bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age dependent effects of protein restriction on dopamine release
Authors: Naneix Fabien , Peters Kate Z. , Young Andrew M. J. , McCutcheon James E. 
Published: April 2020

ABSTRACTDespite the essential role of protein intake for health and development, very little is known about the impact of protein restriction on neurobiological functions, especially at different stages of the lifespan. The dopamine system is a central actor in the integration of food-related processes and is influenced by physiological state and food-related signals. Moreover, it is highly sensitive to dietary effects during early life periods such as adolescence due to its late maturation. In the present study, we investigated the impact of protein restriction either during adolescence or adulthood on the function of the mesolimbic (nucleus accumbens) and nigrostriatal (dorsal striatum) dopamine pathways using fast-scan cyclic voltammetry in rat brain slices. In the nucleus accumbens, protein restriction in adults increased dopamine release in response to low and high frequency trains of stimulation (1-20 Hz). By contrast, protein restriction performed at adolescence decreased nucleus accumbens dopamine release. In the dorsal striatum, protein restriction has no impact on dopamine release when performed at adulthood but in adolescent rats we observed frequency-dependent increases in stimulated dopamine release. Taken together, our results highlight the sensitivity of the different dopamine pathways to the effect of protein restriction, as well as their vulnerability to deleterious diet effects at different life stages.
Calcitriol increases frataxin levels and restores altered markers in cell models of Friedreich Ataxia
Authors: Britti E. , Delaspre F. , Medina-Carbonero M. , Sanz A. , Llovera M. , Purroy R. , Mincheva-Tasheva S. , Tamarit J. , Ros J. 
Published: April 2020

ABSTRACTFriedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential. Accordingly, apoptotic markers and neurite degeneration are reduced resulting in cell survival recovery with calcitriol supplementation. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.
A tractableDrosophilacell system enables rapid identification ofAcinetobacter baumanniihost factors
Authors: Qin Qing-Ming , Pei Jianwu , Gomez Gabriel , Rice-Ficht Allison , Ficht Thomas A. , de Figueiredo Paul 
Published: April 2020

AbstractAcinetobacter baumanniiis an important causative agent of nosocomial infections worldwide. The pathogen also readily acquires resistance to antibiotics, and pan-resistant strains have been reported.A. baumanniiis widely regarded as an extracellular bacterial pathogen. However, accumulating evidence demonstrates that the pathogen can invade, survive or persist in infected mammalian cells. Unfortunately, the molecular mechanisms controlling these processes remain poorly understood. Here, we show thatDrosophilaS2 cells provide several attractive advantages as a model system for investigating the intracellular lifestyle of the pathogen, including susceptibility to bacterial intracellular replication and limited infection-induced host cell death. We also show that theDrosophilasystem can be used to rapidly identify host factors, including MAP kinase proteins, which confer susceptibility to intracellular parasitism. Finally, analysis of theDrosophilasystem suggested that host proteins that regulate organelle biogenesis and membrane trafficking contribute to regulating the intracellular lifestyle of the pathogen. Taken together, these findings establish a novel model system for elucidating interactions betweenA. baumanniiand host cells, define new factors that regulate bacterial invasion or intracellular persistence, and identify subcellular compartments in host cells that interact with the pathogen.
Friend or foe? Effects of host immune activation on the transient gut microbiome in the caterpillarManduca sexta
Authors: McMillan Laura E. , Adamo Shelley A. 
Published: April 2020

