bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Commercial SARS-CoV-2 Antibody Assays, Jamaica
Authors: Butterfield Tiffany R. , Bruce-Mowatt Alrica , Phillips Yakima Z. R. , Brown Nicole , Francis Keisha , Brown Jabari , Taylor Devon , Bruce Carl A. , McGrowder Donovan , Wharfe Gilian , Sandiford Simone L. , Thompson Tamara K. , Anzinger Joshua J.
Published: September 2020

The performance of the Roche Elecsys® Anti-SARS-CoV-2, Abbott Architect SARS-CoV-2 IgG, Euroimmun SARS-CoV-2 IgA, Euroimmun SARS-CoV-2 IgG ELISA, and Trillium IgG/IgM rapid assays was evaluated in Jamaica, the largest country of the English-speaking Caribbean. Diagnostic sensitivities of the assays were assessed by testing serum samples from SARS-CoV-2 PCR-confirmed persons. Serum samples collected ≥14 days after onset of symptoms, or ≥14 days after an initial SARS-CoV-2 RT-PCR positive test for asymptomatics, showed diagnostic sensitivities ranging from 67.9-75.0% when including all possible disease severities and increased to 90.0-95.0% when examining those with moderate to critical disease. Grouping moderate to critical disease showed a significant association with a SARS-CoV-2 antibody positive result for all assays. Diagnostic specificity, assessed by testing serum samples collected during 2018-2019 from healthy persons and from persons with antibodies to a wide range of viral infections, ranged from 96.7-100.0%. For all assays examined, SARS-CoV-2 real-time PCR cycle threshold (Ct) values of the initial nasopharyngeal swab sample testing positive were significantly different for samples testing antibody positive versus negative. These data from a predominantly African descent Caribbean population shows comparable diagnostic sensitivities and specificities for all testing platforms assessed and limited utility of these tests for persons with asymptomatic and mild infections.
T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses
Authors: Ogbe Ane , Kronsteiner Barbara , Skelly Donal T. , Pace Matthew , Brown Anthony , Adland Emily , Adair Kareena , Akhter Hossain Delowar , Ali Mohammad , Ali Serat-E , Angyal Adrienn , Ansari M. Azim , Arancibia-Cárcamo Carolina V , Brown Helen , Chinnakannan Senthil , Conlon Christopher , de Lara Catherine , de Silva Thushan , Dold Christina , Dong Tao , Donnison Timothy , Eyre David , Flaxman Amy , Fletcher Helen , Gardner Joshua , Grist James T. , Hackstein Carl-Philipp , Jaruthamsophon Kanoot , Jeffrey Katie , Lambe Teresa , Lee Lian , Li Wenqin , Lim Nicholas , Matthews Philippa C. , Mentzer Alexander J. , Moore Shona C. , Naisbitt Dean J , Ogese Monday , Ogg Graham , Openshaw Peter , Pirmohamed Munir , Pollard Andrew J. , Ramamurthy Narayan , Rongkard Patpong , Rowland-Jones Sarah , Sampson Oliver , Screaton Gavin , Sette Alessandro , Stafford Lizzie , Thompson Craig , Thomson Paul J , Thwaites Ryan , Vieira Vinicius , Weiskopf Daniela , Zacharopoulou Panagiota ,   Oxford Immunology Network Covid-19 Response T cell Consortium,   Oxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical team, Turtle Lance , Klenerman Paul , Goulder Philip , Frater John , Barnes Eleanor , Dunachie Susanna
Published: September 2020

A major issue in identification of protective T cell responses against SARS-CoV-2 lies in distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity generated by exposure to other coronaviruses. We characterised SARS-CoV-2 T cell immune responses in 168 PCR-confirmed SARS-CoV-2 infected subjects and 118 seronegative subjects without known SARS-CoV-2 exposure using a range of T cell assays that differentially capture immune cell function. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) were found in those who had been infected by SARS-CoV-2 but were rare in pre-pandemic and unexposed seronegative subjects. However, seronegative doctors with high occupational exposure and recent COVID-19 compatible illness showed patterns of T cell responses characteristic of infection, indicating that these readouts are highly sensitive. By contrast, over 90% of convalescent or unexposed people showed proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on the choice of assay and antigen. Memory responses to specific non-spike proteins provides a method to distinguish recent infection from pre-existing immunity in exposed populations.
Heat-based N95 mask decontamination and reuse in a large hospital setting
Authors: Vora Tushar , Bhattacharya Arnab , Ghosh Shankar , Gowda Kiran , Dhanaki Nandita , Gala Rajul , Dubey Nitin , Raut Vandana , Singh Vikas Kumar , Prakash Gagan , Laskar Sarbani Ghosh , Sengar Manju , Chinnaswamy Girish , Pramesh C S
Published: September 2020

