bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress
Authors: Fitzgerald Eamon , Sinton Matthew C , Wernig-Zorc Sara , Morton Nicholas M , Holmes Megan C , Boardman James P , Drake Amanda J
Published: April 2020

Early life stress during childhood is associated with a number of psychiatric disorders that manifest across the life course. Preterm birth is a profound stressor, and an important cause of cognitive impairment, as well as neurodevelopmental and psychiatric disorders. However, the mechanisms that link events during the early neonatal period with later functional problems are poorly understood. We developed a novel mouse model of early life stress (modified maternal separation; MMS) with specific relevance to preterm birth (PTB) and hypothesised it would affect the hypothalamic transcriptome and DNA methylome and impact on behaviour in adulthood. MMS consisted of repeatedly stimulating pups for 1.5 hours/day, whilst separated from their mother, from postnatal day (P)4-6. 3’ RNA sequencing and DNA methylation immunoprecipitation (meDIP) sequencing was performed on the hypothalamus at P6. Behaviour was assessed with the elevated plus and open field mazes, and in-cage monitoring at 3-4 months of age. Although MMS was only associated with subtle changes in gene expression there were widespread alterations in DNA methylation. Notably, differentially methylated regions were enriched for synapse-associated loci. MMS also resulted in hyperactivity in the elevated plus and open field mazes, but in-cage monitoring revealed that this was not representative of habitual hyperactivity. In conclusion we describe a novel model of early life stress with relevance to PTB, with marked effects on DNA methylation in the hypothalamus and with stress-specific hyperactivity in young adulthood. We suggest that these results have implications for the understanding of early life stress mediated effects on brain development.
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

Despite 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

Friedreich 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

Abstract

Acinetobacter 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

For 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 STATEMENT

This 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

Porcine 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.
A general strategy to red-shift green fluorescent protein based biosensors
Authors: Zhang Shen , Ai Hui-wang
Published: April 2020

Compared to green fluorescent protein (GFP) based biosensors, red fluorescent protein (RFP) based biosensors are inherently advantageous because of reduced phototoxicity, decreased autofluorescence, and enhanced tissue penetration. However, there is a limited choice of RFP-based biosensors and development of each biosensor requires significant effort. Herein, we describe a general and convenient method which uses the genetically encoded amino acid, 3-aminotyrosine (aY), to convert GFPs and GFP-based biosensors into red.
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

The 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

Understanding 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

BACKGROUND

Patients 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.

PURPOSE

To 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 TYPE

Phantom study.

POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL

Gel phantoms and cadaver brain.

FIELD STRENGTH/SEQUENCE

1.5T and 3T, T1-weighted turbo spin echo.

ASSESSMENT

RF heating was measured at tips of DBS leads implanted in brain-mimicking gel.

STATISTICAL TESTS

None.

RESULTS

We 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 CONCLUSION

Device 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

Membrane-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

Extracytoplasmic 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.

Significance

In 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

Aim

The 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.

Methods

Online 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.

Results

In 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.

Conclusions

The 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

Purpose

Coronavirus 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.

Methods

Online 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.

Results

In 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.

Conclusion

Older 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.
BCG protects against COVID-19? A word of caution
Authors: Szigeti Reka , Kellermayer Domos , Kellermayer Richard
Published: April 2020

The COVID-19 pandemic, caused by type 2 Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), puts all of us to the test. Epidemiologic observations could critically aid the development of protective measures to combat this devastating viral outbreak. A recent publication, linked nation based universal Bacillus Calmette-Guerin (BCG) vaccination to potential protection against morbidity and mortality from SARS-CoV-2, and received much attention in public media, even before its peer review. We wished to validate the findings by examining the association between daily rates of COVID-19 case fatality (i.e. Death Per Case) /Days of the endemic [dpc/d]) and the presence of universal BCG vaccination before 1980, or the year of the establishment of universal vaccination. There was no significant association in either analysis. In this work we emphasize caution amidst the publication surge on COVID-19, and highlight the political/economical-, arbitrary selection-, and fear/anxiety related biases, which may obscure scientific rigor. It is underscored that physical (social) distancing (i.e. quarantine) and use of personal protective equipment (PPE) are the only epidemiologic measures (Iceland being a great example, where universal BCG vaccination policy was never in place), which consistently associate with successful counteraction of morbidity and mortality during the pandemic.
Self-collection: an appropriate alternative during the SARS-CoV-2 pandemic
Authors: Wehrhahn Michael C. , Robson Jennifer , Brown Suzanne , Bursle Evan , Byrne Shane , New David , Chong Smathi , Newcombe James P. , Siversten Terri , Hadlow Narelle
Published: April 2020

