bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retinal Microvascular Alterations as the Biomarkers for Alzheimer Disease: Are We There Yet?
Authors: Jiang Hong , Wang Jianhua , Levin Bonnie E. , Baumel Bernard S. , Camargo Christian J. , Signorile Joseph F. , Rundek Tania 
Published: November 2020

Background:
Alzheimer disease (AD) is a heterogeneous and multifactorial disorder with an insidious onset and slowly progressive disease course. To date, there are no effective treatments, but biomarkers for early diagnosis and monitoring of disease progression offer a promising first step in developing and testing potential interventions. Cerebral vascular imaging biomarkers to assess the contributions of vascular dysfunction to AD are strongly recommended to be integrated into the current amyloid-β (Aβ) [A], tau [T], and neurodegeneration [(N)]—the “AT(N)” biomarker system for clinical research. However, the methodology is expensive and often requires invasive procedures to document cerebral vascular dysfunction. The retina has been used as a surrogate to study cerebral vascular changes. There is growing interest in the identification of retinal microvascular changes as a safe, easily accessible, low cost, and time-efficient approach to enhancing our understanding of the vascular pathogenesis associated with AD.

Evidence acquisition:
A systemic review of the literature was performed regarding retinal vascular changes in AD and its prodromal stages, focusing on functional and structural changes of large retinal vessels (vessels visible on fundus photographs) and microvasculature (precapillary arterioles, capillary, and postcapillary venules) that are invisible on fundus photographs.

Results:
Static and dynamic retinal microvascular alterations such as retinal arterial wall motion, blood flow rate, and microvascular network density were reported in AD, mild cognitive impairment, and even in the preclinical stages of the disease. The data are somewhat controversial and inconsistent among the articles reviewed and were obtained based on cross-sectional studies that used different patient cohorts, equipment, techniques, and analysis methods.

Conclusions:
Retinal microvascular alterations exist across the AD spectrum. Further large scale, within-subject longitudinal studies using standardized imaging and analytical methods may advance our knowledge concerning vascular contributions to the pathogenesis of AD.
A retrospective study evaluating efficacy and safety of compassionate use of tocilizumab in 13 patients with severe-to-critically ill COVID-19: analysis of well-responding cases and rapidly-worsening cases after tocilizumab administration
Authors: Hashimoto Shoji , Kitajima Heita , Arai Tsuyoshi , Tamura Yoshitaka , Nagai Takayuki , Morishita Hiroshi , Matsuoka Hiroto , Han Yuki , Minamoto Seijiro , Hirashima Tomonori , Yamada Tomoki , Kashiwa Yozo , Kameda Makoto , Yamaguchi Seiji , Uno Kazuko , Nakayama Emi , Shioda Tatsuo , Yoshizaki Kazuyuki , Kang Sujin , Kishimoto Tadamitsu , Tanaka Toshio 
Published: November 2020

AbstractWe administered tocilizumab into 13 severe-to-critically ill patients with coronavirus disease 2019 (COVID-19) for compassionate use in combination with potential anti-viral agents in those who required an oxygen supply and showed increased laboratory inflammatory markers such as C-reactive protein (CRP) and ferritin. One injection of tocilizumab led to rapid improvements in clinical features, inflammatory findings, and oxygen supply in seven patients with severe COVID-19 and substantial amelioration in two patients who were critically ill, whereas four patients, who exhibited rapidly worsened respiratory function, required artificial ventilatory support even after tocilizumab treatment. Three of these four patients ultimately recovered from deterioration after methylprednisolone treatment. Administration of tocilizumab did not affect viral elimination nor IgG production specific for the virus. Compared with well-responding patients, rapidly-worsened patients showed a significantly higher ratio of ferritin vs. CRP. These findings suggest that tocilizumab has beneficial effects in severe-to-critically ill patients with COVID-19; however, in some cases, addition of methylprednisolone is required for disease rescue.
rawR - Direct access to raw mass spectrometry data in R
Authors: Kockmann Tobias , Panse Christian 
Published: November 2020

AbstractThe Bioconductor project has shown that theRstatistical environment is a highly valuable tool for genomics data analysis1, but with respect to proteomics we are still missing low level infrastructure to enable performant and robust analysis workflows inR. Fundamentally important are libraries that provide raw data access. OurRpackagerawDiaghas provided the proof-of-principle how access to mass spectromerty raw files can be realized by wrapping vendor-provided APIs, but rather focused on meta data analysis and visualization2. Our novel packagerawRnow provides complete, OS independent access to all spectral data logged in Thermo Fisher Scientific raw files. In this technical note we present implementation details and describe the main functionality provided by therawRpackage. In addition, we report two use cases inspired by real-word research task that demonstrate the application of the package.Availabilityhttps://github.com/fgcz/rawR
CoDNaS-RNA: a database of Conformational Diversity in the Native State of RNA
Authors: Buitrón Martín González , Tunque Cahui Ronaldo Romario , Ríos Emilio García , Hirsh Layla , Fornasari María Silvina , Parisi Gustavo , Palopoli Nicolas 
Published: November 2020