The shortage of N95 masks have spurred efforts on developing safe and scientifically-validated decontamination and reuse protocols that are easily scalable and universally applicable even in low-resource settings. We report on the development and implementation of a heat-based N95 mask decontamination system in a large hospital setting (Tata Memorial Hospital, Mumbai, India) with over 8000 N95 masks from about 1400 individual users decontaminated and in reuse till date. We describe the challenges and constraints in choosing a proven, scalable, and easy-to-implement decontamination solution. We discuss the heat treatment and particle filtration efficiency measurement experiments done to validate a decontamination treatment protocol at a target temperature of 70oC for a duration of 60 minutes, and the scaling up of this method using a standard hot drying cabinet at the hospital. The logistics of ensuring optimal utilization of the decontamination facility without compromising on basic safety principles are detailed. Our method relies on equipment available in standard hospitals, is simple to set-up, scalable, and can be easily replicated in low-resource settings. We further believe such limited reuse strategies, even in times of abundant N95 mask availability, would not only be cost-saving but also be environmentally responsible in reducing the amount of medical waste.
DeepCOVID: An Operational Deep Learning-driven Framework for Explainable Real-time COVID-19 Forecasting
Authors: Rodríguez Alexander , Tabassum Anika , Cui Jiaming , Xie Jiajia , Ho Javen , Agarwal Pulak , Adhikari Bijaya , Prakash B. Aditya
Published: September 2020

How do we forecast an emerging pandemic in real time in a purely data-driven manner? How to leverage rich heterogeneous data based on various signals such as mobility, testing, and/or disease exposure for forecasting? How to handle noisy data and generate uncertainties in the forecast? In this paper, we present DeepCovid, an operational deep learning frame-work designed for real-time COVID-19 forecasting. Deep-Covid works well with sparse data and can handle noisy heterogeneous data signals by propagating the uncertainty from the data in a principled manner resulting in meaningful uncertainties in the forecast. The deployed framework also consists of modules for both real-time and retrospective exploratory analysis to enable interpretation of the forecasts. Results from real-time predictions (featured on the CDC website and FiveThirtyEight.com) since April 2020 indicates that our approach is competitive among the methods in the COVID-19 Forecast Hub, especially for short-term predictions.
Comparison of infection control strategies to reduce COVID-19 outbreaks in homeless shelters in the United States: a simulation study
Authors: Chapman Lloyd A.C. , Kushel Margot , Cox Sarah N. , Scarborough Ashley , Cawley Caroline , Nguyen Trang , Rodriguez-Barraquer Isabel , Greenhouse Bryan , Imbert Elizabeth , Lo Nathan C.
Published: September 2020

Background

COVID-19 outbreaks have occurred in homeless shelters across the US, highlighting an urgent need to identify the most effective infection control strategy to prevent future outbreaks.

Methods

We developed a microsimulation model of SARS-CoV-2 transmission in a homeless shelter and calibrated it to data from cross-sectional polymerase-chain-reaction (PCR) surveys conducted during COVID-19 outbreaks in five shelters in three US cities from March 28 to April 10, 2020. We estimated the probability of averting a COVID-19 outbreak when an exposed individual is introduced into a representative homeless shelter of 250 residents and 50 staff over 30 days under different infection control strategies, including daily symptom-based screening, twice-weekly PCR testing and universal mask wearing.