BACKGROUND

Swabs for SARS-CoV-2 are routinely collected by health care workers, putting them at risk of infection and requiring use of personal protective equipment (PPE). Self-collected swabs offer many advantages provided detection rate of SARS-CoV-2 and other respiratory viruses is not compromised.

METHODS

In a prospective study, patients attending dedicated COVID-19 collection clinics were offered the option to first self-collect (SC) nasal and throat swabs prior to health worker collection (HC). Two different laboratory services participated, with HC at Site 1 collecting nasal and throat swabs and at Site 2 nasopharyngeal (NP) and throat swabs. Samples were analysed for SARS-CoV-2 as well as common respiratory viruses. Concordance of results between methods was assessed using Cohen’s kappa (κ).

RESULTS

Of 236 patients sampled by HC and SC, 25 had COVID-19 (24 by HC and 25 by SC) and 63 had other respiratory viruses (56 by HC and 58 by SC). SC was highly concordant with HC (κ = 0.890) for all viruses including SARS-CoV-2 and more concordant than HC to positive results by any method (κ = 0.959 vs 0.933).

CONCLUSIONS

Self-collection of throat and nasal swabs offers a reliable alternative to health worker collection for the diagnosis of SARS-CoV-2 and other common respiratory viruses. High viral load of SARS-CoV-2 throughout the respiratory tract and sensitive molecular methods may explain these findings. Self-collection also provides patients with easier access to testing, reduces the exposure of the community and health workers to those undergoing testing and reduces the requirement for PPE.
Effectiveness of quarantine measure on transmission dynamics of COVID-19 in Hong Kong
Authors: Yuan Hsiang-Yu , Mao Axiu , Han Guiyuan , Yuan Hsiangkuo , Pfeiffer Dirk
Published: April 2020

The rapid expansion of COVID-19 has caused a global pandemic. Although quarantine measures have been used widely, the critical steps among them to suppress the outbreak without a huge social-economic loss remain unknown. Hong Kong, unlike other regions in the world, had a massive number of travellers from Mainland China during the early expansion period, and yet the spread of virus has been relatively limited. Understanding the effect of control measures to reduce the transmission in Hong Kong can improve the control of the virus spreading.

We have developed a susceptible-exposed-infectious-quarantined-recovered (SEIQR) meta-population model that can stratify the infections into imported and subsequent local infections, and therefore to obtain the control effects on transmissibility in a region with many imported cases. We fitted the model to both imported and local confirmed cases with symptom onset from 18 January to 29 February 2020 in Hong Kong with daily transportation data and the transmission dynamics from Wuhan and Mainland China.

The model estimated that the reproductive number was dropped from 2.32 to 0.76 (95% CI, 0.66 to 0.86) after an infected case was estimated to be quarantined half day before the symptom onset, corresponding to the incubation time of 5.43 days (95% CI, 1.30-9.47). If the quarantine happened about one day after the onset, community spread would be likely to occur, indicated by the reproductive number larger than one. The results suggest that the early quarantine for a suspected case before the symptom onset is a key factor to suppress COVID-19.
How much of SARS-CoV-2 Infections is India detecting? A model-based estimation
Authors: Goli Srinivas , James K.S.
Published: April 2020

Background and Rationale

Amid SARS-CoV-2 outbreak, the low number of infections for a population size of 1.38 billion is widely discussed, but with no definite answers.

Methods

We used the model proposed by Bommer and Vollmer to assess the quality of official case records. The infection fatality rates were taken from Verity et al (2020). Age distribution of the population for India and states are taken from the Census of India (2011). Reported number of deaths and SARS-CoV-2 confirmed cases from https://www.covid19india.org. The reported numbers of samples tests were collected from the reports of the Indian Council for Medical Research (ICMR).

