bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness and Safety of Chloroquine or Hydroxychloroquine as a mono-therapy or in combination with Azithromycin in the treatment of COVID-19 patients: Systematic Review and Meta-Analysis
Authors: Ghazy Ramy Mohamed , Elmaghraby Abdallah , Shaaban Ramy , Kamal Ahmed , Beshir Hatem , Moursi Amr , Ramadan Ahmed , Taha Sarah Hamed N. 
Published: July 2020

AbstractMany recent studies have investigated the role of either Chloroquine (CQ) alone, Hydroxychloroquine (HCQ) alone, or CQ/HCQ in combination with azithromycin (AZM) in management of the emerging coronavirus. This systematic review and meta-analysis of either published or preprint observational or interventional studies were conducted to assess the cure rate, duration of hospital stay, radiological progression, clinical worsening, need for mechanical ventilation, the occurrence of side effects, and mortality. A search of the online database through June 2020 was performed and examined the reference lists of pertinent articles for in-vivo studies only. Pooled relative risks (RRs), standard mean, of 95 % confidence intervals (CIs) were calculated with the random-effects model.ResultsThe duration of hospital stay was shorter in the standard care in comparison with HCQ group, the standard mean of hospital stay was 0.57, 95% CI, and 0.20-0.94. Overall virological cure, or more specifically at day 4, 10, and 14 among patients exposed to HCQ did not differ significantly from the standard care [(RR=0.92, 95% CI 0.78-1.15), (RR=1.11, 95% CI 0.74-1.65), (RR=1.21, 95%CI 0.70-2.01), and (RR=0.98, 95% CI, 0.76-1.27)] respectively. Radiological improvement or clinical worsening was not statistically different between HCQ and standard care [(RR=1.11, 95% CI 0.64-1.65) and (RR=1.28, 95% CI 0.33-4.99)]. The need for mechanical ventilation (MV) was not significant between the HCQ group and the standard care (RR= 1.5, 95%CI 0.78-2.89). Side effects were more reported in the HCQ group than the standard care (RR=3.14, 95% CI 1.58-6.24). Mortality among HCQ was not affected by receiving HCQ (RR=3.14, 95% CI 1.58-6.24), meta-regression analysis revealed that country is a strong predictor of mortality. The duration of hospital stay among the HCQ and AZM didn’t differ significantly from the standard care (standard mean= 0.77, 95% CI 0.46-1.08). Despite virological cure and need for MV did not differ significantly [(RR= 3.23, 95% CI 0.70-14.97) and (RR=1.27, 95%CI 0.7-2.13)] respectively. Mortality among the HCQ+AZM was more significantly higher than among the standard care (RR= 1.8, 95% CI 1.19-2.27).ConclusionDespite the scarcity of published data of good quality, the effectiveness and safety of either HCQ alone or in combination with AZM in treating the pandemic of COVID-19 can’t be assured. Future randomized control trials need to be carried out to verify this conclusion.RegistrationPROSPERO registration number: CRD42020192084
Comprehensive phenotyping of 3q29 deletion syndrome: recommendations for clinical care
Authors: Russo Rossana Sanchez , Gambello Michael J. , Murphy Melissa M. , Aberizk Katrina , Black Emily , Burrell T. Lindsey , Carlock Grace , Cubells Joseph F. , Epstein Michael T. , Espana Roberto , Goines Katrina , Guest Ryan , Klaiman Cheryl , Koh Sookyong , Leslie Elizabeth , Li Longchuan , Novacek Derek , Saulnier Celine A. , Sefik Esra , Schultz Sarah , Walker Elaine , White Stormi ,   The Emory 3q29 Project, Mulle Jennifer Gladys 
Published: July 2020

AbstractPurposeTo understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care.Methods32 Individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments.ResultsMedical manifestations were varied and reported across nearly every bodily system, with congenital heart defects (25%) the most severe and heterogeneous gastrointestinal symptoms (81%) the most common. Physical exam revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with schizophrenia prodrome (15%), psychosis (20%), anxiety disorders (40%) and ADHD (63%). On neurological exam study subjects displayed only mild or moderate motor difficulties.ConclusionsBy direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.
Development of a small molecule that corrects misfolding and increases secretion of Z α1-antitrypsin
Authors: Lomas David A. , Irving James A. , Arico-Muendel Christopher , Belyanskaya Svetlana , Brewster Andrew , Brown Murray , Chung Chun-wa , Dave Hitesh , Denis Alexis , Dodic Nerina , Dossang Anthony , Eddershaw Peter , Klimaszewska Diana , Haq Imran , Holmes Duncan S. , Hutchinson Jonathan P. , Jagger Alistair , Jakhria Toral , Jigorel Emilie , Liddle John , Lind Ken , Marciniak Stefan J. , Messer Jeff , Neu Margaret , Olszewski Allison , Ordonez Adriana , Ronzoni Riccardo , Rowedder James , Rüdiger Martin , Skinner Steve , Smith Kathrine J. , Terry Rebecca , Trottet Lionel , Uings Iain , Wilson Steve , Zhu Zhengrong , Pearce Andrew C. 
Published: July 2020