Results

The proportion of PCR-positive residents and staff at the shelters with observed outbreaks ranged from 2.6% to 51.6%, which translated to basic reproduction number (R0) estimates of 2.9–6.2. The probability of averting an outbreak diminished with higher transmissibility (R0) within the simulated shelter and increasing incidence in the local community. With moderate community incidence (~30 confirmed cases/1,000,000 people/day), the estimated probabilities of averting an outbreak in a low-risk (R0=1.5), moderate-risk (R0=2.9), and high-risk (R0=6.2) shelter were, respectively: 0.35, 0.13 and 0.04 for daily symptom-based screening; 0.53, 0.20, and 0.09 for twice-weekly PCR testing; 0.62, 0.27 and 0.08 for universal masking; and 0.74, 0.42 and 0.19 for these strategies combined.

Conclusions

In high-risk homeless shelter environments and locations with high community incidence of COVID-19, even intensive infection control strategies (incorporating daily symptom-screening, frequent PCR testing and universal mask wearing) are unlikely to prevent outbreaks, suggesting a need for non-congregate housing arrangements for people experiencing homelessness. In lower-risk environments, combined interventions should be employed to reduce outbreak risk.
Young adults with recurrent low back pain demonstrate altered trunk coordination during gait independent of pain status and attentional demands
Authors: Shih Hai-Jung Steffi , Winstein Carolee J. , Kulig Kornelia
Published: September 2020

Pain influences both attention and motor behavior. We used a dual-task interference paradigm to investigate 1) alterations in attentional performance, 2) the ability to switch task prioritization, and 3) the effect of attentional demand on trunk coordination during narrow-based walking in and out of a painful episode in individuals with recurrent low back pain (LBP). We tested twenty young adults with LBP both in and out of a painful episode and compared them to twenty matched back-healthy individuals. Participants simultaneously performed a narrow step width matching task and an arithmetic task, with and without instructions to prioritize either task. A motion capture system was used to record kinematic data, and frontal plane trunk coordination was analyzed using vector coding on the thorax and pelvis angles. Single task performance, dual-task effect, dual-task performance variability, task prioritization switch, and trunk coordination were analyzed using paired t-tests or repeated measures two-way ANOVAs. Results indicated that active pain has a detrimental effect on attentional processes, indicated by poorer single task performance and increased dual-task performance variability for individuals with recurrent LBP. Individuals with LBP, regardless of pain status, were able to switch task prioritization to a similar degree as their back-healthy counterparts. Compared to the control group, individuals with recurrent LBP exhibited a less in-phase, more pelvis-dominated trunk coordination during narrow-based walking, independent of pain status and regardless of attentional manipulations. Thus, altered trunk coordination in persons with LBP appears to be habitual, automatic, and persists beyond symptom duration.
Two Color Single Molecule Sequencing on GenoCare™ 1600 Platform to Facilitate Clinical Applications
Authors: Chen Fang , Liu Bin , Chen Meirong , Jiang Zefei , Zhou Zhiliang , Wu Ping , Zhang Meng , Jin Huan , Li Linsen , Lu Liuyan , Wang Qi , Shang Huan , Xie Bing , Liu Lei , Lin Xia , Chen Weiyue , Xu Jianfeng , Sun Ruitao , Wang Guangming , Zheng Jiao , Qi Jifang , Yang Bo , Chen Dexia , Zeng Lidong , Li Gailing , Li Yan , Lv Hui , Zhao Nannan , Zhou Bo , Wang Wen , Cai Jinsen , Liu Siyu , Luo Weiwei , Zhang Juan , Zhang Yanhua , Lu Yongyi , Fan Jicai , Dan Haitao , He Xuesen , Liu Lichun , Feng Yan , Chen Jianglin , Huang Wei , Sun Lei , Yan Qin
Published: September 2020

With the rapid development of precision medicine industry, DNA sequencing becomes increasingly important as a research and diagnosis tool. For clinical applications, medical professionals require a platform which is fast, easy to use, and presents clear information relevant to definitive diagnosis. We have developed a single molecule desktop sequencing platform, GenoCare™ 1600. Fast library preparation (without amplification) and simple instrument operation make it friendlier for clinical use. Here we presented sequencing data of E. coli sample from GenoCare™ 1600 with consensus accuracy reaches 99.99%. We also demonstrated sequencing of microbial mixtures and COVID-19 samples from throat swabs. Our data show accurate quantitation of microbial, sensitive identification of SARS-CoV-2 virus and detection of variants confirmed by Sanger sequencing.
Efficacy of Famotidine for COVID-19: A Systematic Review and Meta-analysis
Authors: Sethia Rahul , Prasad Manya , Mahapatra Soumya Jagannath , Nischal Neeraj , Soneja Manish , Garg Pramod , Shalimar
Published: September 2020

Background

Coronavirus Disease 2019 (COVID-19) pandemic continues unabated in many parts of the world. In the absence of any definite antiviral therapy except some benefit of remdesivir, there is an ongoing search for effective therapy. Famotidine has been shown to reduce mortality in hospitalized patients in a few studies. We conducted a systematic review on the use of famotidine in COVID-19.