Results

The findings suggest that India is detecting just 3.6% of the total number of infections with a huge variation across its states. Among 13 states which have more than 100 COVID-19 cases, the detection rate varies from 81.9% (of 410 estimated infections) in Kerala to 0.8% (of 35487 estimated infections) in Madhya Pradesh and 2.4% (of 7431 estimated infections) in Gujarat.

Conclusion

As the study reports a lower number of deaths and higher recovery rates in the states with a high detection rate, thus suggest that India must enhance its testing capacity and go for widespread testing. Late detection puts patients in greater need of mechanical ventilation and ICU care, which imposes greater costs on the health system. The country should also adopt population-level random testing to assess the prevalence of the infection.
Single-cell atlas of a non-human primate reveals new pathogenic mechanisms of COVID-19
Authors: Han Lei , Wei Xiaoyu , Liu Chuanyu , Volpe Giacomo , Wang Zhifeng , Pan Taotao , Yuan Yue , Lei Ying , Lai Yiwei , Ward Carl , Yu Yeya , Wang Mingyue , Shi Quan , Wu Tao , Wu Liang , Liu Ya , Wang Chunqing , Zhang Yuanhang , Sun Haixi , Yu Hao , Zhuang Zhenkun , Tang Tingting , Huang Yunting , Lu Haorong , Xu Liqin , Xu Jiangshan , Cheng Mengnan , Liu Yang , Wong Chi Wai , Tan Tao , Ji Weizhi , Maxwell Patrick H. , Yang Huanming , Wang Jian , Zhu Shida , Liu Shiping , Xu Xun , Hou Yong , Esteban Miguel A. , Liu Longqi ,   South China Greater Bay Area-Single Cell Consortium (SC-GBA-C)
Published: April 2020

Stopping COVID-19 is a priority worldwide. Understanding which cell types are targeted by SARS-CoV-2 virus, whether interspecies differences exist, and how variations in cell state influence viral entry is fundamental for accelerating therapeutic and preventative approaches. In this endeavor, we profiled the transcriptome of nine tissues from aMacaca fascicularismonkey at single-cell resolution. The distribution of SARS-CoV-2 facilitators, ACE2 and TMRPSS2, in different cell subtypes showed substantial heterogeneity across lung, kidney, and liver. Through co-expression analysis, we identified immunomodulatory proteins such as IDO2 and ANPEP as potential SARS-CoV-2 targets responsible for immune cell exhaustion. Furthermore, single-cell chromatin accessibility analysis of the kidney unveiled a plausible link between IL6-mediated innate immune responses aiming to protect tissue and enhanced ACE2 expression that could promote viral entry. Our work constitutes a unique resource for understanding the physiology and pathophysiology of two phylogenetically close species, which might guide in the development of therapeutic approaches in humans.

Bullet points

We generated a single-cell transcriptome atlas of 9 monkey tissues to study COVID-19.

ACE2+TMPRSS2+epithelial cells of lung, kidney and liver are targets for SARS-CoV-2.

ACE2correlation analysis showsIDO2andANPEPas potential therapeutic opportunities.

We unveil a link between IL6, STAT transcription factors and boosted SARS-CoV-2 entry.
The boundaries of State-Space Granger Causality Analysis applied to BOLD simulated data: a comparative modelling and simulation approach
Authors: Timóteo Fernandes Tiago , Direito Bruno , Sayal Alexandre , Pereira João , Andrade Alexandre , Castelo-Branco Miguel
Published: April 2020

Background

The analysis of connectivity has become a fundamental tool in human neuroscience. Granger Causality Mapping is a data-driven method that uses Granger Causality (GC) to assess the existence and direction of influence between signals, based on temporal precedence of information. More recently, a theory of Granger causality has been developed for state-space (SS-GC) processes, but little is known about its statistical validation and application on functional magnetic resonance imaging (fMRI) data.

New Method

We implemented a new heuristic, focusing on the application of SS-GC with a distinct statistical validation technique - Time Reversed Testing - to generative synthetic models and compare it to classical multivariate computational frameworks. We also test a range of experimental parameters, including block structure, sampling frequency, noise and system mean pairwise correlation, using a statistical framework of binary classification.

Results

We found that SS-GC with time reversed testing outperforms other frameworks. The results validate the application of SS-GC to generative models. When estimating reliable causal relations, SS-GC returns promising results, especially when considering synthetic data with an high impact of noise and sampling rate.

