bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein structure analysis of the interactions between SARS-CoV-2 spike protein and the human ACE2 receptor: from conformational changes to novel neutralizing antibodies
Authors: Mercurio Ivan , Tragni Vincenzo , Busco Francesco , De Grassi Anna , Pierri Ciro Leonardo 
Published: April 2020

ABSTRACTThe recent severe acute respiratory syndrome, known as Corona Virus Disease 2019 (COVID-19) has spread so much rapidly and severely to induce World Health Organization (WHO) to declare state of emergency over the new coronavirus SARS-CoV-2 pandemic. While several countries have chosen the almost complete lock-down for slowing down SARS-CoV-2 spread, scientific community is called to respond to the devastating outbreak by identifying new tools for diagnosis and treatment of the dangerous COVID-19. With this aim we performed anin silicocomparative modeling analysis, which allows to gain new insights about the main conformational changes occurring in the SARS-CoV-2 spike protein, at the level of the receptor binding domain (RBD), along interactions with human cells angiotensin converting enzyme 2 (ACE2) receptor, that favour human cell invasion. Furthermore, our analysis provides i) an ideal pipeline to identify already characterized antibodies that might target SARS-CoV-2 spike RBD, for preventing interactions with the human ACE2, and ii) instructions for building new possible neutralizing antibodies, according to chemical/physical space restraints and complementary determining regions (CDR) mutagenesis of the identified existing antibodies. The proposed antibodies showin silicoa high affinity for SARS-CoV-2 spike RBD and can be used as reference antibodies also for building new high affinity antibodies against present and future coronavirus able to invade human cells through interactions of their spike proteins with the human ACE2. More in general, our analysis provides indications for the set-up of the right biological molecular context for investigating spike RBD-ACE2 interactions for the development of new vaccines, diagnosis kits and other treatments based on the usage or the targeting of SARS-CoV-2 spike protein.
Pandemic Publishing: Medical journals drastically speed up their publication process for Covid-19
Authors: Horbach Serge P.J.M. 
Published: April 2020

AbstractIn times of public crises, including the current Covid-19 pandemic, rapid dissemination of relevant scientific knowledge is of paramount importance. The duration of scholarly journals’ publication process is one of the main factors hindering quick delivery of new information. While proper editorial assessment and peer review obviously require some time, turnaround times for medical journals can be up to several months, which is undesirable in the era of a crisis. Following initiatives of medical journals and scholarly publishers to accelerate their publication process, this study assesses whether medical journals have indeed managed to speed up their publication process for Covid-19 related articles. It studies the duration of 14 medical journals’ publication process both during and prior to the current pandemic. Assessing a total of 669 articles, the study concludes that medical journals have indeed drastically accelerated the publication process for Covid-19 related articles since the outbreak of the pandemic. Compared to articles published in the same journals before the pandemic, turnaround times have decreased on average by 49%. The largest decrease in number of days between submission and publication of articles was due to a decrease in the number of days required for peer review. For articles not related to Covid-19, no acceleration of the publication process is found. While the acceleration of journals’ publication process is laudable from the perspective of quick information dissemination, it also raises concerns relating to the quality of the peer review process and the quality of the resulting publications.
Aligned and Conductive 3D Collagen Scaffolds for Skeletal Muscle Tissue Engineering
Authors: Basurto Ivan M. , Mora Mark T. , Gardner Gregg M. , Christ George J. , Caliari Steven R. 
Published: April 2020