Methods

We searched the databases Medline, Embase, Cochrane CENTRAL and Medrxiv. Title/abstract screening, full text screening and data abstraction were carried out in by two reviewers. Case series, cohort studies and randomized trials were included.

Results

Five studies were eligible for inclusion: all were retrospective cohort or case series. Low quality evidence suggests a likely clinical benefit for the use of famotidine in decreasing mortality in hospitalized patients with moderate to severe COVID-19. A meta-analysis of two cohort studies showed a statistically significant decrease in the composite outcome for death and intubation with famotidine (HR 0.44, 95% CI 0.27 to 0.73).

Conclusion

Further evidence from RCTs is required for famotidine to treat COVID 19.
Association study of BDNF Val66Met gene polymorphism with bipolar disorder and lithium treatment response in Indian population
Authors: Paul Pradip , Nadella Ravi Kumar , Sen Somdatta , Ithal Dhruva , Mahadevan Jayant , Reddy Y C Janardhan , Jain Sanjeev , Purushottam Meera , Viswanath Biju
Published: September 2020

Background

The association of the Val66Met (rs6265) polymorphism in the brain derived neurotrophic factor (BDNF) gene with bipolar disorder (BD) and response to lithium treatment has been suggested, though inconsistently. The considerable diversity of allele frequency across different populations contributes to this. There is no data from South Asia till date. Hence, we examined the association of this polymorphism in BD cases from India, and its correlation with lithium treatment response.

Methods

BD patients (N=301) were recruited from the clinical services of National Institute of Mental Health and Neurosciences (NIMHANS), India. Lithium treatment response for 190 BD subjects was assessed using Alda scale by NIMH life charts. Patients with total score ≥ 7 were defined as lithium responders (N=115) and patients with score <7 were defined as lithium non-responders (N=75). Healthy controls (N = 484) with no lifetime history of neuropsychiatric illness, or a family history of mental illness were recruited as control set. Genotyping was performed by TaqMan genotyping assay.

Results

Genotype and allele frequency of BDNF Val66Met SNP was significantly different (χ2 = 7.78, p=0.02) in cases compared to controls, and the Val(G) allele was more frequent (χ2 = 7.08, p=0.008) in BD patients. Although there was trend towards significance for greater occurrence of Val(G) allele among lithium non-responders, this difference did not persist in an analysis of extreme response groups.

Conclusions

The Val(G) allele of BDNF Val66Met polymorphism is associated with risk of BD in this sample, but is not related to response to lithium.
EPI Distortion Correction is Easy and Useful, and You Should Use It: A case study with toddler data
Authors: Roopchansingh Vinai , French Jerry J. , Nielson Dylan M. , Reynolds Richard C. , Glen Daniel R. , D’ Souza Precilla , Taylor Paul A. , Cox Robert W. , Thurm Audrey E.
Published: September 2020

Task, resting state, and diffusion MRI data are usually acquired from subjects using echo-planar based imaging techniques. These techniques are highly susceptible to B0homogeneity effects that result in geometric distortions in the reconstructed images. As researchers work to link the information from these scans back to various developmental stages, or to conditions and diseases in specific regions or structures of the brain, it becomes critical to have accurate correspondence between more geometrically distorted echo-planar images and less geometrically distorted anatomical images. A variety of techniques and tools have been developed to improve this correspondence. The basic premise behind most techniques used to mitigate geometric distortion is to acquire enough information to inform software tools how echo-planar images are warped, then have them undo that warping. Here, we investigate the application of two common methods: B0correction, and reverse-polarity phase-encoding (or reverse blip) correction. We implement each of these in two separate, widely used software packages in the field: AFNI and FSL. We find that using either technique in either software package results in reduced geometric distortions in the EPI images. We discuss the practical implementations of these methods (e.g., increased scan and processing time). In general, however, both methods possess readily available data acquisition schemes, and are highly efficient to include in processing streams. Due to the overall data improvement, we strongly recommend that researchers include one of these methods in their standard protocols.
The composition of the microbiota in the full-term fetal gut and amniotic fluid: a bovine caesarean section study
Authors: Husso Aleksi , Lietaer Leen , Pessa-Morikawa Tiina , Grönthal Thomas , Govaere Jan , Van Soom Ann , Iivanainen Antti , Opsomer Geert , Niku Mikael
Published: September 2020

