bluuebunny/crossref_metadata_2025 huggingface dataset:
Comorbid neuropathological diagnoses in early vs late-onset Alzheimer’s disease
Authors: Spina Salvatore , Joie Renaud La , Petersen Cathrine , Nolan Amber L. , Cuevas Deion , Cosme Celica , Hepker Mackenzie , Hwang Ji-Hye , Miller Zachary A. , Huang Eric J. , Karydas Anna M. , Grant Harli , Boxer Adam L. , Gorno-Tempini Maria Luisa , Rosen Howard J. , Kramer Joel H. , Miller Bruce L. , Seeley William W. , Rabinovici Gil D. , Grinberg Lea T.
Published: October 2020

Copathologies play an important role in the expression of the AD clinical phenotype and may influence treatment efficacy. Early-onset AD (EOAD), defined as manifesting before age 65, has been viewed as a relatively pure form of AD with a more homogenous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with EOAD (median age of onset = 55 years, 44 females) and 48 with late-onset AD (LOAD) (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of AD. Prevalence and stage of Lewy body disease (LBD), limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease (AGD), hippocampal sclerosis (HS), cerebral amyloid angiopathy (CAA), vascular brain injury (VBI) and aging-related tau astrogliopathy (ARTAG) were compared between the two cohorts. We found at least one non-AD pathological diagnosis in 98% of patients with EOAD (versus 100% of LOAD), and the number of comorbid diagnoses per patient was lower in EOAD than in LOAD (median=2 versus 3, Mann-Whitney Z=3.00, p=0.002). LBD and CAA were common in both EOAD and LOAD (CAA: 86% versus 79%, Fisher exact p=0.33; LBD: 49% versus 42%, p=0.48, respectively), although amygdala-predominant LBD was more commonly found in EOAD than LOAD (22% versus 6%, p=0.02). In contrast, LATE (35% versus 8%, p<0.001), HS (15% versus 3%, p=0.02), AGD (58% versus 41%, p=0.052), and VBI (65% versus 39%, p=0.004) were more common in LOAD than EOAD, respectively. The number of copathologies predicted worse cognitive performance at the time of death on MMSE (1.4 points/pathology (95%CI [−2.5, −0.2]) and Clinical Dementia Rating – Sum of Boxes (1.15 point/pathology, 95%CI [0.45, 1.84]), across the EOAD and the LOAD cohorts. Prevalence of at least one ApoE e4 allele was similar across the two cohorts (52%) and was associated with a greater number of copathologies (+0.42, 95%CI [0.01, 0.82], p=0.04), independent of age of symptom onset. Our findings suggest that non-AD pathological diagnoses play an important role in the clinical phenotype of EOAD with potentially significant implications for clinical practice and clinical trials design.
Population attributable fraction for continuously distributed exposures
Authors: Ferguson John , Maturo Fabrizio , Yusuf Salim , O’Donnell Martin
Published: October 2020

When estimating population attributable fractions (PAF), it is common to partition a naturally continuous exposure into a categorical risk factor. While prior risk factor categorization can help estimation and interpretation, it can result in underestimation of the disease burden attributable to the exposure as well as biased comparisons across different exposures and risk factors. Here, we propose sensible PAF estimands for continuous exposures under a potential outcomes framework. In contrast to previous approaches, we incorporate estimation of the minimum risk exposure value (MREV) into our procedures. While for exposures such as tobacco usage, a sensible value of the MREV is known, often it is unknown and needs to be estimated. Second, in the setting that the MREV value is an extreme-value of the exposure lying in the distributional tail, we argue that the natural estimator of PAF may be both statistically biased and highly volatile; instead, we consider a family of modified PAFs which include the natural estimate of PAF as a limit. A graphical comparison of this set of modified PAF for differing risk factors may be a better way to rank risk factors as intervention targets, compared to the standard PAF calculation. Finally, we analyse the bias that may ensue from prior risk factor categorization, examining whether categorization is ever a good idea, and suggest interpretations of categorized-estimands within a causal inference setting.
COVID-19 neutralizing antibodies predict disease severity and survival
Authors: Garcia-Beltran Wilfredo F. , Lam Evan C. , Astudillo Michael G. , Yang Diane , Miller Tyler E. , Feldman Jared , Hauser Blake M. , Caradonna Timothy M. , Clayton Kiera L. , Nitido Adam D. , Murali Mandakolathur R. , Alter Galit , Charles Richelle C. , Dighe Anand , Branda John A. , Lennerz Jochen K. , Lingwood Daniel , Schmidt Aaron G. , Iafrate A. John , Balazs Alejandro B.
Published: October 2020

COVID-19 exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, and high anti-RBD antibody levels. While anti-RBD IgG levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting protection from reinfection by this strain. However, SARS-CoV-2 sera was unable to cross-neutralize a highly-homologous pre-emergent bat coronavirus, WIV1-CoV, that has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.
Genome-Wide Polygenic Risk Score Identifies Individuals at Elevated Parkinson’s Disease Risk
Authors: Han Yingnan , Teeple Erin , Shankara Srinivas , Sadeghi Mahdiar , Zhu Cheng , Liu Dongyu ,   FinnGen, Wang Clarence , Frau Francesca , Klinger Katherine W. , Madden Stephen L. , Rajpal Deepak , Sardi S. Pablo , Kumar Dinesh
Published: October 2020