Conclusions

SS-GC with time reversed testing offers a possible framework for future analysis of fMRI data in the context of data-driven causality analysis.

Highlights

State-Space GC was combined with a statistical validation step, using a Time Reversed Testing.

This novel heuristic overpowers classical GC, when applied to generative models.

Correctly identified connections between variables increase with the increase of number of blocks and number of points per block.

SNR and subsampling have a significant impact on the results.
A novel mapping strategy utilizing mouse chromosome substitution strains identifies multiple epistatic interactions that regulate complex traits
Authors: Miller Anna K. , Chen Anlu , Bartlett Jacquelaine , Wang Li , Williams Scott M. , Buchner David A.
Published: April 2020

The genetic contribution of additive versus non-additive (epistatic) effects in the regulation of complex traits is unclear. While genome-wide association studies typically ignore gene-gene interactions, in part because of the lack of statistical power for detecting them, mouse chromosome substitution strains (CSSs) represent an alternate and powerful model for detecting epistasis given their limited allelic variation. Therefore, we utilized CSSs to identify and map both additive and epistatic loci that regulate a range of hematologic- and metabolism-related traits, as well as hepatic gene expression. Quantitative trait loci (QTLs) were identified using a CSS-based backcross strategy involving the segregation of variants on the A/J-derived substituted chromosomes 4 and 6 on an otherwise C57BL/6J genetic background. In the liver transcriptomes of offspring from this cross, we identified and mapped additive QTLs regulating the hepatic expression of 768 genes, and epistatic QTL pairs for 519 genes. Similarly, we identified additive QTLs for fat pad weight, platelets, and the percentage of granulocytes in blood, as well as epistatic QTL pairs controlling the percentage of lymphocytes in blood and red cell distribution width. The variance attributed to the epistatic QTL pairs was approximately equal to that of the additive QTLs; however, the SNPs in the epistatic QTL pairs that accounted for the largest variances were undetected in our single locus association analyses. These findings highlight the need to account for epistasis in association studies, and more broadly demonstrate the importance of identifying genetic interactions to understand the complete genetic architecture of complex traits.
A high-throughput screening platform for pigment regulating agents using pluripotent stem cell derived melanocytes
Authors: Parat Valentin , Onteniente Brigitte , Maruotti Julien
Published: April 2020

In this study, we describe a simple and straight-forward assay using induced pluripotent stem cell derived melanocytes and high-throughput flow cytometry, to screen and identify pigment regulating agents. The assays is based on the correlation between forward light-scatter characteristics and melanin content, with pigmented cells displaying high light absorption/low forward light-scatter, while the opposite is true for lowly pigmented melanocytes, as a result of genetic background or chemical treatments. Orthogonal validation is then performed by regular melanin quantification. Such approach was validated using a set of 80 small molecules, and yielded a confirmed hit. The assay described in this study may prove a useful tool to identify modulators of melanogenesis in human melanocytes.
Identity-by-descent relatedness estimates with uncertainty characterise departure from isolation-by-distance betweenPlasmodium falciparumpopulations on the Colombian-Pacific coast
Authors: Taylor Aimee R. , Echeverry Diego F. , Anderson Timothy J. C. , Neafsey Daniel E. , Buckee Caroline O.
Published: April 2020