AbstractSevere α1-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1-antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high throughput screen to identify small molecules that bind to, and stabilise Z α1-antitrypsin. The lead compound blocks Z α1-antitrypsin polymerisationin vitro, reduces intracellular polymerisation and increases the secretion of Z α1-antitrypsin three-fold in mammalian cells including an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerization pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1-antitrypsin into the plasma by 7-fold. There was no observable clearance of hepatic inclusions with respect to controls. This study provides proof-of-principle that ‘mutation ameliorating’ small molecules are a viable approach to treat protein conformational diseases.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling
Authors: Zheng Yi , Zhuang Meng-Wei , Han Lulu , Zhang Jing , Nan Mei-Ling , Gao Chengjiang , Wang Pei-Hui 
Published: July 2020

AbstractThe coronavirus disease 2019 (COVID-19) caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread worldwide and has infected more than ten million individuals. One of the typical features of COVID-19 is that both type I and III interferon (IFN)-mediated antiviral immunity are suppressed. However, the molecular mechanism by which SARS-CoV-2 evades this antiviral immunity remains elusive. Here, we report that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway of RIG-I/MDA-5-MAVS signaling. The SARS-CoV2 M protein also dampens type I and III IFN induction stimulated by Sendai virus infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1 and prevents the formation of a multi-protein complex containing RIG-I, MAVS, TRAF3, and TBK1, thus impeding IRF3 phosphorylation, nuclear translocation, and activation. Consequently, the ectopic expression of the SARS-CoV2 M protein facilitates the replication of vesicular stomatitis virus (VSV). Taken together, the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of the SARS-CoV-2-induced antiviral immune suppression and sheds light on the pathogenic mechanism of COVID-19.
Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing
Authors: Sahakijpijarn Sawittree , Moon Chaeho , Koleng John J. , Christensen Dale J. , Williams Robert O. 
Published: July 2020

AbstractRemdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for Emergency Use. To maximize delivery to the lungs, we formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF; 0.82μm MMAD). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one-month storage at 25 °C/60%RH. In vivo pharmacokinetic evaluation showed that TFF-remdesivir-leucine was poorly absorbed into systemic circulation while TFF-remdesivir-Captisol® demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in lung, and levels of GS-441524 were greater in lung with the leucine formulation compared to Captisol®. In conclusion, TFF technology produces high potency remdesivir dry powder formulations for inhalation suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.
Levels of the TNF related cytokine, LIGHT increase in hospitalized COVID-19 patients with Cytokine Release Syndrome and ARDS
Authors: Perlin David S. , Zafir-Lavie Inbal , Roadcap Lori , Raines Shane , Ware Carl F. , Neil Garry A. 
Published: July 2020

AbstractMany COVID-19 patients demonstrate lethal respiratory complications caused by cytokine release syndrome (CRS). Multiple cytokines have been implicated in CRS, but TNFSF14 (LIGHT) has not been previously measured in this setting. In this study, we observed significantly elevated serum LIGHT levels in hospitalized COVID-19 patients as compared to healthy age and gender matched control patients. The assay detected bioavailable LIGHT unbound to the inhibitor Decoy receptor-3 (DcR3). Bioavailable LIGHT levels were elevated in patients both on and off ventilatory support, with a trend toward higher levels in patients requiring mechanical ventilation. In hospitalized patients over the age of 60, who exhibited a mortality rate of 82%, LIGHT levels were significantly higher (p=0.0209) in those who died compared to survivors. As previously reported, interleukin 6 (IL-6) levels were also elevated in these patients with significantly (p=0.0076) higher levels observed in patients who died vs. survivors, paralleling the LIGHT levels. Although attempts to block IL-6 binding to its receptor have shown limited effect in COVID-19 CRS, neutralization of LIGHT may prove to be more effective owing to its more central role in regulating antiviral immune responses.
Ocular Dominance Plasticity: Measurement Reliability and Variability
Authors: Min Seung Hyun , Gong Ling , Baldwin Alex S. , Reynaud Alexandre , He Zhifen , Zhou Jiawei , Hess Robert F. 
Published: July 2020