Parkinson’s Disease (PD) is the second most common and fastest-growing neurological disorder. Polygenic Risk Scores (PRS) using hundreds to thousands of PD-associated variants support polygenic heritability. Here, for the first time, we apply a genome-wide polygenic risk score approach using 6.2 million variants to compute a PD genome-wide polygenic risk score (PD-GPRS) via the LDPred algorithm. PD-GPRS validation and testing used Accelerating Medicines Partnership – Parkinson’s Disease (AMP-PD) and FinnGen Consortia genomic data from 1,654 PD Cases and 79,123 Controls. PD odds for the top 8%, 2.5%, and 1% of PD-GPRS were three-, four-, and seven times greater compared with lower percentiles, respectively (p<1e-10). PD age of onset and MDS-UPDRS motor scores also differed by PD-GPRS decile. Enrichment for phagosome related, dopamine signaling, immune related, and neuronal signaling pathways was found for genes nearest high PD-GPRS variants identified by MAF analysis. PD-GPRS offers a promising screening tool to identify high-risk individuals for preventive lifestyle or new drug therapy trials.

In Brief

In Han and Teeple et al., Parkinson’s Disease inherited risk is quantified by a genome-wide polygenic risk score (PD-GPRS) approach using 6.2 million variants and data from 80,777 individuals. For the top 2.5% and 1% of PD-GPRS, individuals had five- and seven-fold greater odds of PD, respectively. PD-GPRS was found to be associated with overall PD risk, earlier age of onset, and MDS-UPDRS motor scores. Genes nearest to variants observed at higher frequencies among high-GPRS individuals are enriched for PD-implicated pathways.

HIGHLIGHTS

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Parkinson’s Disease genome-wide polygenic risk score (PD-GPRS) calculated from 6.2 million variants identifies individuals with inherited clinically significant increased neurodegeneration risk.

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Top percentile PD-GPRS individuals were found to have up to seven-fold greater odds of PD and earlier age at PD diagnosis.

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PD-GPRS scores correlated with all-subjects cohort mean MDS-UPDRS motor scores.

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Pathway analysis of genes adjacent to frequently occurring variants in the high PD-GPRS population identified polygenic risk contributions for variations in PD-implicated pathways including dopamine signaling, immune responses, and autophagy pathways.
A Study on the Effects of Containment Policies and Vaccination on the Spread of SARS-CoV-2
Authors: Bokharaie Vahid S.
Published: October 2020

This paper presents a method to predict the spread of the SARS-CoV-2 in a population with a known age-structure, and then, to quantify the effects of various containment policies, including those policies that affect each age-group differently. The model itself is a compartmental model in which each compartment is divided into a number of age-groups. The parameters of the model are estimated using an optimisation scheme and some known results from the theory of monotone systems such that the model output agrees with some collected data on the spread of SARS-CoV-2.

To highlight the strengths of this framework, a few case studies are presented in which different populations are subjected to different containment strategies. They include cases in which the containment policies switch between scenarios with different levels of severity. Then a case study on herd immunity due to vaccination is presented. And then it is shown how we can use this framework to optimally distribute a limited number of vaccine units in a given population to maximise their impact and reduce the total number of infectious individuals.

MSC subclass

92C60, 92C50
Tobacco control policies and smoking cessation treatment utilization: a moderated mediation analysis
Authors: Thrul Johannes , Riehm Kira E. , Cohen Joanna E. , Alexander G. Caleb , Vernick Jon S. , Mojtabai Ramin
Published: October 2020

Background

Tobacco policies, including clean indoor air laws and cigarette taxes, increase smoking cessation in part by stimulating the use of cessation treatments. We explored whether the mediating effect of such treatments varies across socio-demographic groups.

Methods

We used data from 62,165 U.S. adult participants in the 2003 and 2010/11 Current Population Survey-Tobacco Use Supplement (CPS-TUS) who reported smoking cigarettes during the past year. Building on prior structural equation models used to quantify the degree to which smoking cessation treatments (prescription medications, nicotine replacement therapy, counselling/support groups, quitlines, and internet resources) mediated the association between clean indoor air laws, cigarette excise taxes, and recent smoking cessation, we added selected moderators to each model to investigate whether mediation effects varied by sex, race/ethnicity, education, income, and health insurance status.

Results

For clean indoor air laws, the mediating effect of prescription medication and nicotine replacement therapies varied significantly between racial/ethnic, age, and education groups in 2003. However, none of these moderation effects remained significant in 2010/11. For cigarette excise taxes in 2010/2011, the mediating effect of counseling was stronger in older adults; whereas, the mediating effect of prescription medications tended to be stronger in younger adults. No other moderator reached statistical significance. Smoking cessation treatments did not mediate the effect of taxes on smoking cessation in 2003 and were not included in these analyses.

