bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitophagy protects beta cells from inflammatory damage in diabetes
Authors: Sidarala Vaibhav , Pearson Gemma L. , Parekh Vishal S. , Thompson Benjamin , Christen Lisa , Gingerich Morgan A. , Zhu Jie , Stromer Tracy , Ren Jianhua , Reck Emma , Chai Biaoxin , Corbett John A. , Mandrup-Poulsen Thomas , Satin Leslie S. , Soleimanpour Scott A.
Published: June 2020

Inflammatory damage contributes to β-cell failure in type 1 and 2 diabetes (T1D and T2D). Mitochondria are damaged by inflammatory signaling in β-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent β-cells. Utilizingin vivomitophagy reporters, we observed that diabetogenic pro-inflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient β-cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased β-cell death, and hyperglycemia. Overexpression ofCLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human β-cell apoptosis. Thus, mitophagy promotes β-cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent β-cell failure in diabetes and may be beneficial in other inflammatory conditions.
Metabolic plasticity in cancer activates apocryphal pathways for lipid desaturation
Authors: Young Reuben S.E. , Bowman Andrew P. , Williams Elizabeth D. , Tousignant Kaylyn D. , Bidgood Charles L. , Narreddula Venkateswara R. , Gupta Rajesh , Marshall David L. , Poad Berwyck L.J. , Nelson Colleen C. , Ellis Shane R. , Heeren Ron M.A. , Sadowski Martin C. , Blanksby Stephen J.
Published: June 2020

Fatty acid (FA) modifications, such as enzymatic desaturation and elongation, have long been thought to involve sequential and highly specific enzyme-substrate interactions, which result in canonical products that are well-defined in their chain lengths, degree of unsaturation and double bond positions.1These products act as a supply of building blocks for the synthesis of complex lipids supporting a symphony of lipid signals and membrane macrostructure. Recently, it was brought to light that differences in substrate availability due to enzyme inhibition can activate alternative pathways in a range of cancers, potentially altering the total species repertoire of FA metabolism.2,3We have used isomer-resolved lipidomics to analyse human prostate tumours and cancer cell lines and reveal, for the first-time, the full extent of metabolic plasticity in cancer. Assigning the double bond position(s) in simple and complex lipids allows mapping of fatty acid desaturation and elongation via hitherto apocryphal metabolic pathways that generate FAs with unusual sites of unsaturation. Downstream utilisation of these FAs is demonstrated by their incorporation into complex structural lipids. The unsaturation profiles of different phospholipids reveal substantive structural variation between classes that will, necessarily, modulate lipid-centred biological processes in cancer cells including membrane fluidity3-5and signal transduction.6-8
Higher rates of processed pseudogene acquisition in humans and three great apes revealed by long read assemblies
Authors: Feng Xiaowen , Li Heng
Published: June 2020

LINE-1 mediated retrotransposition of protein-coding mRNAs is an active process in modern humans for both germline and somatic genomes. Prior works that surveyed human data or human cohorts mostly relied on detecting discordant mappings of paired-end short reads, or assumed L1 hallmarks such as polyA tails and target site duplications. Moreover, there has been few genome-wide comparison between gene retrocopies in great apes and humans. In this study, we introduced a more sensitive and accurate approach to the discovery of processed pseudogene. Our method utilizes long read assemblies, and more importantly, is able to provide full retrocopy sequences as well as the neighboring sequences which are missed by short-read based methods reads. We provided an overview of novel gene retrocopies of 40 events (38 parent genes) in 20 human assemblies, a significantly higher discovery rate than previous reports (39 events of 36 parent genes out of 939 individuals). We also performed comprehensive analysis of lineage specific retrocopies in chimpanzee, gorilla and orangutan genomes.
Mortality Analysis of COVID-19 Confirmed Cases in Pakistan
Authors: Chaudhry Ambreen , Ikram Aamer , Baig Mirza Amir , Salman Muhammad , Ghafoor Tamkeen , Zakir Hussain , Khan Mumtaz Ali , Ansari Jamil Ahmed , Syed Asif , Javed Wasif , Larik Ehsan , Mohsan Muhammad , Masood Naveed , Iqbal Zeeshan , Akram Khurram
Published: June 2020

Introduction

COVID-19, a novel disease, appeared in December 2019 in China and rapidly spread across the world. Till second week of April 2020, high incidence (2.9/100,000) and cases fatality rates (1.7%)was observed in Pakistan.

This study was conducted to determine temporal and spatial distribution of first 100 deaths attributed to COVID-19 in Pakistan and their associated demographic factors.

Method

We conducted a descriptive epidemiological analysis of first 100 deaths reported among RT-PCR confirmed COVID-19 cases. Demographic, epidemiological and risk factors information was obtained associated comorbidities and clinical signs and symptoms were recorded and frequencies were determined.