AbstractSkeletal muscle is characterized by its three-dimensional (3D) anisotropic architecture composed of highly aligned, organized, and electrically excitable muscle fibers that enable normal locomotion. Biomaterial-based tissue engineering approaches to repair skeletal muscle injuries are limited due to difficulties in combining 3D structural alignment (to guide cell/matrix organization) and electrical conductivity (to enable electrically excitable myotube assembly and maturation). In this work we successfully produced aligned and electrically conductive 3D collagen scaffolds using a freeze-drying approach. Conductive polypyrrole (PPy) microparticles were synthesized and directly mixed into a suspension of type I collagen and chondroitin sulfate followed by directional lyophilization. Scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), and confocal microscopy analyses showed that directional solidification resulted in scaffolds with longitudinally aligned macropores (transverse plane: 155 ± 27 µm, longitudinal plane: 218 ± 49 µm) with homogeneously-distributed PPy content. Chronopotentiometry verified that PPy incorporation resulted in a five-fold increase in conductivity when compared to non-PPy containing collagen scaffolds without detrimentally affecting C2C12 mouse myoblast metabolic activity. Furthermore, the aligned scaffold microstructure provided contact guidance cues that directed myoblast growth and organization. Incorporation of PPy also promoted enhanced myotube formation and maturation as measured by myosin heavy chain (MHC) expression and number of nuclei per myotube. Together these data suggest that aligned and conductive 3D collagen scaffolds could be useful for skeletal muscle tissue engineering.
ABHD11 regulates 2-oxoglutarate abundance by protecting mitochondrial lipoylated proteins from lipid peroxidation damage
Authors: Bailey Peter S J , Ortmann Brian M , Houghton Jack W , Costa Ana S H , Antrobus Robin , Frezza Christian , Nathan James A 
Published: April 2020

Abstract2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases (2-OG DDs) involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG DD function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc) – the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 protects the catalytic lipoyl domain from lipid peroxidation products formed by oxidative damage, demonstrating a requirement for a lipoyl repair pathway in human cells, and highlighting how the redox sensitivity of lipoylation modulates 2-OG metabolism.
Development of early-stage type 1 diabetes in germ-free interleukin-10 deficient mice
Authors: Bobe Alexandria M. , Miyoshi Jun , Moore Patrick , Devkota Suzanne , Leone Vanessa , Martinez Kristina , Theriault Betty R. , Musch Mark W. , Wasserfall Clive , Atkinson Mark , Rhodes Christopher J. , Chang Eugene B. 
Published: April 2020

AbstractSeveral experimental models demonstrate a role for gut microbiota in the progression of type 1 diabetes (T1D) in genetically prone hosts. While the association between disturbances in gut microbiota, or microbial dysbiosis, and complex immune diseases such as inflammatory bowel diseases (IBD) are well established, less is known about its role in T1D pathogenesis. In IBD-prone interleukin-10 deficient (IL-10 KO) mice, the absence of gut microbiota under germ-free (GF) conditions prevents IBD development. However, in aged GF IL-10 KO mice (>6-months of age), polyuria and pancreatic lymphocytic infiltration resembling T1D lesions was observed. Approximately 50% of male and female mice above 6-months of age develop pancreatic immune cell infiltration, as compared to none in conventionally-raised and fecal microbiota transplanted (FMT) IL-10 KO counterparts. Immunofluorescence staining of islet infiltrates was positive for adaptive and innate immunological markers, including lymphoid and myeloid cell markers, which typically characterize autoimmune T1D lesions. A subset of GF IL-10 KO mice was also positive for insulin autoantibodies (IAA), but the majority of mice did not become diabetic. Our findings of early stage lymphocytic infiltrates in the pancreas and IAA in the absence of overt diabetes in GF IL-10 KO mice embody the early stages of T1D pathogenesis. As such, we propose that the presence of gut microbiota play a protective role against immune infiltration in the pancreas of genetically prone hosts. Moreover, our model provides an opportunity to better understand the role of the microbiota in the early stages of immune pathogenesis and perhaps conceive the development of microbe-mediated prophylactic strategies to treat or even prevent T1D.
Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target
Authors: Shields Cara E. , Potlapalli Sindhu , Cuya-Smith Selma M. , Chappell Sarah K. , Chen Dongdong , Martinez Daniel , Pogoriler Jennifer , Rathi Komal S. , Patel Shiv A. , Maris John M. , Schnepp Robert W. 
Published: April 2020

ABSTRACTRhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma that continues to present significant challenges to pediatric oncology. There are two major subtypes of pediatric rhabdomyosarcoma, alveolar and embryonal. Alveolar rhabdomyosarcomas are characterized by the presence of a PAX-FOXO1 fusion protein and termed fusion-positive (FP-RMS); embryonal rhabdomyosarcomas (ERMS) lack these fusions and are termed fusion-negative (FN-RMS).Fusion-positive rhabdomyosarcoma (FP-RMS) harbors PAX-FOXO1 fusion proteins and has a worse overall outcome compared to FN-RMS, underscoring the critical need to identify novel targets for this disease. While fusion proteins remain challenging therapeutic targets, recent studies have begun to reveal the key intersection of PAX-FOXO1 fusion proteins with the malignant epigenome, suggesting that epigenetic proteins may serve as novel targets in FP-RMS. Here, we investigate the contribution of the epigenetic regulator BMI1 to FP-RMS.We examined RNA-seq tumor datasets and determined thatBMI1is robustly expressed in FP-RMS tumors, patient derived xenografts (PDXs), and cell lines. We depleted BMI1 using RNA interference and find that this leads to a marked decrease in cell growth. Next, we used two BMI1 inhibitors, PTC-209 and PTC-028, and showed that BMI1 inhibition decreases cell cycle progression and increases apoptosis in FP-RMS cell lines. In thein vivosetting, targeting BMI1 leads to decreased tumor growth. Mechanistically, we observe that BMI1 inhibition activates the tumor suppressive Hippo pathway. Collectively, these results identify BMI1 as a novel therapeutic vulnerability in FP-RMS and provide a foundation for further investigation of BMI1 in both FP-RMS and additional sarcoma histotypes.
Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex
Authors: Bhargava Hersh K. , Tabata Keisuke , Byck Jordan M. , Hamasaki Maho , Farrell Daniel P. , Anishchenko Ivan , DiMaio Frank , Im Young Jun , Yoshimori Tamotsu , Hurley James H. 
Published: April 2020

AbstractRubicon is a potent negative regulator of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon-mediated inhibition of autophagy requires the interaction of the C-terminal Rubicon homology (RH) domain of Rubicon with Rab7-GTP. Here we report the 2.8 Å crystal structure of the Rubicon RH domain in complex with Rab7-GTP. Our structure reveals a novel fold for the RH domain built around four zinc clusters. The switch regions of Rab7 insert into pockets on the surface of the RH domain in a mode that is distinct from those of other Rab-effector complexes. Rubicon residues at the dimer interface are required for Rubicon and Rab7 to colocalize in living cells. Mutation of Rubicon RH residues in the Rab7 binding site restore efficient autophagic flux in the presence of overexpressed Rubicon, validating the Rubicon RH domain as a promising therapeutic target.
Clinical presentation and management of acquired thrombotic thrombocytopenic purpura: A case series of 55 patients
Authors: Sun Rui‐Xue , Xu Jun , Zhu Hua‐Dong , Yu Xue‐Zhong , Yang Jing 
Published: April 2020

AbstractThe aim of this study was to explore the clinical characteristics and treatment of acquired thrombotic thrombocytopenic purpura (TTP). The clinical manifestations, laboratory findings, differential diagnoses, therapeutic methods, and prognosis of 55 patients with acquired TTP were retrospectively analyzed. Among the 55 TTP patients, 17 were males and 38 were females, with a mean age of 40 ± 15 years. Twenty‐one patients had the Triad syndrome, which included neurological syndromes, microangiopathic hemolytic anemia, and thrombocytopenia. Twenty‐three patients had the Quinary syndrome, which included fever, microangiopathic hemolytic anemia, thrombocytopenia, renal insufficiency, and neurological symptoms. Twenty‐eight patients received the measurement for a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity and 23 patients had <10% of the normal range. ADAMTS13 inhibitor was tested in 20 patients and was positive in 18 patients. Both ADAMTS13 activity and ADAMTS13 inhibitor were examined in 20 patients and 90% of the patients showed double positive results. The treatment methods included plasma exchange, glucocorticoids, rituximab, immunosuppressants, and intravenous immunoglobulin. Thirty‐three patients survived, and 22 patients died. Plasma exchange improved the remission rate from 16.7% to 65.3% (P = .022). The combined immunosuppressive therapy based on plasma exchange and glucocorticoids raised the remission rate from 43.8% to 75.8%. Most of acquired TTP patients had the Triad syndrome or the Quinary syndrome. A high proportion of TTP patients had ADAMTS13 activity reduction and ADAMTS13 inhibitor positivity. Plasma exchange and immunosuppressive therapy may improve the prognosis of this disease.
Hybridization ddRAD‐sequencing for population genomics of nonmodel plants using highly degraded historical specimen DNA
Authors: Lang Patricia L. M. , Weiß Clemens L. , Kersten Sonja , Latorre Sergio M. , Nagel Sarah , Nickel Birgit , Meyer Matthias , Burbano Hernán A. 
Published: April 2020