Conclusions

Sociodemographic differences in how smoking cessation treatment use mediates between clean indoor air laws and smoking cessation have decreased from 2003 to 2010/11. In most cases, policies appear to stimulate smoking cessation treatment use similarly across varied sociodemographic groups.
Biomimetic Virus-like Particles as SARS-CoV-2 Positive Controls for RT-PCR Diagnostics
Authors: Chan Soo Khim , Du Pinyi , Ignacio Karole , Metha Sanjay , Newton Isabel G. , Steinmetz Nicole F.
Published: October 2020

Coronavirus disease 2019 (COVID-19) is a highly transmissible disease that has affected more than 90% of the countries worldwide. At least 17 million individuals have been infected, and some countries are still battling first or second waves of the pandemic. Nucleic acid tests, especially reverse-transcription polymerase chain reaction (RT-PCR), have become the workhorse for early detection of COVID-19 infection. Positive controls for the molecular assays have been developed to validate each test and to provide high accuracy. However, most available positive controls require cold-chain distribution and cannot serve as full-process control. To overcome these shortcomings, we report the production of biomimetic virus-like particles (VLPs) as SARS-CoV-2 positive controls. A SARS-CoV-2 detection module for RT-PCR was encapsidated into VLPs from a bacteriophage and a plant virus. The chimeric VLPs were obtained either by in vivo reconstitution and co-expression of the target detection module and coat proteins or by in vitro assembly of purified detection module RNA sequences and coat proteins. These VLP-based positive controls mimic SARS-CoV-2 packaged RNA while being non-infectious. Most importantly, we demonstrated that the positive controls are scalable, stable, and can serve broadly as controls, from RNA extraction to PCR in clinical settings.

Table of contents graphic
Development and pre-clinical characterization of two therapeutic equine formulations towards SARS-CoV-2 proteins for the potential treatment of COVID-19
Authors: León Guillermo , Herrera María , Vargas Mariángela , Arguedas Mauricio , Sánchez Andrés , Segura Álvaro , Gómez Aarón , Solano Gabriela , Corrales-Aguilar Eugenia , Risner Kenneth , Narayanan Aarthi , Bailey Charles , Villalta Mauren , Hernández Andrés , Sánchez Adriana , Cordero Daniel , Solano Daniela , Durán Gina , Segura Eduardo , Cerdas Maykel , Umaña Deibid , Moscoso Edwin , Estrada Ricardo , Gutiérrez Jairo , Méndez Marcos , Castillo Ana Cecilia , Sánchez Laura , Gutiérrez José María , Díaz Cecilia , Alape Alberto
Published: October 2020

In the current global emergency due to SARS-CoV-2 outbreak, passive immunotherapy emerges as a promising treatment for COVID-19. Among animal-derived products, equine formulations are still the cornerstone therapy for treating envenomations due to animal bites and stings. Therefore, drawing upon decades of experience in manufacturing snake antivenom, we developed and preclinically evaluated two anti-SARS-CoV-2 polyclonal equine formulations as potential alternative therapy for COVID-19. We immunized two groups of horses with either S1 (anti-S1) or a mixture of S1, N, and SEM mosaic (anti-Mix) viral recombinant proteins. Horses reached a maximum anti-viral antibody level at 7 weeks following priming, and showed no major adverse acute or chronic clinical alterations. Two whole-IgG formulations were prepared via hyperimmune plasma precipitation with caprylic acid and then formulated for parenteral use. Both preparations had similar physicochemical and microbiological quality and showed ELISA immunoreactivity towards S1 protein and the receptor binding domain (RBD). The anti-Mix formulation also presented immunoreactivity against N protein. Due to high anti-S1 and anti-RBD antibody content, final products exhibited highin vitroneutralizing capacity of SARS-CoV-2 infection, 80 times higher than a pool of human convalescent plasma. Pre-clinical quality profiles were similar among both products, but clinical efficacy and safety must be tested in clinical trials. The technological strategy we describe here can be adapted by other producers, particularly in low- and middle-income countries.
METAMVGL: a multi-view graph-based metagenomic contig binning algorithm by integrating assembly and paired-end graphs
Authors: Zhang Zhenmiao , Zhang Lu
Published: October 2020

Motivation

Due to the complexity of metagenomic community,de novoassembly on next generation sequencing data is commonly unable to produce microbial complete genomes. Metagenomic binning is a crucial task that could group the fragmented contigs into clusters based on their nucleotide compositions and read depths. These features work well on the long contigs, but are not stable for the short ones. Assembly and paired-end graphs can provide the connectedness between contigs, where the linked contigs have high chance to be derived from the same clusters.

Results

We developed METAMVGL, a multi-view graph-based metagenomic contig binning algorithm by integrating both assembly and paired-end graphs. It could strikingly rescue the short contigs and correct the binning errors from dead ends subgraphs. METAMVGL could learn the graphs’ weights automatically and predict the contig labels in a uniform multi-view label propagation framework. In the experiments, we observed METAMVGL significantly increased the high-confident edges in the combined graph and linked dead ends to the main graph. It also outperformed with many state-of-the-art binning methods, MaxBin2, MetaBAT2, MyCC, CONCOCT, SolidBin and Graphbin on the metagenomic sequencing from simulation, two mock communities and realSharondata.