Results

A total of 100 mortalities with overall Case Fatality Rate 1.67% (CFR) were analysed. Median age of patients was 64.5 years (IQR: 54–70) with 75% (n = 75) Males. Among all deaths reported, 71 (71%) cases had one or more documented comorbidities at the time of diagnosis. Most frequently reported co-morbidities were; hypertension (67 %), followed by Diabetes Mellitus 945%) and Ischemic Heart Diseases (27%). First death was reported on 18 March 2020 and the most frequent presenting symptoms were shortness of breath (87%) and fever (79%). Median duration of illness was eight days (IQR: 4–11 days), median delay reaching hospital to seek health care was three days (IQR: 0–6 days) while median duration of hospital stay was also three days (IQR: 1–7 days). Among all reported deaths, 62% were attributed to local transmission as these cases had no history of international travel. The most affected age group was 60–69 years while no death reported in age group below 20 years.

Conclusion

High CFR among old age group and its association with co-morbidities (chronic disease) suggests targeted interventions such as social distancing and strict quarantine measure for elderly and morbid people. Comparative studies among deaths and recovered patients are recommended to explore further disease dynamics.
Dynamics of IgG seroconversion and pathophysiology of COVID-19 infections
Authors: Staines Henry M , Kirwan Daniela E , Clark David J , Adams Emily R , Augustin Yolanda , Byrne Rachel L , Cocozza Michael , Cubas-Atienzar Ana I , Cuevas Luis E. , Cusinato Martina , Davies Benedict M O , Davis Mark , Davis Paul , Duvoix Annelyse , Eckersley Nicholas M , Forton Daniel , Fraser Alice J , Garrod Gala , Hadcocks Linda , Hu Qinxue , Johnson Michael , Kay Grant A , Klekotko Kesja , Lewis Zawditu , Macallan Derek C , Mensah-Kane Josephine , Menzies Stefanie , Monahan Irene , Moore Catherine M , Nebe-von-Caron Gerhard , Owen Sophie I , Sainter Chris , Sall Amadou A , Schouten James , Williams Chris , Wilkins John , Woolston Kevin , Fitchett Joseph R A , Krishna Sanjeev , Planche Tim
Published: June 2020

We report dynamics of seroconversion to SARS-CoV-2 infections detected by IgG ELISA in 177 individuals diagnosed by RT-PCR. Longitudinal analysis identifies 2-8.5% of individuals who do not seroconvert even weeks after infection. They are younger than seroconverters who have increased co-morbidity and higher inflammatory markers such as C-Reactive Protein. Higher antibody responses are associated with non-white ethnicity. Antibody responses do not decline during follow up almost to 2 months. Serological assays increase understanding of disease severity. Their application in regular surveillance will clarify the duration and protective nature of humoral responses to SARS-CoV-2.
Impact of Timing of and Adherence to Social Distancing Measures on COVID-19 Burden in the US: A Simulation Modeling Approach
Authors: Alagoz Oguzhan , Sethi Ajay K. , Patterson Brian W. , Churpek Matthew , Safdar Nasia
Published: June 2020

Background

Across the U.S., various social distancing measures were implemented to control COVID-19 pandemic. However, there is uncertainty in the effectiveness of such measures for specific regions with varying population demographics and different levels of adherence to social distancing. The objective of this paper is to determine the impact of social distancing measures in unique regions.

Methods

We developed COVid-19 Agent-based simulation Model (COVAM), an agent-based simulation model (ABM) that represents the social network and interactions among the people in a region considering population demographics, limited testing availability, imported infections from outside of the region, asymptomatic disease transmission, and adherence to social distancing measures. We adopted COVAM to represent COVID-19-associated events in Dane County, Wisconsin, Milwaukee metropolitan area, and New York City (NYC). We used COVAM to evaluate the impact of three different aspects of social distancing: 1) Adherence to social distancing measures; 2) timing of implementing social distancing; and 3) timing of easing social distancing.

Results

We found that the timing of social distancing and adherence level had a major effect on COVID-19 occurrence. For example, in NYC, implementing social distancing measures on March 5, 2020 instead of March 12, 2020 would have reduced the total number of confirmed cases from 191,984 to 43,968 as of May 30, whereas a 1-week delay in implementing such measures could have increased the number of confirmed cases to 1,299,420. Easing social distancing measures on June 1, 2020 instead of June 15, 2020 in NYC would increase the total number of confirmed cases from 275,587 to 379,858 as of July 31.

Conclusion

The timing of implementing social distancing measures, adherence to the measures, and timing of their easing have major effects on the number of COVID-19 cases.

Primary Funding Source

National Institute of Allergy and Infectious Diseases Institute
Cooperative interactions among females and even more extraordinary sex ratios
Authors: Iritani Ryosuke , West Stuart A , Abe Jun
Published: June 2020

Hamilton’s local mate competition theory provided an explanation for extraordinary female biased sex ratios in a range of organisms. When mating takes place locally, in structured populations, a female biased sex ratio is favoured to reduce competition between related males, and to provide more mates for males. However, there are a number of wasp species where the sex ratios appear to more female biased than predicted by Hamilton’s theory. We investigated theoretically the extent to which cooperative interactions between related females can interact with local mate competition to favour even more female biased sex ratios. We found that: (i) cooperative interactions between females can lead to sex ratios that are more female biased than predicted by local competition theory alone; (ii) sex ratios can be more female biased when the cooperative interactions are offspring helping parents before dispersal, rather than cooperation between siblings after dispersal. Our results can be applied to a range of organisms, and provide an explanation for the extreme sex ratio biases that have been observed inSclerodermusandMelittobiawasps.
Reconstructing Full-Field Flapping Wing Dynamics from Sparse Measurements
Authors: Johns William , Davis Lisa , Jankauski Mark
Published: June 2020