ABSTRACTFor many animals the gut microbiome plays an essential role in immunity and digestion. However, certain animals, such as the caterpillarManduca sexta, do not have a resident gut microbiome. Although these animals do have bacteria that pass through their gut from their natural environment, the absence of such bacteria does not reduce growth or survival. We hypothesized thatManduca sextawould sterilize their gut as a protective measure against secondary infection when faced with a gut infection, or exposure to heat-killed bacteria in the blood (hemolymph). However, we found that gut sterilization did not occur during either type of immune challenge, i.e. bacterial numbers did not decrease. By examing the pattern of immune-related gene expression, gut pH, live bacterial counts, and weight change (as a measure of sickness behaviour), we found evidence for physiological trade-offs between between regulating the microbiome and defending against systemic infections. Caterpillars exposed to both gut pathogens and a systemic immune challenge had higher numbers of bacteria in their gut than caterpillars exposed to a single challenge. Following a principal component analysis, we found that the response patterns following an oral challenge, systemic challenge or dual challenge were unique. Our results suggest that the immune response for each challenge resulted in a different configuration of the immunophysiological network. We hypothesize that these different configurations represent different resolutions of physiological trade-offs based on the immune responses needed to best protect against the present immune challenges.SUMMARY STATEMENTThis paper investigates the strategies that animals may use to regulate their microbiome during infection.
Porcine reproductive and respiratory syndrome virus dissemination across pig production systems in the United States
Authors: Jara Manuel , Rasmussen David A. , Corzo Cesar A. , Machado Gustavo 
Published: April 2020

SummaryPorcine reproductive and respiratory syndrome virus (PRRSV) remains widespread in the North American pig population. Despite improvements in virus characterization, it is unclear whether PRRSV infections are a product of viral circulation within a farm, within production systems (local) or across production systems (external). Here we examined the dissemination dynamics of PRRSV and the processes facilitating its spread within and among pig farms in three production systems. Overall, PRRSV genetic diversity declined since 2018, while phylodynamic results support frequent transmission across-production systems. We found that PRRSV dissemination occurred mostly through transmission between farms of different production companies, which were predominant for several months, especially from November until May when PRRSV tends to peak in the studied region. Within production systems, dissemination occurred mainly through regular pig flow (from sow to nursery and then to finisher farms); nevertheless, an important flux of PRRSV dissemination from finisher to sow and nursery farms highlighted the importance of downstream farms as sources of the virus. Farms at areas with pig density from 500 to 1000 pig/km2and farms located at a range within 0.5 km and 0.7 km from major roads were more likely to infect by PRRSV, whereas farms at elevation between 41 and 61 meters and denser vegetation acted as dissemination barriers. Although remains a challenge, there is a need to disentangle the route of PRRSV transmission, results evidenced that dissemination among commercially unrelated pig production systems was intense, reinforcing the importance of farm proximity on PRRSV spread. Thus, consideration of farm location and their geographic characteristics may help to forecast dissemination. The understanding of PRRSV transmission routes has the potential to inform targeted strategies for its prevention and control. Further studies are needed to quantify the relative contribution of PRRSV transmission routes.
De novo design of high-affinity antibody variable regions (Fv) against the SARS-CoV-2 spike protein
Authors: Boorla Veda Sheersh , Chowdhury Ratul , Maranas Costas D. 
Published: April 2020

AbstractThe emergence of SARS-CoV-2 is responsible for the pandemic of respiratory disease known as COVID-19, which emerged in the city of Wuhan, Hubei province, China in late 2019. Both vaccines and targeted therapeutics for treatment of this disease are currently lacking. Viral entry requires binding of the viral spike receptor binding domain (RBD) with the human angiotensin converting enzyme (hACE2). In an earlier paper1, we report on the specific residue interactions underpinning this event. Here we report on the de novo computational design of high affinity antibody variable regions through the recombination of VDJ genes targeting the most solvent-exposed hACE2-binding residues of the SARS-CoV-2 spike protein using the software tool OptMAVEn-2.02. Subsequently, we carry out computational affinity maturation of the designed prototype variable regions through point mutations for improved binding with the target epitope. Immunogenicity was restricted by preferring designs that match sequences from a 9-mer library of “human antibodies” based on H-score (human string content, HSC)3. We generated 106 different designs and report in detail on the top five that trade-off the greatest affinity for the spike RBD epitope (quantified using the Rosetta binding energies) with low H-scores. By grafting the designed Heavy (VH) and Light (VL) chain variable regions onto a human framework (Fc), high-affinity and potentially neutralizing full-length monoclonal antibodies (mAb) can be constructed. Having a potent antibody that can recognize the viral spike protein with high affinity would be enabling for both the design of sensitive SARS-CoV-2 detection devices and for their deployment as therapeutic antibodies.
Development of a Coupled Simulation Toolkit for Computational Radiation Biology Based on Geant4 and CompuCell3D
Authors: Liu Ruirui , Higley Kathryn A. , Swat Maciej H. , Chaplain Mark A. J , Powathil Gibin G. , Glazier James A. 
Published: April 2020