Availability and implementation

The software is available athttps://github.com/ZhangZhenmiao/METAMVGL.
The central THαβ immunity associated cytokine: IL-10 has a strong anti-tumor ability toward established cancer models in vivo and toward cancer cells in vitro
Authors: Hu Wan-Chung
Published: October 2020

Cancer immunotherapy is a promising new approach for cancer treatment. We propose to use a new host immunological pathway: THαβ immunity for cancer treatment. THαβ immunity is a natural host immunity which can be used IFN-α/β and its major effectors are IL-10 and IL-15. Thus, we here used these cytokines for treatment both in a mice breast cancer 4T1 model and in a neuroblastoma NXS2 model. 4T1 cells and NXS2 cells were inoculated subcutaneously to wild type BALB/c female mice and AJ mice, respectively. Both Cytokines and an antibody treatment with variable dosages were given. Our results show that IL-10 and IL-15 treatments have significant effects on not only tumor volume shrinkage and but also on mice survival. However, IFN-γ even worsens the tumor volume and mice survival. Antibodies plus IL-10 is no better than IL-10 alone for cancer immunotherapy. This can be due to GD2 antigen expression on immune cells. Moreover, an anti-GD2 antibody could harm immune cells themselves. We found that IL-10 has direct toxicity on tumor cells in vitro. Our results conclude that using THαβ immunity is a good strategy for cancer immunotherapy.
WHIRLY1 of barley and maize share a PRAPP motif conferring nucleoid compaction
Authors: Oetke Svenja , Scheidig Axel J. , Krupinska Karin
Published: October 2020

WHIRLY1 in barley was shown to be a major architect of plastid nucleoids. Its accumulation in cells ofE. colicoincided with an induction of nucleoid compaction and growth retardation. While WHIRLY1 of maize had similar effects onE. colicells, WHIRLY1 proteins of Arabidopsis and potato a well as WHIRLY2 proteins had no impact on nucleoid compaction inE. coli. By mutagenesis ofHvWHIRLY1the PRAPP motif at the N-terminus preceding the highly conserved WHIRLY domain was identified to be responsible for the nucleoid compacting activity of HvWHIRLY1 in bacteria. This motif is found in WHIRLY1 proteins of most members of the Poaceae family, but neither in the WHIRLY2 proteins of the family nor in any WHIRLY protein of eudicot species such asArabidopsis thaliana. This finding indicates that a subset of the monocot WHIRLY1 proteins has acquired a specific function as nucleoid compacters by sequence variation in the N-terminal part preceding the conserved WHIRLY domain and that in different groups of higher plants the compaction of nucleoids is mediated by other proteins.
Effect of high proportion concentrate dietary on Yak jejunal structure, physiological function and protein composition during cold season
Authors: Jia Jianlei , Liang Chunnian , Wu Xiaoyun , Xiong Lin , Bao Pengjia , Chen Qian , Yan Ping
Published: October 2020

The current study aimed to investigate the damage of long-term high concentrate diet feeding pattern on Yak jejunal structure, physiological function and protein composition during cold season. Twelve Datong male Yak (Bos grunniens) with the same age from cold season were randomly selected and slaughtered to determine Yak jejunal digestive enzyme activity, morphology and protein composition on different feeding patterns in Tibetan Plateau. The results showed that Yak jejunum digestive enzyme activity and morphology of grazing reared group were better than those in the intensively reared group. A total of 96 differentially expressed proteins were identified by label-free Mass Spectrometry (MS), which could be concluded to two predominant themes: protein structure and inflammatory response. Nine differentially expressed proteins were correlated in Yak jejunum damage in different feeding patterns. According to our study, feeding patterns resulted in the differences in Yak jejunum physiological function, morphology and protein composition. Our results confirmed that feeding of long-term high concentrate diet could damage the jejunum epithelial morphology and function.
Genome-wide characterization and expression profiling of B3 superfamily during flower induction stage in pineapple (Ananas comosusL.)
Authors: Ruan Cheng Cheng , Chen Zhe , Hu Fu Chu , Wang Xiang He , Guo Li Jun , Fan Hong Yan , Luo Zhi Wen , Zhang Zhi Li
Published: October 2020

The B3 superfamily is a plant-specific family, which involves in growth and development process. By now, the identification of B3 superfamily in pineapple (Ananas comosus) has not reported. In this study, 57B3genes were identified and further phylogenetically classified into five subfamilies, all genes contained B3 domain. Chromosomal localization analysis revealed that 54 of 57AcB3genes were located on 21 chromosomes.Collinearity analysis indicated that the segmental duplication was the main event in the evolution of B3 gene superfamily and most of them were under purifying selection. Moreover, there were 7 and 39 pairs of orthologous B3s were identified between pineapple andArabidopsisor rice, respectively, which indicated the closer genetic relationship between pineapple and rice. Most genes hadcis-element of abscisic acid, ethylene, MeJA, light, and abiotic stress. qRT-PCR showed that the expression level of mostAcB3genes were up-regulated within 1 d after ethephon treatment and expressed high level in flower bud differentiation period in stem apex. This study provide a comprehensive understanding ofAcB3sand a basis for future molecular studies of ethephon induced pineapple flowering.
Child abuse associates with increased recruitment of perineuronal nets in the ventromedial prefrontal cortex: a possible implication of oligodendrocyte progenitor cells
Authors: Tanti Arnaud , Belliveau Claudia , Nagy Corina , Maitra Malosree , Denux Fanny , Perlman Kelly , Chen Frank , Mpai Refilwe , Canonne Candice , Théberge Stéphanie , McFarquhar Ashley , Davoli Maria Antonietta , Belzung Catherine , Turecki Gustavo , Mechawar Naguib
Published: October 2020