Flapping insect wings deform during flight. This deformation benefits the insect’s aerodynamic force production as well as energetic efficiency. However, it is challenging to measure wing displacement field in flying insects. Many points must be tracked over the wing’s surface to resolve its instantaneous shape. To reduce the number of points one is required to track, we propose a physics-based reconstruction method called System Equivalent Reduction Expansion Processes (SEREP) to estimate wing deformation and strain from sparse measurements. Measurement locations are determined using a Weighted Normalized Modal Displacement (NMD) method. We experimentally validate the reconstruction technique by flapping a paper wing from 5-9 Hz with 45° and measuring strain at three locations. Two measurements are used for the reconstruction and the third for validation. Strain reconstructions had a maximal error of 30% in amplitude. We extend this methodology to a more realistic insect wing through numerical simulation. We show that wing displacement can be estimated from sparse displacement or strain measurements, and that additional sensors spatially average measurement noise to improve reconstruction accuracy. This research helps overcome some of the challenges of measuring full-field dynamics in flying insects and provides a framework for strain-based sensing in insect-inspired flapping robots.
ATAV: a comprehensive platform for population-scale genomic analyses
Authors: Ren Zhong , Povysil Gundula , Goldstein David B.
Published: June 2020

Background

A common approach for sequencing studies is to do joint-calling and store variants of all samples in a single file. If new samples keep being added or controls are re-used for several studies, the cost and time required to perform joint-calling for each analysis can become prohibitive.

Results

We present ATAV, an analysis platform for large-scale whole-exome and whole-genome sequencing projects. ATAV stores variant and per site coverage data for all samples in a centralized database, which is efficiently queried by ATAV to support diagnostic analyses for trios and singletons, as well as rare-variant collapsing analyses for finding disease associations in complex diseases. Runtime logs ensure full reproducibility and the modularized ATAV framework makes it extensible to continuous development. Besides helping with the identification of disease-causing variants for a range of diseases, ATAV has also enabled the discovery of disease-genes by rare-variant collapsing on datasets containing more than 20,000 samples. Analyses to date have been performed on data of more than 110,000 individuals demonstrating the scalability of the framework.

The ATAV data browser (http://atavdb.org/) is a web-based interface that allows users to easily access variant-level data directly from the database. Summary-level data for more than 40,000 samples can be queried by the general public representing a mix of cases and controls of diverse ancestries. Users have access to phenotype categories of variant carriers, as well as predicted ancestry, gender, and quality metrics. In contrast to many other platforms, the data browser is able to show data of newly-added samples in real-time and is therefore evolving rapidly as more and more samples are sequenced.

Conclusions

Since all code is freely available on GitHub, ATAV can easily be used by other groups to build up their own platform, database, and user interface. In addition to that users can query one of the largest variant databases for patients sequenced at a tertiary care center and look up their own genes or variants of interest.
Temporal expectation modulates the neural dynamics of delayed responses to working memory representations
Authors: Chen Fang-Wen , Li Chun-Hui , Kuo Bo-Cheng
Published: June 2020

Temporal expectation can induce anticipatory attention to enhance perceptual processing and optimise behaviours. However, it remains unexplored whether temporal expectation benefits delayed responses to information maintained in working memory (WM) and the underlying neural dynamics that support the benefits. Here we addressed these issues in behavioural and electroencephalography (EEG) experiments. Participants performed a rotation discrimination WM task. Temporal expectation was manipulated by varying the predictability for when a test probe would occur after a delay interval. We first demonstrated that temporal predictability benefited WM performance. Our EEG results showed decreased alpha power over the left posterior brain regions during the delay interval for high than low predictability trials. Importantly, we found earlier enhancement of the lateralised alpha power and the lateralised readiness potential for high than low predictability trials when WM contents were accessed for responses during the probe period. Finally, we found concurrent selection and preparation for responses when the probe onset was predictable but motor preparation lagged behind response selection when the probe onset was more variable. Together, this study provides new insights into the proactive, dynamic nature of the anticipatory deployment of attention in guiding WM maintenance and delayed responses.
SARS-CoV-2-specific T cells exhibit phenotypic features reflecting robust helper function, lack of terminal differentiation, and high proliferative potential
Authors: Neidleman Jason , Luo Xiaoyu , Frouard Julie , Xie Guorui , Gill Gurjot , Stein Ellen S. , McGregor Matthew , Ma Tongcui , George Ashley F. , Kosters Astrid , Greene Warner C. , Vasquez Joshua , Ghosn Eliver , Lee Sulggi , Roan Nadia R.
Published: June 2020