AbstractConformational changes in RNA native ensembles are central to fulfill many of their biological roles. Systematic knowledge of the extent and possible modulators of this conformational diversity is desirable to better understand the relationship between RNA dynamics and function.We have developed CoDNaS-RNA as the first database of conformational diversity in RNA molecules. Known RNA structures are retrieved and clustered to identify alternative conformers of each molecule. Pairwise structural comparisons within each cluster allows to measure the variability of the molecule. Additional data on structural features, molecular interactions and functional annotations are provided. CoDNaS-RNA is implemented as a public resource that can be of much interest for computational and bench scientists alike.AvailabilityCoDNaS-RNA is freely accessible athttp://ufq.unq.edu.ar/codnasrnaContactnpalopoli@unq.edu.ar
An insight into SARS-CoV-2 Membrane protein interaction with Spike, Envelope, and Nucleocapsid proteins
Authors: Kumar Prateek , Kumar Amit , Garg Neha , Giri Rajanish 
Published: November 2020

AbstractIntraviral protein-protein interactions are crucial for replication, pathogenicity, and viral assembly. Among these, virus assembly is a critical step as it regulates the arrangements of viral structural proteins and helps in the encapsulation of genomic material. SARS-CoV-2 structural proteins play an essential role in the self-rearrangement, RNA encapsulation, and mature virus particle formation. In SARS-CoV, the membrane protein interacts with the envelope and spike protein in Endoplasmic Reticulum Golgi Intermediate Complex (ERGIC) to form an assembly in the lipid bilayer, followed by membrane-ribonucleoprotein (nucleocapsid) interaction. In this study, we tried to understand the interaction of membrane protein’s interaction with envelope, spike, and nucleocapsid proteins using protein-protein docking. Further, simulation studies performed up to 100 ns to examine the stability of protein-protein complexes of Membrane-Envelope, Membrane-Spike, and Membrane-Nucleocapsid. Prime MM-GBSA showed high binding energy calculations than the docked complex. The interactions identified in our study will be of great importance, as it provides valuable insight into the protein-protein complex, which could be the potential drug targets for future studies.
Differential alteration of plant functions by homologous fungal candidate effectors
Authors: dos Santos Karen Cristine Goncalves , Pelletier Gervais , Séguin Armand , Guillemette François , Hawkes Jeffrey , Desgagné-Penix Isabel , Germain Hugo 
Published: November 2020

AbstractRust fungi are plant pathogens that cause epidemics that threaten the production of important plant species, such as wheat, soy, coffee and poplar.Melampsora larici-populina(Mlp) causes the poplar rust and encodes at least 1 184 candidate effectors (CEs), however their functions are poorly known. In this study, we usedArabidopsisplants constitutively expressing CEs ofMlpto discover processes targeted by these fungal proteins. For this purpose, we sequenced the transcriptome and used mass spectrometry to analyse the metabolome ofArabidopsisplants expressing individually one of the 14 selected CEs and of a control line. We found 2 299 deregulated genes across the experiment. Among the down-regulated genes, the KEGG pathways “MAPK signaling pathway” and “Plant-pathogen interaction” were respectively over-represented in six and five of the 14 transgenic lines. Moreover, genes related to hormone response and defense were down-regulated across all transgenic lines are. We further observed that there were 680 metabolites deregulated in at least one CE-expressing transgenic line, with highly unsaturated and phenolic compounds enriched in up-regulated metabolites and peptides enriched among down-regulated metabolites. Interestingly, we found that transgenic lines expressing unrelated CEs had correlated patterns of gene and metabolite deregulation, while expression of CEs belonging to the same family deregulated different genes and metabolites. Taken together, our results indicate that the sequence of effectors and their belonging to families may not be a good predictor of their impact on the plant.ImportanceRust fungi are plant pathogens that threaten the production of important crops, including wheat, soy, coffee and poplar. Effectors are used by pathogens to control the host, however in the case ofMelampsora larici-populina, the causal agent of the poplar rust, and other rust fungi these proteins are poorly known. We usedArabidopsisplants expressing candidate effectors (CEs) ofMlpto better understand the interaction between this pathogen and its hosts. We found that expression of unrelated CEs led to similar patterns of gene and metabolite deregulation, while transgenic lines expressing CEs belonging to the same family showed different groups of different genes and metabolites deregulated. Thus, our results suggest that functional annotation of effectors based on sequence similarity may be misleading.
Adenomatous Polyposis Coli Loss Controls Cell Cycle Regulators and Response to Paclitaxel
Authors: Astarita Emily M. , Hoover Camden A. , Maloney Sara M. , Nair T. Murlidharan , Prosperi Jenifer R. 
Published: November 2020

AbstractAdenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in PTX-treated APC shRNA1 cells compared to PTX-treated controls, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations.
Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations
Authors: Miersch Shane , Li Zhijie , Saberianfar Reza , Ustav Mart , Case James Brett , Blazer Levi , Chen Chao , Ye Wei , Pavlenco Alevtina , Gorelik Maryna , Perez Julia Garcia , Subramania Suryasree , Singh Serena , Ploder Lynda , Ganaie Safder , Chen Rita E. , Leung Daisy W. , Pandolfi Pier Paolo , Novelli Giuseppe , Matusali Giulia , Colavita Francesca , Capobianchi Maria R. , Jain Suresh , Gupta J.B. , Amarasinghe Gaya K. , Diamond Michael S. , Rini James , Sidhu Sachdev S. 
Published: November 2020

SUMMARYNeutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and its tetravalent versions can block entry with a potency that exceeds the bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, observations consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show much increased tolerance to potential virus escape mutants. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for developing potent antiviral therapies against COVID-19 and related viral threats, and our strategy can be readily applied to any antibody drug currently in development.
Anopheles coluzziiinfection by the microsporidian,Vavraia culicis: the effect of host age
Authors: Vyas-Patel Nayna 
Published: November 2020

AbstractHost age at infection has important implications for disease development. In mosquitoes, infections with microsporidia and later concurrent infections with malaria parasites, leads to a suppression in the development of malaria parasites. Host age at infection with microsporidia could have implications for disease outcomes when infection occurs subsequently with malaria parasites. Mosquito larvae can take between five to seven days or more depending on the temperature to reach the adult stage, giving the microsporidianVavraia culicis, a theoretical head start in establishing and developing within larvae and possibly resulting in different levels of infection in emergent adult mosquitoes. To determine the effects of early or late infection withV. culicis, equal numbers ofAnopheles coluzziilarvae were infected individually with a high or low dose ofV. culicis, at different ages post hatching.Significantly fewer spores were produced from mosquitoes infected later, than ones infected earlier with microsporidia and there was an initial delay in the production of spores from later infected mosquitoes. In early infected larvae, there was no such initial delay and spore production took off unchecked. The infectious dose ofV. culicisdid not affect the total spore count per mosquito. Male mosquitoes produced fewer spores than females. Daily mosquito longevity and pupation was not affected significantly by infection, the infectious dose ofV.culicisgiven or by the sex of the mosquito. Considering hourly deaths, early infected hosts died 17 to 18 hours earlier than later infected larvae. The number ofV. culicisspores rose with increasing duration of infection. When equal duration of infection was considered, the findings remained the same. Host age at infection influences disease outcomes and virulence.
A model for pH coupling of the SARS-CoV-2 spike protein open/closed equilibrium
Authors: Warwicker Jim 
Published: November 2020

AbstractSARS-CoV-2, causative agent of the COVID-19 pandemic, is thought to release its RNA genome at either the cell surface or within endosomes, the balance being dependent on spike protein stability, and the complement of receptors, co-receptors and proteases. To investigate possible mediators of pH-dependence, pKa calculations have been made on a set of structures for spike protein ectodomain and fragments from SARS-CoV-2 and other coronaviruses. Dominating a heat map of the aggregated predictions, 3 histidine residues in S2 are consistently predicted as destabilising in pre-fusion (all 3) and post-fusion (2 of 3) structures. Other predicted features include the more moderate energetics of surface salt-bridge interactions, and sidechain-mainchain interactions. Two aspartic acid residues in partially buried salt-bridges (D290 – R273 and R355 – D398) have pKas that are calculated to be elevated and destabilising in more open forms of the spike trimer. These aspartic acids are most stabilised in a tightly closed conformation that has been observed when linoleic acid is bound, and which also affects the interactions of D614. The D614G mutation is known to modulate the balance of closed to open trimer. It is suggested that D398 in particular contributes to a pH-dependence of the open/closed equilibrium, potentially coupled to the effects of linoleic acid binding and D614G mutation, and possibly also A570D mutation. These observations are discussed in the context of SARS-CoV-2 infection, mutagenesis studies, and other human coronaviruses.
Priority effects alter interaction outcomes in a legume-rhizobium mutualism
Authors: Boyle Julia A. , Simonsen Anna K. , Frederickson Megan E. , Stinchcombe John R. 
Published: November 2020