Child abuse (CA) is a strong predictor of psychopathologies and suicide, altering normal trajectories of brain development in areas closely linked to emotional responses such as the prefrontal cortex (PFC). Yet, the cellular underpinnings of these enduring effects are unclear. Childhood and adolescence are marked by the protracted formation of perineuronal nets (PNNs), which orchestrate the closure of developmental windows of cortical plasticity by regulating the functional integration of parvalbumin interneurons (PV) into neuronal circuits. Using well-characterized post-mortem brain samples, we show that a history of CA is specifically associated with increased densities and morphological complexity of WFL-labeled PNNs in the ventromedial PFC (BA11/12), possibly suggesting increased recruitment and maturation of PNNs. Through single-nucleus sequencing and fluorescent in-situ hybridization, we found that the expression of canonical components of PNNs is enriched in oligodendrocyte progenitor cells (OPCs), and that they are upregulated in CA victims. These correlational findings suggest that early-life adversity may lead to persistent patterns of maladaptive behaviors by reducing the neuroplasticity of cortical circuits through the enhancement of developmental OPC-mediated PNN formation.
Pore constrictions in intervessel pit membranes reduce the risk of embolism spreading in angiosperm xylem
Authors: Kaack Lucian , Weber Matthias , Isasa Emilie , Karimi Zohreh , Li Shan , Pereira Luciano , Trabi Christophe L. , Zhang Ya , Schenk H. Jochen , Schuldt Bernhard , Schmidt Volker , Jansen Steven
Published: October 2020

Embolism spreading in angiosperm xylem occurs via mesoporous pit membranes between vessels. Here, we investigate how the size of pore constrictions in pit membranes is related to pit membrane thickness and embolism resistance.

In three models, pit membranes are modelled as multiple layers to investigate how pit membrane thickness and the number of intervessel pits per vessel determine pore constriction sizes, the probability of encountering large pores, and air-seeding. These estimations were complemented by measurements of pit membrane thickness, embolism resistance, and number of intervessel pits per vessel (n= 31, 31, and 20 species, respectively).

Constriction sizes in pores decreased with increasing pit membrane thickness, which agreed with the measured relationship between pit membrane thickness and embolism resistance. The number of pits per vessel affected constriction size and embolism resistance much less than pit membrane thickness. A strong relationship between estimated air-seeding pressures and measured embolism resistance was observed.

Pore constrictions provide a mechanistic explanation why pit membrane thickness determines embolism resistance, and suggest that hydraulic safety can be uncoupled from hydraulic efficiency. Although embolism spreading remains puzzling and encompasses more than pore constriction sizes, angiosperms are unlikely to have leaky pit membranes, which enables tensile transport of water.
Structural basis of SARS-CoV-2 polymerase inhibition by Favipiravir
Authors: Peng Qi , Peng Ruchao , Yuan Bin , Wang Min , Zhao Jingru , Fu Lifeng , Qi Jianxun , Shi Yi
Published: October 2020

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into an unprecedented global pandemic. Nucleoside analogues, such as Remdesivir and Favipiravir, can serve as the first-line broad-spectrum antiviral drugs against the newly emerging viral diseases. Recent clinical trials of these two drugs for SARS-CoV-2 treatment revealed antiviral efficacies as well as side effects with different extents1–4. As a pyrazine derivative, Favipiravir could be incorporated into the viral RNA products by mimicking both adenine and guanine nucleotides, which may further lead to mutations in progeny RNA copies due to the non-conserved base-pairing capacity5. Here, we determined the cryo-EM structure of Favipiravir bound to the replicating polymerase complex of SARS-CoV-2 in the pre-catalytic state. This structure provides a missing snapshot for visualizing the catalysis dynamics of coronavirus polymerase, and reveals an unexpected base-pairing pattern between Favipiravir and pyrimidine residues which may explain its capacity for mimicking both adenine and guanine nucleotides. These findings shed lights on the mechanism of coronavirus polymerase catalysis and provide a rational basis for developing antiviral drugs to combat the SARS-CoV-2 pandemic.
EVALUATION OF ANTI-BACTERIAL AND ANTHELMINTIC ACTIVITIES OF BARK OF PLANTCASSIA FISTULALinn
Authors: Nayabaniya Anant , Aryal Samyam , Dahal Bibek , Khanal Hemanta , Gupta Anil K.
Published: October 2020

This study deals with phytochemical screening and evaluation of anti-bacterial and anthelmintic activities of the bark extracts ofCassia fistulaL. The extraction with different solvents - methanol, acetone, distilled water - had been carried out. The anti-bacterial assay was done against two gram +ve and two gram −ve bacteria by agar cup diffusion method. The anthelmintic activity was done onPheretima posthuma(earthworm) by recording the paralyzing and death time under different concentrations. Methanolic extract showed the maximum activity on both fronts be it anti-bacterial or anthelmintic. The extract was effective only against gram +ve bacteria. AmongStaphylococcus aureusandStreptococci faecalis, the former was more susceptible. The activity against gram −ve bacteria was not found. In case of anthelmintic activity, the concentration of 50 mg/ml was effective and near to the paralyzing and death time as recorded for the 10 mg/ml concentration of the standard Albendazole. However, aqueous extract was more effective than the acetone extract.
Prioritization of prostate cancer to immune checkpoint therapy by ranking tumors along IFN-γ axis and identification of immune resistance mechanisms
Authors: Reva Boris , Omelchenko Tatiana , Calinawan Anna , Nair Sujit , Schadt Eric , Tewari Ash
Published: October 2020