Convalescing COVID-19 patients mount robust T cell responses against SARS-CoV-2, suggesting an important role for T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells, and predominantly Tcm with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can homeostatically proliferate, and can persist for over two months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection, and support an important role for SARS-CoV-2-specific T cells in host control of COVID-19.
Rapid whole genome sequence typing reveals multiple waves of SARS-CoV-2 spread
Authors: Moustafa Ahmed M. , Planet Paul J.
Published: June 2020

As the pandemic SARS-CoV-2 virus has spread globally its genome has diversified to an extent that distinct clones can now be recognized, tracked, and traced. Identifying clonal groups allows for assessment of geographic spread, transmission events, and identification of new or emerging strains that may be more virulent or more transmissible. Here we present a rapid, whole genome, allele-based method (GNUVID) for assigning sequence types to sequenced isolates of SARS-CoV-2 sequences. This sequence typing scheme can be updated with new genomic information extremely rapidly, making our technique continually adaptable as databases grow. We show that our method is consistent with phylogeny and recovers waves of expansion and replacement of sequence types/clonal complexes in different geographical locations.

GNUVID is available as a command line application (https://github.com/ahmedmagds/GNUVID).
An Inexpensive RT-PCR Endpoint Diagnostic Assay for SARS-CoV-2 Using Nested PCR: Direct Assessment of Detection Efficiency of RT-qPCR Tests and Suitability for Surveillance
Authors: Davda Jayeshkumar Narsibhai , Frank Keith , Prakash Sivakumar , Purohit Gunjan , Vijayashankar Devi Prasad , Vedagiri Dhiviya , Tallapaka Karthik Bharadwaj , Harshan Krishnan Harinivas , Siva Archana Bharadwaj , Mishra Rakesh Kumar , Dhawan Jyotsna , Siddiqi Imran
Published: June 2020

With a view to extending testing capabilities for the ongoing SARS-CoV-2 pandemic we have developed a test that lowers cost and does not require real time quantitative reverse transcription polymerase chain reaction (RT-qPCR). We developed a reverse transcription nested PCR endpoint assay (RT-nPCR) and showed that RT-nPCR has comparable performance to the standard RT-qPCR test. In the course of comparing the results of both tests, we found that the standard RT-qPCR test can have low detection efficiency (less than 50%) in a real testing scenario which may be only partly explained by low viral representation in many samples. This finding points to the importance of directly monitoring detection efficiency in test environments. We also suggest measures that would improve detection efficiency.
Enhanced production of taxadiene inSaccharomyces cerevisiae
Authors: Nowrouzi Behnaz , Li Rachel , Walls Laura E. , d’Espaux Leopold , Malci Koray , Lungang Liang , Borrego Nestor Jonguitud , Escalera Albert I. Lerma , Morones-Ramirez Jose R. , Keasling Jay D. , Solis Leonardo Rios
Published: June 2020

Cost-effective production of the highly effective anti-cancer drug, paclitaxel (Taxol®), remains limited despite growing global demands. Low yields of the critical taxadiene precursor remains a key bottleneck in microbial production. In this study, the key challenge of poor taxadiene synthase (TASY) solubility inS. cerevisiaewas revealed, and the strains were strategically engineered to relieve this bottleneck. Multi-copy chromosomal integration ofTASYharbouring a selection of fusion solubility tags improved taxadiene titres 22-fold, up to 57 ± 3 mg/L at 30 °C at shake flask scale. The scalability of the process was highlighted through achieving similar titres during scale up to 25 mL and 250 mL in shake flask and bioreactor cultivations, respectively. Maximum taxadiene titres of 129 ± 15 mg/L and 119 mg/L were achieved through shake flask and bioreactor cultivation, respectively, of the optimal strain at a reduced temperature of 20 °C. The results highlight the positive effect of coupling molecular biology tools with bioprocess variable optimisation on synthetic pathway development.

Highlights

Maximum taxadiene titre of 129 ± 15 mg/L inSaccharomyces cerevisiaeat 20 °C

Integrating fusion protein tagged-taxadiene synthase improved taxadiene titre.

Consistent taxadiene titres were achieved at the micro-and mini-bioreactor scales.
Satellite repeat transcripts modulate heterochromatin condensates and safeguard chromosome stability in mouse embryonic stem cells
Authors: Novo Clara Lopes , Wong Emily , Hockings Colin , Poudel Chetan , Sheekey Eleanor , Walker Simon , Schierle Gabriele S. Kaminski , Narlikar Geeta J. , Rugg-Gunn Peter J.
Published: June 2020