Characterising connectivity between geographically separated biological populations is a common goal in many fields. Recent approaches to understanding connectivity between malaria parasite populations, with implications for disease control efforts, have used estimates of relatedness based on identity-by-descent (IBD). However, uncertainty around estimated relatedness has not been accounted for to date. IBD-based relatedness estimates with uncertainty were computed for pairs of monoclonalPlasmodium falciparumsamples collected from five cities on the Colombian-Pacific coast where long-term clonal propagation ofP. falciparumis frequent. The cities include two official ports, Buenaventura and Tumaco, that are separated geographically but connected by frequent marine traffic. The fraction of highly-related sample pairs (whose classification accounts for uncertainty) was greater within cities versus between. However, based on both the fraction of highly-related sample pairs and on a threshold-free approach (Wasserstein distances between parasite populations) connectivity between Buenaventura and Tumaco was disproportionally high. Buenaventura-Tumaco connectivity was consistent with three separate transmission events involving parasites from five different clonal components (groups of statistically indistinguishable parasites identified under a graph theoretic framework). To conclude,P. falciparumpopulation connectivity on the Colombian-Pacific coast abides by accessibility not isolation-by-distance, potentially implicating marine traffic in malaria transmission with opportunities for targeted intervention. Further investigations are required to test this and alternative hypotheses. For the first time in malaria epidemiology, we account for uncertainty around estimated relatedness (an important consideration for future studies that plan to use genotype versus whole genome sequence data to estimate IBD-based relatedness); we also use a threshold-free approach to compare parasite populations, and identify clonal components in a statistically principled manner. The approaches we employ could be adapted to other recombining organisms with mixed mating systems, thus have broad relevance.
Adaptive evolution of olfactory degeneration in recently flightless insects
Authors: Neupert Stefanie , McCulloch Graham A. , Foster Brodie J. , Waters Jonathan M. , Szyszka Paul
Published: April 2020

Fast-moving animals need fast-acting sensory systems. Flying insects have thus evolved exceptionally quick visual (1) and olfactory processing ability (2). For example, flighted insects can track the temporal structure of turbulent odor plumes at rates above 100 Hz (3). The evolutionary lability of such sensory systems, however, remains unknown. We test for rapid evolutionary shifts in olfactory processing speed associated with flight loss, through neurobiological comparisons of sympatric flighted versus flightless lineages within a wing-polymorphic stonefly species. Our analyses of sensory responses reveal that recently-evolved flightless lineages have substantially degraded olfactory acuity. By comparing flighted versus flightless ecotypes with similar genetic backgrounds (4), we eliminate other confounding factors that might have affected the evolution of their olfactory reception mechanisms. Our detection of different patterns of degraded olfactory sensitivity and speed in independently wing-reduced lineages highlights parallel evolution of sensory degeneration. These reductions in sensory ability also echo the rapid vestigialization of wings themselves (4, 5), and represent a neurobiological parallel to the convergent phenotypic shifts seen under sharp selective gradients in other systems (e.g. parallel loss of vision in diverse cave fauna (6)). Our study provides the first direct evidence for the hypothesis that flight poses a selective pressure on the speed of olfactory receptor neurons. Our findings also emphasize the energetic costs of rapid olfaction, and the key role of natural selection in shaping dramatic neurobiological shifts.

Significance Statement

Flying insects move fast and have therefore evolved exceptionally quick-acting sensory systems. The speed with which such neurobiological shifts can evolve, however, remains unclear. Under the ‘use it or lose it’ hypothesis, loss of flight should lead to degradation of this fast sensory processing ability. We test for evolutionary reductions in olfactory acuity linked to flight loss, through neurobiological comparisons of flightless versus flighted lineages within a wing-polymorphic insect. Our analyses reveal that newly wing-reduced populations have substantially degraded olfactory acuity, with parallel reductions in this sensory ability detected in independently flightless lineages. These findings reveal that flight poses strong selective pressure for rapid olfaction, and highlight the potential of natural selection in rapidly shaping adaptive shifts in animal sensory systems.
A High-Resolution In Vivo Atlas of the Human Brain’s Benzodiazepine Binding Site of GABAAReceptors
Authors: Nørgaard Martin , Beliveau Vincent , Ganz Melanie , Svarer Claus , Pinborg Lars H , Keller Sune H , Jensen Peter S , Greve Douglas N. , Knudsen Gitte M.
Published: April 2020

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and depression. The binding of benzodiazepines to the benzodiazepine receptor sites (BZR) located on GABAAreceptors (GABAARs) potentiates the inhibitory effect of GABA leading to the anxiolytic, anticonvulsant and sedative effects used for treatment of those disorders. However, the function of GABAARs and the expression of BZR protein is determined by the GABAAR subunit stoichiometry (19 genes coding for individual subunits), and it remains to be established how the pentamer composition varies between brain regions and individuals.

Here, we present a quantitative high-resolution in vivo atlas of the human brain BZRs, generated on the basis of [11C]flumazenil Positron Emission Tomography (PET) data. Next, based on autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association with mRNA expression for the 19 subunits in the GABAAR, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein.

This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABAAR and the BZR density at each location in the brain.