We propose priotirization of prostate cancer patients to PD-L1 checkpoint therapy by assessing activity of IFN-γ/PD-L1 signaling in tumor from transcriptional profile. To this end, we introduced a new approach for inferring pathway activity and suppression (IPAS) by assessing significance of positioning pathway’s genes expression levels at top (activation) or bottom (suppression) in gene expression profile of a given tumor. By ordering tumors along IFN-γ/PD-L1 axis, we determined distinct “IFN-γ-depleted” and “IFN-γ-enriched” immune subtypes, genes involved in immune evasion and potential targets for combination therapy. Using IPAS scoring method, we proposed biomarker panels for accurate ranking tumors along IFN-γ/PD-L1 axis.
Real-Time Observation of Structure and Dynamics during the Liquid-to-Solid Transition of FUS LC
Authors: Berkeley Raymond F. , Kashefi Maryam , Debelouchina Galia T.
Published: October 2020

Many of the proteins found in pathological protein fibrils also exhibit tendencies for liquid-liquid phase separation (LLPS) bothin vitroand in cells. The mechanisms underlying the connection between these phase transitions have been challenging to study due to the heterogeneous and dynamic nature of the states formed during the maturation of LLPS protein droplets into gels and solid aggregates. Here, we interrogate the liquid-to-solid transition of the low complexity domain of the RNA binding protein FUS (FUS LC), which has been shown to adopt LLPS, gel-like, and amyloid states. We employ magic-angle spinning (MAS) NMR spectroscopy which has allowed us to follow these transitions in real time and with residue specific resolution. We observe the development of β-sheet structure through the maturation process and show that the final state of FUS LC fibrils produced through LLPS is distinct from that grown from fibrillar seeds. We also apply our methodology to FUS LC G156E, a clinically relevant FUS mutant that exhibits accelerated fibrillization rates. We observe significant changes in dynamics during the transformation of the FUS LC G156E construct and begin to unravel the sequence specific contributions to this phenomenon with computational studies of the phase separated state of FUS LC and FUS LC G156E.

Significance

The presence of protein aggregates and plaques in the brain is a common pathological sign of neurodegenerative disease. Recent work has revealed that many of the proteins found in these aggregates can also form liquid-liquid droplets and gels. While the interconversion from one state to another can have vast implications for cell function and disease, the molecular mechanisms that underlie these processes are not well understood. Here, we combine MAS NMR spectroscopy with other biophysical and computational tools to follow the transitions of the stress response protein FUS. This approach has allowed us to observe real-time changes in structure and dynamics as the protein undergoes these transitions, and to reveal the intricate effects of disease-relevant mutations on the transformation process.
Differences in cofactor, oxygen and sulfur requirements influence niche adaptation in deep-sea vesicomyid clam symbioses
Authors: Breusing Corinna , Perez Maёva , Beinart Roxanne A. , Young C. Robert
Published: October 2020

Vertical transmission of bacterial endosymbionts is accompanied by virtually irreversible gene loss that can provide insights into adaptation to divergent ecological niches. While patterns of genome reduction have been well described in some terrestrial symbioses, they are less understood in marine systems where vertical transmission is relatively rare. The association between deep-sea vesicomyid clams and chemosynthetic Gammaproteobacteria is one example of maternally inherited symbioses in the ocean. Differences in nitrogen and sulfur physiology between the two dominant symbiont groups,Ca.Ruthia andCa.Vesicomyosocius, have been hypothesized to influence niche exploitation, which likely affects gene content evolution in these symbionts. However, genomic data are currently limited to confirm this assumption. In the present study we sequenced and compared 11 vesicomyid symbiont genomes with existing assemblies forCa. Vesicomyosocius okutanii andCa. Ruthia magnifica. Our analyses indicate that the two vesicomyid symbiont groups have a common core genome related to chemosynthetic metabolism, but differ in their potential for nitrate respiration and flexibility to environmental sulfide concentrations. Moreover,Ca. Vesicomyosocius andCa. Ruthia have different enzymatic requirements for cobalamin and nickel and show contrasting capacities to acquire foreign genetic material. Tests for site-specific positive selection in metabolic candidate genes imply that the observed physiological differences are adaptive and thus likely correspond to ecological niches available to each symbiont group. These findings highlight the role of niche differentiation in creating divergent paths of reductive genome evolution in vertically transmitted symbionts.
Constructing Gene Regulatory Networks using Epigenetic Data
Authors: Sonawane Abhijeet Rajendra , DeMeo Dawn L. , Quackenbush John , Glass Kimberly
Published: October 2020