Heterochromatin maintains genome integrity and function, and is organised into distinct nuclear domains. Some of these domains are proposed to form by phase separation through the accumulation of HP1α. Mammalian heterochromatin contains noncoding major satellite repeats (MSR), which are highly transcribed in mouse embryonic stem cells (ESCs). Here, we report that MSR transcripts can drive the formation of HP1α dropletsin vitro, and scaffold heterochromatin into dynamic condensates in ESCs, leading to the formation of large nuclear domains that are characteristic of pluripotent cells. Depleting MSR transcripts causes heterochromatin to transition into a more compact and static state. Unexpectedly, changing heterochromatin’s biophysical properties has severe consequences for ESCs, including chromosome instability and mitotic defects. These findings uncover an essential role for MSR transcripts in modulating the organisation and properties of heterochromatin to preserve genome stability. They also provide new insights into the processes that could regulate phase separation and the functional consequences of disrupting the properties of heterochromatin condensates.
Root economics spectrum and construction costs in Mediterranean woody plants: the role of symbiotic associations and the environment
Authors: de la Riva Enrique G. , Prieto Iván , Marañón Teodoro , Pérez Ramos Ignacio M. , Olmo Manuel , Villar Rafael
Published: June 2020

Quantifying the functional variation of fine root traits and their interactions with symbiotic organisms is an uprising research topic to understand the overarching trade-off between maximizing resource acquisition or conservation (root economics spectrum -RES-). The currency of root traits economy is based on the carbon required to construct them; however, we lack a clear understanding of this question.

Our main aim was to quantify construction costs (CC) of fine roots (<2 mm) and their underlying components (concentration of carbon, minerals and organic nitrogen) in 60 Mediterranean woody species with contrasting symbiotic association types (ectomycorrhizas, arbuscular and ericoid mycorrhizas and N-Fixing nodules). We examined (1) if the CC depended on the symbiotic type, and if they were associated with morphological traits; (2) the relation of each component of the CC with the root structure for each symbiotic type; and (3) whether soil water and nutrient availability determined differences in CC across sites and symbiotic types.

The multivariate analysis of root traits showed a main plane of covariation accordingly to the RES expectations, with contrasting symbiotic types at both ends of the spectrum. We found a significant relationship between root CC and RES; interestingly the slopes of this relationship differed among symbiotic types, which was mainly due to the different role that each specific components of CC plays across them. In addition, independently of the symbiotic type, the CC decreased linearly with the nutrient availability and quadratic with the water availability.

Synthesis. Our study demonstrates that woody plants have different strategies in their root carbon investment, which depend on their position along the economics spectrum (RES) and on their main symbiotic association preference. The intrinsic components of the cost of root production varied across species with contrasting symbiotic associations, pointing to a trade-off between structural and metabolic compounds. We also found that root CC are strongly modulated by soil resource availability, following a non-linear pattern with water availability. Thus, CC shifts from high to low at the most arid sites, which points to a strong role of symbiotic associations in this shift.
Understanding pigeon pea (Cajanus cajan) production conditions, stakeholders’ preferences for varietal traits and their implications for breeding programmes in India
Authors: Singh A. , Fromm I. , Jha G. K. , Venkatesh P. , Tewari H. , Padaria R. , Egger U.
Published: June 2020

Pigeon pea (Cajanus cajan) is an important pulse crop in the Indian diet and one of the most important sources of dietary protein for the population. In the context of the fourth phase of the Indo-Swiss Collaboration in Biotechnology, an assessment how farmers and consumers perceive new pigeon pea cultivars and what are their preferred traits was conducted. This investigation assessed India’s food security implications due to stagnating and low yield of pigeon pea and ascertain farmers’ preferences of pigeon pea varietal traits, production constraints and farmers’ coping strategies in diverse pigeon pea production environments. Results indicated that production constraints in the studied regions were basically similar, with majority of the farmers identifying pod borer & pod fly as the major pest, and wilt as the major disease and drought as a major production constraint. Farmers indicated the use of clean seed, high yielding varieties, inter & mixed cropping, planting density, and manure application as some of the strategies they used to cope with the production constraints. In terms of preference for new cultivars, farmers want high grain yield with drought tolerance, medium to early maturity, pod borer resistance, tolerance to wilt disease, moderate plant height and ease of threshing without compromising other preferred attributes. The analysis of processors’ preference of grain types for dal processing showed that uniform size, oval shape, orange coloured seed and most importantly moderately hard seed coat are highly desirable. Consumers lacked awareness on the varieties, but considered traits like uniform seeds and reduced cooking time traits more desirable.
Nutritional combinatorial impact on the gut microbiota and plasma short-chain fatty acids levels in the prevention of mammary cancer in Her2/neu estrogen receptor-negative transgenic mice
Authors: Sharma Manvi , Arora Itika , Stoll Matthew L. , Li Yuanyuan , Morrow Casey D. , Barnes Stephen , Berryhill Taylor F. , Li Shizhao , Tollefsbol Trygve O.
Published: June 2020

