A. , Jarrett Sanchez M. , Kollman Justin M. , Blacklow Stephen C. , De Yoreo James J , Ruohola-Baker Hannele , Derivery Emmanuel , Baker David 
Published: September 2020

AbstractProteins that assemble into ordered two-dimensional arrays such as S-layers1,2and designed analogues3–5have intrigued bioengineers,6,7but with the exception of a single lattice formed through non-rigid template streptavidin linkers,8they are constituted from just one protein component. For modulating assembly dynamics and incorporating more complex functionality, materials composed of two components would have considerable advantages.9–12Here we describe a computational method to generate de-novo binary 2D non-covalent co-assemblies by designing rigid asymmetric interfaces between two distinct protein dihedral building-blocks. The designed array components are soluble at mM concentrations, but when combined at nM concentrations, rapidly assemble into nearly-crystalline micrometer-scale p6m arrays nearly identical to the computational design model in vitro and in cells without the need of a two-dimensional support. Because the material is designed from the ground up, the components can be readily functionalized, and their symmetry reconfigured, enabling formation of ligand arrays with distinguishable surfaces to drive extensive receptor clustering, downstream protein recruitment, and signaling. Using quantitative microscopy we show that arrays assembled on living cells have component stoichiometry and likely structure similar to arrays formed in vitro, suggesting that our material can impose order onto fundamentally disordered substrates like cell membranes. We find further that in sharp contrast to previously characterized cell surface receptor binding assemblies such as antibodies and nanocages, which are rapidly endocytosed, large arrays assembled at the cell surface suppress endocytosis in a tunable manner, with potential therapeutic relevance for extending receptor engagement and immune evasion. Our work paves the way towards synthetic cell biology, where a new generation of multi-protein macroscale materials is designed to modulate cell responses and reshape synthetic and living systems.One Sentence SummaryCo-assembling binary 2D protein crystals enables robust formation of complex large scale ordered biologically active materials
Life cycle process dependencies of positive-sense RNA viruses suggest strategies for inhibiting productive cellular infection
Authors: Chhajer Harsh , Rizvi Vaseef A. , Roy Rahul 
Published: September 2020

AbstractLife cycle processes of positive-strand (+)RNA viruses are broadly conserved across families, yet they employ different life cycle strategies to grow in the cell. Using a generalized dynamical model for intracellular (+)ssRNA virus growth, we decipher these life cycle determinants and their dependencies for several viruses and parse the effect of viral mutations and host cell permissivity. We show that Poliovirus employs rapid replication and virus assembly whereas Japanese Encephalitis virus leverages its higher rate of translation and efficient cellular reorganization compared to Hepatitis C virus. Stochastic simulations of the model demonstrate infection extinction if all seeding viral RNA degrade before establishing robust replication. The probability of productive cellular infection is affected by virus-host processes, defined by early life cycle events and viral seeding. Synergy among these parameters in limiting infection suggests new avenues for inhibiting viral infections by targeting early life cycle bottlenecks.
Genomic stability of Self-inactivating Rabies
Authors: Ciabatti Ernesto , González-Rueda Ana , de Malmazet Daniel , Lee Hassal , Morgese Fabio , Tripodi Marco 
Published: September 2020

AbstractTranssynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit function. Among them, the retrograde monosynaptic ΔG-Rabies has been widely used in neuroscience research. A recently developed engineered version of the ΔG-Rabies, the non-toxic self-inactivating (SiR) virus, represents the first tool for open-ended genetic manipulation of neural circuits. However, the high mutational rate of the rabies virus poses a risk that mutations targeting the key genetic regulatory element in the SiR genome could emerge and revert it to a canonical ΔG-Rabies. Such revertant mutations have recently been identified in a SiR batch. To address the origin, incidence and relevance of these mutations, we investigated the genomic stability of SiRin vitroandin vivo. We found that “revertant” mutations are rare and accumulate only when SiR is extensively amplifiedin vitro, particularly in suboptimal production cell lines that have insufficient levels of TEV protease activity. Moreover, we confirmed that SiR-CRE, unlike canonical ΔG-Rab-CRE or revertant-SiR-CRE, is non-toxic and that revertant mutations do not emergein vivoduring long-term experiments.HighlightsRevertant mutations are rare and do not accumulate when SiR is produced in high-TEVp expressing production cell linesSiR is non-toxicin vivoRevertant SiR mutations do not accumulate duringin vivoexperiments
A critical role for B cells in cancer immune surveillance
Authors: Rawat Kavita , Tewari Anita , Jakubzick Claudia V. 
Published: September 2020