AbstractUnderstanding and designing clinical radiation therapy is one of the most important areas of state-of-the-art oncological treatment regimens. Decades of research have gone into developing sophisticated treatment devices and optimization protocols for schedules and dosages. In this paper, we presented a comprehensive computational platform that facilitates building of the sophisticated multi-cell-based model of how radiation affects the biology of living tissue. We designed and implemented a coupled simulation method, including a radiation transport model, and a cell biology model, to simulate the tumor response after irradiation. The radiation transport simulation was implemented through Geant4 which is an open-source Monte Carlo simulation platform that provides many flexibilities for users, as well as low energy DNA damage simulation physics, Geant4-DNA. The cell biology simulation was implemented using CompuCell3D (CC3D) which is a cell biology simulation platform. In order to couple Geant4 solver with CC3D, we developed a “bridging” module that extracts tumor cellular geometry of the CC3D simulation (including specification of the individual cells) and ported it to the Geant4 for radiation transport simulation. The cell dose and cell DNA damage distribution in multicellular system were obtained using Geant4. The tumor response was simulated using cell-based tissue models based on CC3D. By merging two powerful and widely used modeling platforms, CC3D and Geant4, we delivered a novel tool that can give us the ability to simulate the dynamics of biological tissue in the presence of ionizing radiation, which provides a powerful framework for quantifying the biological consequences of radiation therapy. The developed tool has an advantage on that it has strong extensibility due to the exploitability of two modeling platforms. In this introductory methods paper, we described our modeling platform in detail and showed how it can be applied to study the application of radiotherapy to a vascularized tumor.
The effect of device configuration and patient’s body composition on image artifact and RF heating of deep brain stimulation devices during MRI at 1.5T and 3T
Authors: Bhusal Bhumi , Nguyen Bach T. , Vu Jasmine , Elahi Behzad , Rosenow Joshua , Nolt Mark J. , Lopez-Rosado Roberto , Pilitsis Julie , DiMarzio Marisa , Golestanirad Laleh 
Published: April 2020

AbstractBACKGROUNDPatients with deep brain stimulation (DBS) implants have limited access to MRI due to safety concerns associated with RF-induced heating. Currently, MRI in these patients is allowed only in 1.5T horizontal scanners and with pulse sequences with reduced power. Nevertheless, off-label use of MRI at 3T is increasingly reported based on limited safety assessments. Here we present results of systematic RF heating measurements for two commercially available DBS systems during MRI at 1.5T and 3T.PURPOSETo assess the effect of imaging landmark, DBS lead configuration, and patient body composition on RF heating of DBS leads during MRI at 1.5 T and 3T.STUDY TYPEPhantom study.POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODELGel phantoms and cadaver brain.FIELD STRENGTH/SEQUENCE1.5T and 3T, T1-weighted turbo spin echo.ASSESSMENTRF heating was measured at tips of DBS leads implanted in brain-mimicking gel.STATISTICAL TESTSNone.RESULTSWe observed substantial fluctuation in RF heating mainly affected by phantom composition and DBS lead configuration, ranging from 0.14°C to 23.73°C at 1.5 T, and from 0.10°C to 7.39°C at 3T. The presence of subcutaneous fat substantially altered RF heating at electrode tips (−3.06°C < ΔT< 19.05°C). Introducing concentric loops in the extracranial portion of the lead at the surgical burr hole reduced RF heating by up to 89% at 1.5T and up to 98% at 3T compared to worst case heating scenarios.DATA CONCLUSIONDevice configuration and patient body composition significantly altered the RF heating of DBS leads during MRI at 1.5T and 3T. Interestingly, certain lead trajectories consistently reduced RF heating and image artifact over different imaging landmarks, RF frequencies, and phantom compositions. Such trajectories could be implemented in patients with minimal disruption to the surgical workflow.
MARCH8 inhibits viral infection by two different mechanisms
Authors: Zhang Yanzhao , Tada Takuya , Ozono Seiya , Kishigami Satoshi , Fujita Hideaki , Tokunaga Kenzo 
Published: April 2020