Breast cancer is the second leading cause of cancer-related mortality in women. Various nutritional compounds possess anti-carcinogenic properties which may be mediated through their effects on the gut microbiota and its production of short-chain fatty acids (SCFAs) for the prevention of breast cancer. We evaluated the impact of broccoli sprouts (BSp), green tea polyphenols (GTPs) and their combination on the gut microbiota and SCFAs metabolism from the microbiota in Her2/neu transgenic mice that spontaneously develop estrogen receptor-negative [ER (-)] mammary tumors. The mice were grouped based on the dietary treatment: control, BSp, GTPs or their combination from beginning in early life (BE) or life-long from conception (LC). We found that the combination group showed the strongest inhibiting effect on tumor growth volume and a significant increase in tumor latency. BSp treatment was integrally more efficacious than the GTPs group when compared to the control group. There was similar clustering of microbiota of BSp-fed mice with combination-fed mice, and GTPs-fed mice with control-fed mice at pre-tumor and post-tumor in both BE and LC groups. The mice on all dietary treatment groups incurred a significant increase ofAdlercreutziagenus and S24-7 family in the both BE and LC groups. We found no change in SCFAs levels in the plasma of BSp-fed, GTPs-fed and combination-fed mice of the BE group. Marked changes were observed in the mice of the LC group consisting of significant increases in propionate and isobutyrate in GTPs-fed and combination-fed mice. These studies indicate that nutrients such as BSp and GTPs differentially affect the gut microbial composition in both the BE and LC groups and the key metabolites (SCFAs) levels in the LC group. The findings also suggest that temporal factors related to different time windows of consumption during the life-span can have a promising influence on the gut microbial composition, SCFAs profiles and ER (-) breast cancer prevention.
Structural Motifs, Disorder, and the Efficacy of Viral Vaccines
Authors: Makin Robert A. , Durbin Steven M.
Published: June 2020

We demonstrate that it is possible to draw direct numerical correlations between virus particles and effective virus-like particle (VLP) derived vaccines through extraction of a Bragg-Williams order parameter from electron microscopy. The method has its roots in studies of disorder in metal alloys, and is adapted to describe the type and occurrence of structural motifs within the arrangement of viral coat proteins, captured by the value of the order parameter as a measure of disorder. A conventional approach to viral vaccine design consists of replicating select proteins to create a VLP designed to trigger an immune response while remaining non-infectious. Understanding variations between viruses and vaccine strains therefore tends to focus on differences between proteins, which can be characterized through genetic analysis. While such an approach provides vital information about the functioning and interactions of the proteins, it does not yet yield an early-stage pathway towards predicting the efficacy of a vaccine, and so large-scale clinical trials are required to obtain critical information. With the urgency associated with pandemics, including Coronavirus Disease-2019 (COVID-19) originating from the SARS-CoV-2 virus, there is a need for earlier indications of whether a vaccine has the necessary characteristics. Application of the methodology to Dengue and influenza virus particles indicates that temperature and pH during incubation could potentially be exploited to fine-tune the order parameter of VLP-based vaccines to match the corresponding virus. Additionally, utilization of an Ising model plot reveals a clear relationship between case fatality rate and order parameter for distinct virus families.
Barnacle encrustation on molluscan prey offers associational resistance against drilling predation
Authors: Thangarathinam Vigneshbabu , Chattopadhyay Devapriya
Published: June 2020

Predation is one of the driving forces that shaped the marine ecosystems through time. Apart from the anti-predatory strategies adopted by the prey, the predatory outcome is often indirectly influenced by the other members of the ecological community. Association between organisms are often found to influence the outcome and the evolution of such association may have been guided by such interactions. Mollusc-burnacle association, although common, is not explored to assess if the epibiont offers the molluscs any protection against predation (associational resistance) or increases the risk by attracting predators (shared doom). Using a series of controlled experiments with a drilling predator (Paratectonatica tigrina), its prey (Pirenella cingulata) and an epibiont (Amphibalanus amphitrite), we evaluated the effect of epibionts on the drilling behavior of the predator by documenting the successful attack (Drilling frequency, DF), and handling time. Our results show that the prey with epibionts are significantly less likely to be drilled when the predator has sufficient choice of prey, consistent with the tenets of the associational resistance. The preference of choosing the non-encrusted prey, however, diminishes with fewer available prey. The handling time is significantly higher in the attacks on the encrusted prey than non-encrusted prey, even though the barnacles are not drilled. Although the proximity of the drilling site to encrustation tends to increase the handling time, the size of encrustation does not have any effect. Because the profitability of prey largely depends on the ratio of handling time and the energetic yield from consuming the prey, the increase in handling time due to encrustation makes it less profitable for the predator. The role of encrustation as a deterrent to predation might also explain the complex shell architecture in some prey gastropods that increases the likelihood of encrustation besides providing direct resistance against predation.
FasR regulates fatty acid biosynthesis and is essential for virulence ofMycobacterium tuberculosis
Authors: Mondino Sonia , Vázquez Cristina L. , Cabruja Matías , Sala Claudia , Cazenave-Gassiot Amaury , Blanco Federico C. , Wenk Markus R. , Bigi Fabiana , Cole Stewart T. , Gramajo Hugo , Gago Gabriela
Published: June 2020

Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the world’s leading cause of death from an infectious disease. One of the main features of this pathogen is the complex and dynamic lipid composition of the cell envelope, which adapts to the variable host environment and defines the fate of infection by actively interacting with and modulating immune responses. However, while much has been learned about the enzymes of the numerous lipid pathways, little knowledge is available regarding the proteins and metabolic signals regulating lipid metabolism duringM. tuberculosisinfection. In this work, we constructed and characterized a FasR-deficient mutant inM. tuberculosisand demonstrated that FasR positively regulatesfasandacpSexpression. Lipidomic analysis of the wild type and mutant strains revealed complete rearrangement of most lipid components of the cell envelope, with phospholipids, mycolic acids, sulfolipids and phthiocerol dimycocerosates relative abundance severely altered. As a consequence, replication of the mutant strain was impaired in macrophages leading to reduced virulence in a mouse model of infection. Moreover, we show that thefasRmutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation preventedM. tuberculosisinhibition of phagolysosome maturation. This study identified FasR as a novel factor involved in regulation of mycobacterial virulence and provides evidence for the essential role that modulation of lipid homeostasis plays in the outcome ofM. tuberculosisinfection.
Quantifying the contribution of Neanderthal introgression to the heritability of complex traits
Authors: McArthur Evonne , Rinker David , Capra John A.
Published: June 2020

Background

Nearly all Eurasians have ∼2% Neanderthal ancestry due to several events of inbreeding between anatomically modern humans and archaic hominins. Previous studies characterizing the legacy of Neanderthal ancestry in modern Eurasians have identified examples of both adaptive and deleterious effects of admixture. However, we lack a comprehensive understanding of the genome-wide influence of Neanderthal introgression on modern human diseases and traits.

Results

We integrate recent maps of Neanderthal ancestry with well-powered association studies for more than 400 diverse traits to estimate heritability enrichment patterns in regions of the human genome tolerant of Neanderthal ancestry and in introgressed Neanderthal variants themselves. First, we find that variants in regions tolerant of Neanderthal ancestry are depleted of heritability for all traits considered, except skin and hair-related traits. Second, the introgressed variants remaining in modern Europeans are depleted of heritability for most traits; however, we discover that they are enriched for heritability of several traits with potential relevance to human adaptation to non-African environments, including hair and skin traits, autoimmunity, chronotype, bone density, lung capacity, and menopause age. To better understand the phenotypic consequences of these enrichments, we adapt recent methods to test for consistent directional effects of introgressed alleles, and we find directionality for several traits. Finally, we use a direction-of-effect-aware approach to highlight novel candidate introgressed variants that influence risk for disease.

Conclusion

Our results demonstrate that genomic regions retaining Neanderthal ancestry are not only less functional at the molecular-level, but are also depleted for variation influencing a diverse array of complex traits in modern humans. In spite of this depletion, we identify traits where introgression has an outsized effect. Integrating our results, we propose a framework for using quantification of trait heritability and direction of effect in introgressed regions to understand how Neanderthals were different from modern humans, how selection acted on different traits, and how introgression may have facilitated adaptation to non-African environments.
Wiring Up Vision: Minimizing Supervised Synaptic Updates Needed to Produce a Primate Ventral Stream
Authors: Geiger Franziska , Schrimpf Martin , Marques Tiago , DiCarlo James J.
Published: June 2020

After training on large datasets, certain deep neural networks are surprisingly good models of the neural mechanisms of adult primate visual object recognition. Nevertheless, these models are poor models of the development of the visual system because they posit millions of sequential, precisely coordinated synaptic updates, each based on a labeled image. While ongoing research is pursuing the use of unsupervised proxies for labels, we here explore a complementary strategy of reducing the required number of supervised synaptic updates to produce an adult-like ventral visual stream (as judged by the match to V1, V2, V4, IT, and behavior). Such models might require less precise machinery and energy expenditure to coordinate these updates and would thus move us closer to viable neuroscientific hypotheses about how the visual system wires itself up. Relative to the current leading model of the adult ventral stream, we here demonstrate that the total number of supervised weight updates can be substantially reduced using three complementary strategies: First, we find that only 2% of supervised updates (epochs and images) are needed to achieve ~80% of the match to adult ventral stream. Second, by improving the random distribution of synaptic connectivity, we find that 54% of the brain match can already be achieved “at birth” (i.e. no training at all). Third, we find that, by training only ~5% of model synapses, we can still achieve nearly 80% of the match to the ventral stream. When these three strategies are applied in combination, we find that these new models achieve ~80% of a fully trained model’s match to the brain, while using two orders of magnitude fewer supervisedsynapticupdates. These results reflect first steps in modeling not just primate adult visual processing during inference, but also how the ventral visual stream might be “wired up” by evolution (a model’s “birth” state) and by developmental learning (a model’s updates based on visual experience).
Molecular species selectivity of lipid transport creates a mitochondrial sink for di-unsaturated phospholipids
Authors: Renne Mike F. , Bao Xue , Hokken Margriet W.J. , Bierhuizen Adolf S. , Hermansson Martin , Ewing Tom A. , Ma Xiao , Cox Ruud C. , Brouwers Jos F. , De Smet Cedric H. , Ejsing Christer S. , de Kroon Anton I.P.M.
Published: June 2020