AbstractSpecies’ responses at the genetic level are key to understanding the long‐term consequences of anthropogenic global change. Herbaria document such responses, and, with contemporary sampling, provide high‐resolution time‐series of plant evolutionary change. Characterizing genetic diversity is straightforward for model species with small genomes and a reference sequence. For nonmodel species—with small or large genomes—diversity is traditionally assessed using restriction‐enzyme‐based sequencing. However, age‐related DNA damage and fragmentation preclude the use of this approach for ancient herbarium DNA. Here, we combine reduced‐representation sequencing and hybridization‐capture to overcome this challenge and efficiently compare contemporary and historical specimens. Specifically, we describe how homemade DNA baits can be produced from reduced‐representation libraries of fresh samples, and used to efficiently enrich historical libraries for the same fraction of the genome to produce compatible sets of sequence data from both types of material. Applying this approach to both Arabidopsis thaliana and the nonmodel plant Cardamine bulbifera, we discovered polymorphisms de novo in an unbiased, reference‐free manner. We show that the recovered genetic variation recapitulates known genetic diversity in A. thaliana, and recovers geographical origin in both species and over time, independent of bait diversity. Hence, our method enables fast, cost‐efficient, large‐scale integration of contemporary and historical specimens for assessment of genome‐wide genetic trends over time, independent of genome size and presence of a reference genome.
Dose‐dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy
Authors: Chudnovets Anna , Lei Jun , Na Quan , Dong Jie , Narasimhan Harish , Klein Sabra L. , Burd Irina 
Published: April 2020

AbstractProblemSystemic maternal inflammation is associated with adverse neonatal sequelae. We tested the hypothesis that IL‐1β is a key inflammatory regulator of adverse pregnancy outcomes.Method of studyPregnant mice were treated with intraperitoneal injections of IL‐1β (0, 0.1, 0.5, or 1 μg) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL‐1β signaling markers.ResultsAs compared with non‐treated dams, maternal injections with IL‐1β resulted in increased p‐NF‐κB and caspase‐1 in placentas and fetal brains, but not consistently in spleens, suggesting induction of intrinsic IL‐1β production. These findings were confirmed by increased levels of IL‐1β in the placentas of the IL‐1β‐treated dams. Systemic treatment of dams with IL‐1β suppressed Stat1 signaling. Maternal inflammation caused by IL‐1β treatment reduced fetal viability to 80.6% and 58.9%, in dams treated with either 0.5 or 1 μg of IL‐1β, respectively. In the placentas, there was an IL‐1β dose‐dependent distortion of the labyrinth structure, decreased numbers of mononuclear trophoblast giant cells, and reduced proportions of endothelial cells as compared to placentas from control dams. In fetal brains collected at E17, there was an IL‐1β dose‐dependent reduction in cortical neuronal morphology.ConclusionThis work demonstrates that systemic IL‐1β injection causes dose‐dependent structural and functional changes in the placenta and fetal brain.
In‐vivo diagnostic test allergens in Europe: A call to action and proposal for recovery plan—An EAACI position paper
Authors: Klimek Ludger , Hoffmann Hans J. , Kalpaklioglu Ayse F. , Demoly Pascal , Agache Ioana , Popov Todor A. , Muraro Antonella , Schmid‐Grendelmeier Peter , Bonini Sergio , Bonertz Andreas , Mahler Vera , Vieths Stefan , Pfaar Oliver , Zuberbier Torsten , Jutel Marek , Schmidt‐Weber Carsten , Hellings Peter W. , Dreborg Sten , Bonini Matteo , Brough Helen A. , Bousquet Jean , Hoffmann‐Sommergruber Karin , Palomares Oscar , Ollert Markus , Shamji Mohamed H. , Cardona Victoria 
Published: April 2020