ABSTRACTMembrane-associated RING-CH 8 (MARCH8) inhibits infection with both HIV-1 and vesicular stomatitis virus G-glycoprotein (VSV-G)-pseudotyped viruses by reducing virion incorporation of envelope glycoproteins. The molecular mechanisms by which MARCH8 targets envelope glycoproteins remain unknown. Here, we show two different mechanisms by which MARCH8 inhibits viral infection. Viruses pseudotyped with the VSV-G mutant, in which cytoplasmic lysine residues were mutated, were insensitive to the inhibitory effect of MARCH8, whereas those with a similar lysine mutant of HIV-1 Env remained sensitive to it. Indeed, the wild-type VSV-G, but not its lysine mutant, was ubiquitinated by MARCH8. Furthermore, the MARCH8 mutant, which had a disrupted cytoplasmic tyrosine motif that is critical for intracellular protein sorting, did not inhibit HIV-1 Env-mediated infection, while it still impaired infection by VSV-G-pseudotyped viruses. Overall, we conclude that MARCH8 reduces viral infectivity by downregulating envelope glycoproteins through two different mechanisms mediated by a ubiquitination-dependent or tyrosine motif-dependent pathway.
Co-evolutionary analysis reveals a conserved dual binding interface between extracytoplasmic function (ECF) σ factors and class I anti-σ factors
Authors: Casas-Pastor Delia , Diehl Angelika , Fritz Georg 
Published: April 2020

AbstractExtracytoplasmic function σ factors (ECFs) belong to the most abundant signal transduction mechanisms in bacteria. Amongst the diverse regulators of ECF activity, class I anti-σ factors are the most important signal transducers in response to internal and external stress conditions. Despite the conserved secondary structure of the class I anti-σ factor domain (ASDI) that binds and inhibits the ECF under non-inducing conditions, the binding interface between ECFs and ASDIs is surprisingly variable between the published co-crystal structures. In this work, we provide a comprehensive computational analysis of the ASDI protein family and study the different contact themes between ECFs and ASDIs. To this end, we harness the co-evolution of these diverse protein families and predict covarying amino acid residues as likely candidates of an interaction interface. As a result, we find two common binding interfaces linking the first α-helix of the ASDI to the DNA binding region in the σ4domain of the ECF, and the fourth α-helix of the ASDI to the RNA polymerase (RNAP) binding region of the σ2domain. The conservation of these two binding interfaces contrasts with the apparent quaternary structure diversity of the ECF/ASDI complexes, partially explaining the high specificity between cognate ECF and ASDI pairs. Furthermore, we suggest that the dual inhibition of RNAP- and DNA-binding interfaces are likely a universal feature of other ECF anti-σ factors, preventing the formation of non-functional trimeric complexes between σ/anti-σ factors and RNAP or DNA.SignificanceIn the bacterial world, extracytoplasmic function σ factors (ECFs) are the most widespread family of alternative σ factors, mediating many cellular responses to environmental cues, such as stress. This work uses a computational approach to investigate how these σ factors interact with class I anti-σ factors – the most abundant regulators of ECF activity. By comprehensively classifying the anti-σs into phylogenetic groups and by comparing this phylogeny to the one of the cognate ECFs, the study shows how these protein families have co-evolved to maintain their interaction over evolutionary time. These results shed light on the common contact residues that link ECFs and anti-σs in different phylogenetic families and set the basis for the rational design of anti-σs to specifically target certain ECFs. This will help to prevent the cross-talk between heterologous ECF/anti-σ pairs, allowing their use as orthogonal regulators for the construction of genetic circuits in synthetic biology.
Liver injury is associated with severe Coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of retrospective studies
Authors: Parohan Mohammad , Yaghoubi Sajad , Seraj Asal 
Published: April 2020