AbstractIt is commonly believed that B cells play no role in cancer immune surveillance. However, this conclusion is based on studies using only a single B cell-deficient mouse strain, muMT mice, which does not show increased tumorigenesis compared with wild-type (WT) mice. In this study, we demonstrate a critical role for B cells in anti-tumor immunity and identify the cellular mechanisms that make muMT mice a special case. First, we replicate previous findings using a melanoma model in muMT mice. Then, we show that in muMT mice, B-cell deficiency is compensated for by a significant increase in another potent anti-tumor cell type, Type-1 interferon (IFN I)-producing plasmacytoid DCs (pDCs), resulting in normative anti-tumor responses. Depleting pDCs in muMT mice resulted in a significant increase in tumor size and burden. Conversely, adoptive transfer of antibodies from naïve WT serum into pDC-depleted muMT mice significantly decreased the tumor load to WT levels. Additionally, a B cell antibody repertoire-deficient mouse strain, IghelMD4 mice, showed a 3-fold increase in tumors relative to WT mice. Overall, these findings indicate the need for a diverse antibody repertoire for early neoplastic cell recognition and the critical role B cells play in anti-cancer immunity.
Professionalization of crisis management: A case study of local‐level crisis communicators in Sweden
Authors: Deverell Edward 
Published: September 2020

AbstractThis study applies an institutional profession perspective on a significant crisis management actor in an aim to deepen the understanding of collaborative crisis management work and practices. The study argues that a professions perspective holds a key to approaching interagency gaps in status and influence, which tend to affect collaborative crisis management negatively. Empirically the study is based on 19 interviews with local crisis communicators in Sweden. Findings indicate that, in terms of internal collaboration, limited knowledge among organizational members about the role and skills of crisis communicators require communicators to spend time and resources on ‘promoting’ their competence within the organization. Regarding inter‐organizational collaboration, the study shows that the closer a communication officer works to the spatial place of the crisis and to the rescue service, the higher the status of the communication officer. Interestingly enough, relations seem to go both ways as emergency service personnel can also be empowered by becoming more skillful communicators.
Autophagy‐Sirt3 axis decelerates hematopoietic aging
Authors: Fang Yixuan , An Ni , Zhu Lingjiang , Gu Yue , Qian Jiawei , Jiang Gaoyue , Zhao Ruijin , Wei Wen , Xu Li , Zhang Gaochuan , Yao Xingyun , Yuan Na , Zhang Suping , Zhao Yun , Wang Jianrong 
Published: September 2020

ABSTRACTAutophagy suppresses mitochondrial metabolism to preserve hematopoietic stem cells (HSCs) in mice. However, the mechanism by which autophagy regulates hematopoietic aging, in particular in humans, has largely been unexplored. Here, we demonstrate that reduction of autophagy in both hematopoietic cells and their stem cells is associated with aged hematopoiesis in human population. Mechanistically, autophagy delays hematopoietic aging by activating the downstream expression of Sirt3, a key mitochondrial protein capable of rejuvenating blood. Sirt3 is the most abundant Sirtuin family member in HSC‐enriched population, though it declines as the capacity for autophagy deteriorates with aging. Activation of autophagy upregulates Sirt3 in wild‐type mice, whereas in autophagy‐defective mice, Sirt3 expression is crippled in the entire hematopoietic hierarchy, but forced expression of Sirt3 in HSC‐enriched cells reduces oxidative stress and prevents accelerated hematopoietic aging from autophagy defect. Importantly, the upregulation of Sirt3 by manipulation of autophagy is validated in human HSC‐enriched cells. Thus, our results identify an autophagy‐Sirt3 axis in regulating hematopoietic aging and suggest a possible interventional solution to human blood rejuvenation via activation of the axis.
Relationships of reproductive performance indicators in black rhinoceros (Diceros bicornis michaeli) with plant available moisture, plant available nutrients and woody cover
Authors: Okita‐Ouma Benson , van Langevelde Frank , Heitkönig Ignas M. A. , Maina Peter , van Wieren Sip E. , Prins Herbert H. T. 
Published: September 2020

AbstractPlant available moisture and plant available nutrients in soils influence forage quality and availability and subsequently affect reproductive performance in herbivores. However, the relationship of soil moisture, soil nutrients and woody forage with reproductive performance indicators is not well understood in mega‐browsers yet these three are important in selecting suitable areas for conservation of mega‐browsers. Here, the eastern black rhinoceros (Diceros bicornis michaeli), a mega‐browser, was studied in seven geographically distinct populations in Kenya to understand the relationships between its reproductive performance indicators and plant available moisture, plant available nutrients and woody cover. Reproductive parameters showed a complex relationship with plant available moisture and plant available nutrients. We found an increase in the predicted yearly percentage of females calving as plant available nutrients decreased in areas of high levels of plant available moisture but no relationship with plant available nutrients in areas of low plant available moisture. Age at first calving was earlier, inter‐calving interval was longer and yearly percentage of females calving was higher at higher woody cover. Woody plant cover contributes positively to black rhino reproduction performance indicators, whereas plant available moisture and plant available nutrients add to the selection of conservation areas, in more subtle ways.