AbstractPriority effects occur when the order of species arrival affects final community structure. Mutualists often interact with multiple partners in different orders, but if or how priority effects alter interaction outcomes is an open question. In the field, we paired the legumeMedicago lupulinawith two nodulating strains ofEnsiferbacteria that vary in nitrogen-fixing ability. We inoculated plants with strains in different orders and measured interaction outcomes. The first strain to arrive primarily determined plant performance and final relative abundances of rhizobia on roots. Plants that received effective microbes first and ineffective microbes second grew larger than plants inoculated with the same microbes in opposite order. Our results show that mutualism outcomes can be influenced not just by partner identity, but by interaction order. Furthermore, hosts receiving high-quality mutualists early can better tolerate low-quality symbionts later, indicating priority effects may help explain the persistence of ineffective symbionts.
Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 Main Protease complexes reveal the role of a lateral pocket in enhancing the ligand affinity
Authors: Li Weng Ying , Naik Shiv Rakesh , Dingelstad Nadia , Kalyaanamoorthy Subha , Ganesan Aravindhan 
Published: November 2020

AbstractThe 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and a number of countries are already in the middle of the second wave of infection. There is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand bound Mpro complexes in the protein data bank (PDB) that describe structural details of different chemotypes of fragments binding within different sites in Mpro. In this work, we perform rigorous molecular dynamics (MD) simulation of 62 reversible ligand-Mpro complexes in the PDB to gain mechanistic insights about their interactions at atomic level. Using a total of ~2.25 μs long MD trajectories, we identified and characterized different pockets and their conformational dynamics in the apo Mpro structure. Later, using the published PDB structures, we analyzed the dynamic interactions and binding affinity of small ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets in Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in this lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.
TMPRSS2 and ADAM17 interactions with ACE2 complexed with SARS-CoV-2 and B0AT1 putatively in intestine, cardiomyocytes, and kidney
Authors: Stevens Bruce R. 
Published: November 2020

ABSTRACTCOVID-19 outcomes reflect organ-specific interplay of SARS-CoV-2 and its receptor, ACE2, with TMPRSS2 and ADAM17. Confirmed active tropism of SARS-CoV-2 in epithelial cells of intestine and kidney proximal tubule, and in aging cardiomyocytes, capriciously manifests extra-pulmonary organ-related clinical symptoms in about half of COVID-19 patients, occurring by poorly understood mechanisms. We approached this knowledge gap by recognizing a clue that these three particular cell types share a common denominator kindred of uniquely expressing the SLC6A19 neutral amino acid transporter B0AT1 protein (alternatively called NBB, B, B0) serving glutamine and tryptophan uptake. B0AT1 is a cellular trafficking chaperone partner of ACE2, shown by cryo-EM to form a thermodynamically-favored stabilized 2ACE2:2B0AT1 dimer-of-heterodimers. The gut is the body’s site of greatest magnitude expression depot of both ACE2 and B0AT1. This starkly contrasts with pulmonary pneumocyte expression of monomeric ACE2 with conspicuously undetectable B0AT1. We hypothesized that B0AT1 steers the organ-related interplay amongst ACE2, TMPRSS2, ADAM17, and SARS-CoV-2 RBD. The present study employed molecular docking modeling that indicated active site catalytic pocket residues of TMPRSS2 and ADAM17 each formed bonds ≤ 2 A with monomer ACE2 specific residues within a span R652-D713 involved in cleaving sACE2 soluble ectodomain release. These bonds are consistent with competitive binding interactions of experimental anti-SARS-CoV-2 drug small molecules including Camostat and Nafamostat. Without B0AT1, ACE2 residues K657 and N699 dominated docking bonding with TMPRSS2 or ADAM17 active sites, with ACE2 R710 and R709 contributing electrostatic attractions, but notably ACE2 S708 never closer than 16-44 A. However, in the dimer-of-heterodimers arrangement all ACE2 neck region residues were limited to TMPRSS2 or ADAM17 approaches 35 A, with the interference directly attributed to the presence of a neighboring B0AT1 subunit complexed to the partnering ACE2 subunit of 2ACE2:2B0AT1; ADAM17 failed to dock by bumping its active site pocket oriented dysfunctionally outwardly facing 1800away. Results were the same whether the dimer-of-heterodimers was in either the “closed” or “open” conformation, or whether or not SARS-CoV-2 RBD was complexed to ACE2. The results implicate B0AT1-and in particular the 2ACE2:2B0AT1 complex-as a maJor player in the landscape of COVID-19 pathophysiology engaging TMPRSS2 and ADAM17, consistent with experimental evidence in the literature and in clinical reports. These findings provide a gateway to understanding the roles of B0AT1 relating to COVID-19 manifestations putatively assigned to intestinal and renal epithelial cells and cardiomyocytes, with underpinnings useful for considerations in public hygiene policy and drug development.