AbstractIn the last decade, studies have shown that short-term monocular deprivation strengthens the deprived eye’s contribution to binocular vision. However, the magnitude of the change in eye dominance after monocular deprivation (i.e., the patching effect) has been found to be different between for different methods and within the same method. There are three possible explanations for the discrepancy. First, the mechanisms underlying the patching effect that are probed by different measurement tasks might exist at different neural sites. Second, test-retest variability in the measurement might have led to inconsistencies, even within the same method. Third, the patching effect itself in the same subject might fluctuate across separate days or experimental sessions. To explore these possibilities, we assessed the test-retest reliability of the three most commonly used tasks (binocular rivalry, binocular combination, and dichoptic masking) and the repeatability of the shift in eye dominance after short-term monocular deprivation for each of the task. Two variations for binocular phase combination were used, at one and many contrasts of the stimuli. Also, two variations of the dichoptic masking task was tested, in which the orientation of the mask grating was either horizontal or vertical. This makes five different measurement methods in all. We hope to resolve some of the inconsistencies reported in the literature concerning this form of visual plasticity. In this study, we also aim to recommend a measurement method that will allow us to better understand its physiological basis and the underpinning of visual disorders.
Progenitor identification and SARS-CoV-2 infection in long-term human distal lung organoid cultures
Authors: Salahudeen Ameen A. , Choi Shannon S. , Rustagi Arjun , Zhu Junjie , de la O Sean M. , Flynn Ryan A. , Margalef-Català Mar , Santos António J. M. , Ju Jihang , Batish Arpit , van Unen Vincent , Usui Tatsuya , Zheng Grace X.Y. , Edwards Caitlin E. , Wagar Lisa E. , Luca Vincent , Anchang Benedict , Nagendran Monica , Nguyen Khanh , Hart Daniel J. , Terry Jessica M. , Belgrader Phillip , Ziraldo Solongo B. , Mikkelsen Tarjei S. , Harbury Pehr B. , Glenn Jeffrey S. , Garcia K. Christopher , Davis Mark M. , Baric Ralph S. , Sabatti Chiara , Amieva Manuel R. , Blish Catherine A. , Desai Tushar J. , Kuo Calvin J. 
Published: July 2020

ABSTRACTThe distal lung contains terminal bronchioles and alveoli that facilitate gas exchange and is affected by disorders including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. Investigations of these localized pathologies have been hindered by a lack of 3Din vitrohuman distal lung culture systems. Further, human distal lung stem cell identification has been impaired by quiescence, anatomic divergence from mouse and lack of lineage tracing and clonogenic culture. Here, we developed robust feeder-free, chemically-defined culture of distal human lung progenitors as organoids derived clonally from single adult human alveolar epithelial type II (AT2) or KRT5+basal cells. AT2 organoids exhibited AT1 transdifferentiation potential, while basal cell organoids progressively developed lumens lined by differentiated club and ciliated cells. Organoids consisting solely of club cells were not observed. Upon single cell RNA-sequencing (scRNA-seq), alveolar organoids were composed of proliferative AT2 cells; however, basal organoidKRT5+cells contained a distinctITGA6+ITGB4+mitotic population whose proliferation segregated to aTNFRSF12Ahisubfraction. Clonogenic organoid growth was markedly enriched within the TNFRSF12Ahisubset of FACS-purified ITGA6+ITGB4+basal cells from human lung or derivative organoids.In vivo, TNFRSF12A+cells comprised ~10% of KRT5+basal cells and resided in clusters within terminal bronchioles. To model COVID-19 distal lung disease, we everted the polarity of basal and alveolar organoids to rapidly relocate differentiated club and ciliated cells from the organoid lumen to the exterior surface, thus displaying the SARS-CoV-2 receptor ACE2 on the outwardly-facing apical aspect. Accordingly, basal and AT2 “apical-out” organoids were infected by SARS-CoV-2, identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung alveolar and basal stem cells, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and exemplifies progenitor identification within a slowly proliferating human tissue. Further, our studies establish a facilein vitroorganoid model for human distal lung infectious diseases including COVID-19-associated pneumonia.
Incongruent phylogenies and its implications for the study of diversification, taxonomy and genome size evolution ofRhododendron(Ericaceae)
Authors: Khan Gulzar , Nolzen Jennifer , Schepker Hartwig , Albach Dirk C. 
Published: July 2020