AbstractAimThe Coronavirus disease 2019 (COVID-19) outbreak is a major threat to human beings. Lung injury has been reported as the major outcome of COVID-19 infection. However, liver damage has also been considered to occur in severe cases. Current meta-analysis of retrospective studies was done to summarize available findings on the association between liver injury and severity of COVID-19 infection.MethodsOnline databases including PubMed, Scopus, Web of Science and Cochrane Library were searched to detect relevant publications up to 1 April 2020, using relevant keywords. To pool data, a fixed- or random-effects model was used depending on the heterogeneity between studies. Furthermore, publication bias test and sensitivity analysis were also done.ResultsIn total, 20 retrospective studies with 3,428 COVID-19 infected patients (severe cases = 1,455 and mild cases = 1,973), were included in this meta-analysis. Higher serum levels of Aspartate aminotransferase (weighted mean difference = 8.84 U/L, 95% CI = 5.97 to 11.71, P<0.001), Alanine aminotransferase (weighted mean difference = 7.35 U/L, 95% CI = 4.77 to 9.93, P<0.001), total Bilirubin (weighted mean difference = 2.30 mmol/L, 95% CI = 1.24 to 3.36, P<0.001) and lower serum levels of Albumin (weighted mean difference = −4.24 g/L, 95% CI = −6.20 to −2.28, P<0.001), were associated with a significant increase in the severity of COVID-19 infection.ConclusionsThe incidence of liver injury seems to be higher in patients with severe COVID-19 infection. This finding could help physicians to identify patients with poor prognosis at an early stage.
Risk factors for mortality in patients with Coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of observational studies
Authors: Parohan Mohammad , Yaghoubi Sajad , Seraji Asal , Javanbakht Mohammad Hassan , Sarraf Payam , Djalali Mahmoud 
Published: April 2020

AbstractPurposeCoronavirus disease 2019 (COVID-19) is an emerging disease that was first reported in Wuhan city, the capital of Hubei province in China, and has subsequently spread worldwide. Risk factors for mortality have not been well summarized. Current meta-analysis of retrospective cohort studies was done to summarize available findings on the association between age, gender, comorbidities and risk of death from COVID-19 infection.MethodsOnline databases including Web of Science, PubMed, Scopus, Cochrane Library and Google scholar were searched to detect relevant publications up to 1 May 2020, using relevant keywords. To pool data, random-effects model was used. Furthermore, sensitivity analysis and publication bias test were also done.ResultsIn total, 14 studies with 29,909 COVID-19 infected patients and 1,445 cases of death were included in the current meta-analysis. Significant associations were found between older age (≥65 vs <65 years old) (pooled ORs=4.59, 95% CIs=2.61-8.04, p<0.001), gender (male vs female) (pooled ORs=1.50, 95% CIs=1.06-2.12, p=0.021) and risk of death from COVID-19 infection. In addition, hypertension (pooled ORs=2.70, 95% CIs= 1.40-5.24, p=0.003), cardiovascular diseases (CVDs) (pooled ORs=3.72, 95% CIs=1.77-7.83, p=0.001), diabetes (pooled ORs=2.41, 95% CIs=1.05-5.51, p=0.037), chronic obstructive pulmonary disease (COPD) (pooled ORs=3.53, 95% CIs=1.79-6.96, p<0.001) and cancer (pooled ORs=3.04, 95% CIs=1.80-5.14, p<0.001), were associated with higher risk of mortality.ConclusionOlder age (≥65 years old), male gender, hypertension, CVDs, diabetes, COPD and malignancies were associated with greater risk of death from COVID-19 infection. These findings could help clinicians to identify patients with poor prognosis at an early stage.