The biological processes that drive cellular function can be represented by a complex network of interactions between regulators (transcription factors) and their targets (genes). A cell’s epigenetic state plays an important role in mediating these interactions, primarily by influencing chromatin accessibility. However, effectively leveraging epigenetic information when constructing regulatory networks remains a challenge. We developed SPIDER, which incorporates epigenetic information (DNase-Seq) into a message passing framework in order to estimate gene regulatory networks. We validated SPIDER’s predictions using ChlP-Seq data from ENCODE and found that SPIDER networks were more accurate than other publicly available, epigenetically informed regulatory networks as well as networks based on methods that leverage epigenetic data to predict transcription factor binding sites. SPIDER was also able to improve the detection of cell line specific regulatory interactions. Notably, SPIDER can recover ChlP-seq verified transcription factor binding events in the regulatory regions of genes that do not have a corresponding sequence motif. Constructing biologically interpretable, epigenetically informed networks using SPIDER will allow us to better understand gene regulation as well as aid in the identification of cell-specific drivers and biomarkers of cellular phenotypes.
Cyclic-di-GMP induces STING-dependent ILC2 to ILC1 shift during innate type 2 lung inflammation
Authors: Cavagnero Kellen J. , Badrani Jana H. , Naji Luay H. , Amadeo Michael B. , Leng Anthea S. , Lacasa Lee Diego , Strohm Allyssa N. , Doherty Taylor A.
Published: October 2020

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed both lung proliferating CD127+ST2+ ILC2s andAlternaria- and IL-33-induced lung inflammation. Further, transcriptomic analysis of CD127−ST2− Thy1.2+ ILCs, which were expanded and activated by CDG, revealed an ILC1 signature. CDG administration led to accumulation of IFNγ+ and T-bet+ ILC1s, as well as neutrophilia, independent of IL-18R, IL-12, and STAT6 but dependent on stimulator of interferon genes (STING) and partially dependent on type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.
Markov State Models and NMR Uncover an Overlooked Allosteric Loop in p53
Authors: Barros Emilia P. , Demir Özlem , Soto Jenaro , Cocco Melanie J. , Amaro Rommie E.
Published: October 2020

The tumor suppressor p53 is the most frequently mutated gene in human cancer, and thus reactivation of mutated p53 is a promising avenue for cancer therapy. Analysis of wildtype p53 and the Y220C cancer mutant long-timescale molecular dynamics simulations with Markov state models and validation by NMR relaxation studies has uncovered the involvement of loop L6 in the slowest motions of the protein. Due to its distant location from the DNA-binding surface, the conformational dynamics of this loop has so far remained largely unexplored. We observe mutation-induced stabilization of alternate L6 conformations, distinct from all experimentally-determined structures, in which the loop is both extended and located further away from the DNA-interacting surface. Additionally, the effect of the L6-adjacent Y220C mutation on the conformational landscape of the functionally-important loop L1 suggests an allosteric role to this dynamic loop and the inactivation mechanism of the mutation. Finally, the simulations reveal a novel Y220C cryptic pocket that can be targeted for p53 rescue efforts. Our approach exemplifies the power of the MSM methodology for uncovering intrinsic dynamic and kinetic differences among distinct protein ensembles, such as for the investigation of mutation effects on protein function.
Septate junction proteins are required for egg elongation and border cell migration during oogenesis in Drosophila
Authors: Alhadyian Haifa , Shoaib Dania , Ward Robert E.
Published: October 2020

Protein components of the invertebrate occluding junction - known as the septate junction (SJ) - are required for morphogenetic developmental events during embryogenesis inDrosophila melanogaster. In order to determine whether SJ proteins are similarly required for morphogenesis during other developmental stages, we investigated the localization and requirement of four representative SJ proteins during oogenesis: Contactin, Macroglobulin complement-related, Neurexin IV, and Coracle. A number of morphogenetic processes occur during oogenesis, including egg elongation, formation of dorsal appendages, and border cell migration. We found that all four SJ proteins are expressed in egg chambers throughout oogenesis, with the highest and most sustained levels in the follicular epithelium (FE). In the FE, SJ proteins localize along the lateral membrane during early and mid-oogenesis, but become enriched in an apical-lateral domain (the presumptive SJ) by stage 10b. SJ protein relocalization requires the expression of other SJ proteins, as well as rab5 and rab11 in a manner similar to SJ biogenesis in the embryo. Knocking down the expression of these SJ proteins in follicle cells throughout oogenesis results in egg elongation defects and abnormal dorsal appendages. Similarly, reducing the expression of SJ genes in the border cell cluster results in border cell migration defects. Together, these results demonstrate an essential requirement for SJ genes in morphogenesis during oogenesis, and suggests that SJ proteins may have conserved functions in epithelial morphogenesis across developmental stages.

Article Summary

Septate junction (SJ) proteins are essential for forming an occluding junction in epithelial tissues ofDrosophila melanogaster, and also for morphogenetic events that occur prior to the formation of the junction during embryogenesis. Here we show that SJ proteins are expressed in the follicular epithelium of egg chambers during oogenesis and are required for morphogenetic events including egg elongation, dorsal appendages formation, and border cell migration. Additionally, the formation of SJs during oogenesis is similar to that in embryonic epithelia.
Metabolic contributions of an alphaproteobacterial endosymbiont in the apicomplexanCardiosporidium cionae
Authors: Hunter Elizabeth Sage , Paight Christopher J , Lane Christopher E
Published: October 2020