Mitochondria depend on the import of phospholipid precursors for the biosynthesis of the non-bilayer lipids phosphatidylethanolamine (PE) and cardiolipin required for proper function, yet the mechanism of lipid import remains elusive. Pulse labeling yeast with stable isotope-labeled serine followed by mass spectrometry analysis revealed that mitochondria preferentially import di-unsaturated phosphatidylserine (PS) for conversion to PE by the mitochondrial PS decarboxylase Psd1p. Several protein complexes tethering mitochondria to the endomembrane system have been implicated in lipid transport in yeast, including the endoplasmic reticulum (ER)-mitochondrial encounter structure (ERMES), ER-mitochondria complex (EMC) and the vacuole and mitochondria patch (vCLAMP). By limiting the availability of unsaturated phospholipids through overexpression of the glycerol-3-phosphate acyltransferase Sct1p, conditions were created to investigate the mechanism of lipid transfer and the contribution of the tethering complexesin vivo. Under these conditions, inactivation of ERMES components or the vCLAMP component Vps39p exacerbated the lipid phenotype, indicating that ERMES and Vps39 contribute to the mitochondrial sink for unsaturated acyl chains by mediating transfer of di-unsaturated phospholipids. The results support the concept that intermembrane lipid flow is rate-limited by molecular species-dependent lipid efflux from the donor membrane and driven by the lipid species’ concentration gradient between donor and acceptor membrane.
Development of a Nested-MultiLocus Sequence Typing approach for a highly sensitive and specific identification ofXylella fastidiosasubspecies directly from plant samples
Authors: Cesbron Sophie , Dupas Enora , Beaurepère Quentin , Briand Martial , Borrego Miguel Montes , Velasco Amo Maria del Pilar , Landa Blanca B. , Jacques Marie-Agnès
Published: June 2020

Different sequence types (ST) ofXylella fastidiosawere already identified in France and Spain based on direct MultiLocus Sequence Typing (MLST) of plant DNA samples. However, direct typing of plant DNA is partly efficient. In order to improve the sensitivity ofX. fastidiosaidentification, we developed a direct nested-MLST assay on plant extracted DNA. This method was performed based on a largely used scheme targeting seven housekeeping gene (HKG) loci (cysG, gltT, holC, leuA, malF, nuoL, petC). Nested primers were designed from multi-sequence alignments of 38 genomes representing all subspecies and one genome ofXylella taiwanensis. Sequences obtained were long enough to be used for BLAST comparison in PubMLST database. No nonspecific amplification products were observed in these samples. Efficiency of the nested-MLST was tested on extracted DNA from 106 samples proven positive (Cq<35) or equivocal (35≤Cq≤40) using the Harper’s qPCR test. Samples analyzed included 49 plant species and two insect species (Philaenus spumarius, Neophilaenus campestris) that were collected in 2017 (106 plant samples in France), in 2018 (162 plant samples in France, 40 plant samples and 26 insect samples in Spain), and in 2019 (30 plant samples in Spain). With the conventional-MLST assay, no complete MLST profile was obtained for any of the samples from France and for most samples (59/66) from Spain. Conversely, with the nested approach, complete profiles were obtained for six French plant samples, 55 Spanish plant samples and nine Spanish insect samples. The threshold was improved by 100 to 1000 times compared to conventional PCR and was between 22 pg.mL−1to 2.2 pg.mL−1depending on the HKG. Using nested-MLST assay, plants that were not yet considered hosts tested positive and revealed novel alleles in France, whereas for Spanish samples it was possible to assign the subspecies or ST to samples considered as new hosts in Europe. Direct typing by nested-MLST from plant material has an increased sensitivity and may be useful for epidemiological purposes.
Evolutionary and structural analyses of SARS-CoV-2 D614G spike protein mutation now documented worldwide
Authors: Isabel Sandra , Graña-Miraglia Lucía , Gutierrez Jahir M. , Bundalovic-Torma Cedoljub , Groves Helen E. , Isabel Marc R. , Eshaghi AliReza , Patel Samir N. , Gubbay Jonathan B. , Poutanen Tomi , Guttman David S. , Poutanen Susan M.
Published: June 2020

The COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was declared on March 11, 2020 by the World Health Organization. As of the 31st of May, 2020, there have been more than 6 million COVID-19 cases diagnosed worldwide and over 370,000 deaths, according to Johns Hopkins. Thousands of SARS-CoV-2 strains have been sequenced to date, providing a valuable opportunity to investigate the evolution of the virus on a global scale. We performed a phylogenetic analysis of over 1,225 SARS-CoV-2 genomes spanning from late December 2019 to mid-March 2020. We identified a missense mutation, D614G, in the spike protein of SARS-CoV-2, which has emerged as a predominant clade in Europe (954 of 1,449 (66%) sequences) and is spreading worldwide (1,237 of 2,795 (44%) sequences). Molecular dating analysis estimated the emergence of this clade around mid-to-late January (10 - 25 January) 2020. We also applied structural bioinformatics to assess D614G potential impact on the virulence and epidemiology of SARS-CoV-2. In silico analyses on the spike protein structure suggests that the mutation is most likely neutral to protein function as it relates to its interaction with the human ACE2 receptor. The lack of clinical metadata available prevented our investigation of association between viral clade and disease severity phenotype. Future work that can leverage clinical outcome data with both viral and human genomic diversity is needed to monitor the pandemic.