AbstractDiagnostic allergens are defined as medicinal products in the EU. Marketing authorization by national authorities is necessary; however, diagnostic allergens are not homogeneously regulated in different EU member states. Allergen manufacturers argue with increasing costs forcing them to continuously reduce the diagnostic allergen portfolios offered to allergists. In contrast, EAACI and national European Allergy Societies see the need for the availability of a wide range of high‐quality diagnostic allergens for in vivo diagnosis of IgE‐mediated allergies not only covering predominant but also less frequent allergen sources. In a recent EAACI task force survey, the current practice of allergy diagnosis was shown to rely on skin tests as first option in almost 2/3 of all types of allergic diseases and in 90% regarding respiratory allergies.With the need to ensure the availability of high‐quality diagnostic allergens in the EU, an action plan has been set up by EAACI to analyse the current regulatory demands in EU member states and to define possible solutions stated in this document: (a) simplification of authorization for diagnostic allergens; (b) specific regulation of special types of diagnostic allergens; (c) new models beyond the current model of homologous groups; (d) simplification of pharmacovigilance reporting; (e) reduction of regulation fees for diagnostic allergens; (f) reimbursement for diagnostic allergens.Joining forces of allergists, manufacturers and authorities are of high importance to ensure remaining relevant allergens in the EU markets to facilitate a sustainable and comprehensive service for the diagnosis and treatment of allergic diseases.
Association of hMSH5 C85T polymorphism with radiation sensitivity of testicular cell lines GC‐1, GC‐2, TM3, and TM4
Authors: Lin Mingyue , Guo Lihuang , Cheng Zhenbo , Huan Xisha , Huang Yue , Xu Keqian 
Published: April 2020

AbstractBackgroundThe hMSH5 C85T polymorphism, which encodes hMSH5 P29S, is associated with individual differences in spermatogenic abnormalities caused by ionizing radiation (IR), but the molecular mechanisms remain unclear.ObjectivesThis manuscript aims to explore the role of hMSH5 C85T polymorphism in IR‐induced individual differences in spermatogenic abnormalities.Material and methodsWe transfected pcDNA‐hMSH5P29S vector into mouse spermatogonia GC‐1, mouse spermatocytes GC‐2, mouse testicular mesenchymal cells TM3, and mouse testicular support cells TM4. After radiation, we evaluated cell survival with colony formation assay, apoptosis with TUNEL assay and caspase‐3 activity assay, DNA damage with comet assay and an in vivo NHEJ activity assay.ResultsResults showed that only spermatocytes GC‐2 transfected with pcDNA‐hMSH5P29S vector had significant differences in IR‐induced cell survival and apoptosis when compared to that transfected with pcDNA empty vector and pcDNA‐wild‐hMSH5 vector, while there was no statistical difference in GC‐1, TM3, and TM4. In addition, comet assay showed that the DNA damage of GC‐2 transfected with pcDNA‐hMSH5P29S vector increased significantly compared to that transfected with pcDNA empty vector and pcDNA‐wild‐hMSH5 vector after IR. And in vivo NHEJ activity assay showed that the NHEJ activity of GC‐2 transfected with pcDNA‐hMSH5P29S vector was statistically higher than that transfected with pcDNA empty vector and pcDNA‐wild‐hMSH5 vector.ConclusionOur study indicates that the hMSH5 C85T polymorphism leads to an abnormal increase in apoptosis and lessen the control on error‐prone NHEJ of spermatocyte GC‐2, thereby altering the difference of radiation sensitivity of spermatogenesis.