Apicomplexa is a diverse protistan phylum composed almost exclusively of metazoan-infecting parasites, including the causative agents of malaria, cryptosporidiosis, and toxoplasmosis. A single apicomplexan genus,Nephromyces, was described in 2010 as a mutualist partner to its tunicate host. Here we present genomic and transcriptomic data from the parasitic sister species to this mutualist,Cardiosporidium cionae,and its associated bacterial endosymbiont.Cardiosporidium cionaeandNephromycesboth infect tunicate hosts, localize to similar organs within these hosts, and maintain bacterial endosymbionts. Though many other protists are known to harbor bacterial endosymbionts, these associations are completely unknown in Apicomplexa outside of the Nephromycidae clade. Our data indicate that a vertically transmittedα-proteobacteria has been retained in each lineage sinceNephromycesandCardiosporidiumdiverged. Thisα-proteobacterial endosymbiont has highly reduced metabolic capabilities, but contributes the essential amino acid lysine, and essential cofactor lipoic acid toC. cionae. This partnership likely reduces resource competition with the tunicate host. However, our data indicate that the contribution of the singleα-proteobacterial endosymbiont inC. cionaeis minimal compared to the three taxa of endosymbionts present in theNephromycessystem, and is a potential explanation for the virulence disparity between these lineages.
Dynamic pulse-to-pulse thermal load effects in pulse-train-mode self-seeded X-ray free-electron laser
Authors: Qu Zhengxian , Ma Yanbao , Zhou Guanqun , Wu Juhao
Published: October 2020

Thermal load has been a haunting factor that undermines the brightness and coherence of the self-seeded X-ray free-electron laser. Different from uniformly pulsed mode, in pulse train mode a thermal quasi-steady state of the crystal monochromator may not be reached. This leads to a dynamic thermal distortion of the spectral transmission curves and seed quality degradation. In this paper, the pulse-to-pulse thermal load effects on the spectral transmission curves and seed quality are shown, and some instructive information for the tuning process is provided.
Influence of spin orbit splitting and satellite transitions on nickel soft X-ray optical properties near its L
2,3 absorption edge region
Authors: Kiranjot  , Modi Mohammed H. , Gupta Raj Kumar , Sinha Mangalika , Yadav Praveen Kumar
Published: October 2020

Transition elements exhibit strong correlations and configuration interactions between core and valence excited states, which give rise to different excitations inside materials. Nickel exhibits satellite features in its emission and absorption spectra. Effects of such transitions on the optical constants of nickel have not been reported earlier and the available database of Henke et al. does not represent such fine features. In this study, the optical behaviour of ion beam sputter deposited Ni thin film near the L
2,3-edge region is investigated using reflection spectroscopy techniques, and distinct signatures of various transitions are observed. The soft X-ray reflectivity measurements in the 500–1500 eV photon energy region are performed using the soft X-ray reflectivity beamline at the Indus-2 synchrotron radiation source. Kramers–Kronig analysis of the measured reflectivity data exhibit features corresponding to spin orbital splitting and satellite transitions in the real and imaginary part of the refractive index (refraction and absorption spectra). Details of fine features observed in the optical spectra are discussed. To the best of our knowledge, this is the first study reporting fine features in the measured optical spectra of Ni near its L
2,3-edge region.
Energy and exergy prices of the jet kerosene fuel with carbon emission equivalents for an aircraft used in the air transport sector in Turkey
Authors: Yildiz Ibrahim , Caliskan Hakan
Published: October 2020

Purpose

The purpose of this study is to evaluate the energy and exergy prices and carbon emission equivalents of the jet kerosene (Jet A-1) fuel considering 12 months data for an air craft used in the air transport sector in Turkey.

Design/methodology/approach

In the selection of the energy resources, one of the most important factors besides the need is the price of the energy resources. To use and save the energy resources efficiently, the prices should be evaluated in terms of exergy too. In this context, the exergy prices and carbon emission equivalents of the jet kerosene fuel have been examined.

Findings

According to analysis results, after January 2020, a steady decline in energy prices has been obtained until April 2020. In this regard, directly proportional changes have been obtained in exergy prices. The minimum exergy price of the fuel is calculated as 74.36 US cents/kWh for April 2020, while the maximum exergy price of the fuel is calculated as 150.02 US cents/kWh for September 2019. The minimum exergy price based carbon emission equivalents for the jet kerosene fuel is determined as 1,099.98 US cents/kg for April 2020, while the maximum exergy price based carbon emission equivalents for the jet kerosene fuel is found to be 2,219.29 US cents/kg for September 2019.

Originality/value

The new contribution has been made to the open literature by examining the energy and exergy prices of the jet kerosene fuel. In addition, the carbon emission equivalents of the jet kerosene fuel have been determined not only energy but also exergy methods.
A numerical algorithm based on scale-3 Haar wavelets for fractional advection dispersion equation
Authors: Pandit Sapna , Mittal R.C.
Published: October 2020

Purpose

This paper aims to propose a novel approach based on uniform scale-3 Haar wavelets for unsteady state space fractional advection-dispersion partial differential equation which arises in complex network, fluid dynamics in porous media, biology, chemistry and biochemistry, electrode – electrolyte polarization, finance, system control, etc.

Design/methodology/approach

Scale-3 Haar wavelets are used to approximate the space and time variables. Scale-3 Haar wavelets converts the problems into linear system. After that Gauss elimination is used to find the wavelet coefficients.

Findings

A novel algorithm based on Haar wavelet for two-dimensional fractional partial differential equations is established. Error estimation has been derived by use of property of compactly supported orthonormality. The correctness and effectiveness of the theoretical arguments by numerical tests are confirmed.

Originality/value

Scale-3 Haar wavelets are used first time for these types of problems. Second, error analysis in new work in this direction.