PREMISERhododendronL. (Ericaceae Juss.), is the most species-rich genus of woody flowering plants with > 1000 species. Despite the interest in the genus and numerous previous phylogenetic analysis, the infrageneric classification for the genus is still debated, partly due to its huge diversity, partly due to homoplasy in key characters and partly due to incongruence between phylogenetic markers. Here, we provide a broad coverage of representative species of allRhododendronsubgenera, sections, and most subsections to resolve its infrageneric phylogeny or highlight areas of incongruence, support previous analyses of diversification patterns and establish a relationship between genome size evolution and its diversification.METHODSWe generated sequences of two plastid (trnK andtrnL-F) and two nuclear (ITS andrpb2-i) markers for a total of 259Rhododendronspecies, and used likelihood and Bayesian statistics to analyze the data. We analyzed the markers separately to discuss and understand incongruence among the data sets and among previous studies.RESULTSWe found that the larger a subgenus, the more strongly it is supported as monophyletic. However, the smaller subgenera pose several problems, e.g.,R. subgen.Azaleastrumconsists of two sections inferred to be polyphyletic. The main shift to higher diversification in the genus occurred in the Himalayan/SE Asian clade ofR. subgen.Hymenanthes. We found that polyploidy occurs in almost all subgenera but most polyploid species are withinR. subgen.RhododendronsectionsRhododendronandSchistanthe.CONCLUSIONWhereas previous reports stated that genome sizes of tropical plants are lower than those of colder and temperate regions in angiosperms in general, our study provides evidence for such a shift to small genome-tropical species within a genus. Taken together, we see the merit in the recognition of the five major clades at the sub generic level but given the amount of incongruence a large amount of species cannot be confidently assigned to one of these five clades. Further, genome-wide data will be necessary to assess whether these currently unassignable taxa are independent taxa, assignable to one of the five major clades or whether they are inter-subgeneric hybrids.
Hierarchical design of multi-scale protein complexes by combinatorial assembly of oligomeric helical bundle and repeat protein building blocks
Authors: Hsia Yang , Mout Rubul , Sheffler William , Edman Natasha I. , Vulovic Ivan , Park Young-Jun , Redler Rachel L. , Bick Matthew J. , Bera Asim K. , Courbet Alexis , Kang Alex , Brunette TJ , Nattermann Una , Tsai Evelyn , Saleem Ayesha , Chow Cameron M. , Ekiert Damian , Bhabha Gira , Veesler David , Baker David 
Published: July 2020

AbstractA goal ofde novoprotein design is to develop a systematic and robust approach to generating complex nanomaterials from stable building blocks. Due to their structural regularity and simplicity, a wide range of monomeric repeat proteins and oligomeric helical bundle structures have been designed and characterized. Here we describe a stepwise hierarchical approach to building up multi-component symmetric protein assemblies using these structures. We first connect designed helical repeat proteins (DHRs) to designed helical bundle proteins (HBs) to generate a large library of heterodimeric and homooligomeric building blocks; the latter have cyclic symmetries ranging from C2 to C6. All of the building blocks have repeat proteins with accessible termini, which we take advantage of in a second round of architecture guided rigid helical fusion (WORMS) to generate larger symmetric assemblies including C3 and C5 cyclic and D2 dihedral rings, a tetrahedral cage, and a 120 subunit icosahedral cage. Characterization of the structures by small angle x-ray scattering, x-ray crystallography, and cryo-electron microscopy demonstrates that the hierarchical design approach can accurately and robustly generate a wide range of macromolecular assemblies; with a diameter of 43nm, the icosahedral nanocage is the largest structurally validated designed cage to date. The computational methods and building block sets described here provide a very general route to newde novodesigned symmetric protein nanomaterials.
A small, computationally flexible network produces the phenotypic diversity of song recognition in crickets
Authors: Clemens Jan , Schöneich Stefan , Kostarakos Konstantinos , Hennig R. Matthias , Hedwig Berthold 
Published: July 2020

AbstractHow neural networks evolved to generate the diversity of species-specific communication signals is unknown. For receivers of the signals one hypothesis is that novel recognition phenotypes arise from parameter variation in computationally flexible feature detection networks. We test this hypothesis in crickets, where males generate and females recognize the mating songs with a species-specific pulse pattern, by investigating whether the song recognition network in the cricket brain has the computational flexibility to recognize different temporal features. Using electrophysiological recordings from the network that recognizes crucial properties of the pulse pattern on the short timescale in the cricketGryllus bimaculatus, we built a computational model that reproduces the neuronal and behavioral tuning of that species. An analysis of the model’s parameter space reveals that the network can provide all recognition phenotypes for pulse duration and pause known in crickets and even other insects. Phenotypic diversity in the model is consistent with known preference types in crickets and other insects, and arise from computations that likely evolved to increase energy efficiency and robustness of pattern recognition. The model’s parameter to phenotype mapping is degenerate—different network parameters can create similar changes in the phenotype—which likely supports evolutionary plasticity. Our study suggests that computationally flexible networks underlie the diverse pattern recognition phenotypes and we reveal network properties that constrain and support behavioral diversity.