The fetal development of the intestinal immune system is stimulated by the maternal microbiota, but it is still unclear whether viable bacteria exist in the healthy fetus. Analysis of such low microbial biomass environments are challenging due to contamination issues. The aims of the current study were to assess the bacterial load and characterize the bacterial composition of the amniotic fluid and meconium of full-term calves, leading to a better knowledge of prenatal bacterial seeding of the fetal intestine. Amniotic fluid and rectal meconium samples were collected during and immediately after elective caesarean section, performed in 25 Belgian Blue cow-calf couples. The samples were analyzed by qPCR, bacterial culture using GAM agar and 16S rRNA gene amplicon sequencing. To minimize the effects of contaminants, we included multiple technical controls and stringently filtered the 16S rRNA gene sequencing data to exclude putative contaminant sequences. The meconium samples contained a significantly higher amount of bacterial DNA than the negative controls and 5 of 24 samples contained culturable bacteria. In the amniotic fluid, the amount of bacterial DNA was not significantly different from the negative controls and all samples were culture negative. Bacterial sequences were identified in both sample types and were primarily of phyla Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria, with some individual variation. We conclude that most calves encounterin uteromaternal-fetal transmission of bacterial DNA, but the amount of bacterial DNA is low and viable bacteria are rare.
Interpreting blood GLUcose data with R package iglu
Authors: Broll Steven , Urbanek Jacek , Buchanan David , Chun Elizabeth , Muschelli John , Punjabi Naresh , Gaynanova Irina
Published: September 2020

Continuous Glucose Monitoring (CGM) data play an increasing role in clinical practice as they provide detailed quantification of blood glucose levels during the entire 24-hour period. The R package iglu implements a wide range of CGM-derived metrics for measuring glucose control and glucose variability. The package also allows to visualize CGM data using time-series and lasagna plots. A distinct advantage of iglu is that it comes with a point-and-click graphical user interface (GUI), which makes the package widely accessible to users regardless of their programming experience. Thus, open-source and easy to use iglu package will help advance CGM research and CGM data analyses. R package iglu is publicly available on CRAN and at https://github.com/irinagain/iglu.
Prime-boost vaccination of mice and Rhesus macaques with two novel adenovirus vectored COVID-19 vaccine candidates
Authors: Luo Shengxue , Zhang Panli , Liu Bochao , Yang Chan , Liang Chaolan , Wang Qi , Zhang Ling , Tang Xi , Li Jinfeng , Hou Shuiping , Zeng Jinfeng , Fu Yongshui , Allain Jean-Pierre , Li Tingting , Zhang Yuming , Li Chengyao
Published: September 2020

COVID-19 vaccines are being developed urgently worldwide, among which single-shot adenovirus vectored vaccines represent a major approach. Here, we constructed two novel adenovirus vectored COVID-19 vaccine candidates on simian adenovirus serotype 23 (Sad23L) and human adenovirus serotype 49 vectors (Ad49L) carrying the full-length gene of SARS-CoV-2 spike protein (S), designated Sad23L-nCoV-S and Ad49L-nCoV-S vaccines, respectively. The immunogenicity elicited by these two vaccine strains was individually evaluated in mice. Specific humoral and cellular immune responses were proportionally observed in a dose-dependent manner, and stronger response was obtained by boosting. Furthermore, five rhesus macaques were intramuscularly injected with a dose of 5×109PFU Sad23L-nCoV-S vaccine for prime vaccination, followed by boosting with 5×109PFU of Ad49L-nCoV-S vaccine at 4-week interval. Three macaques were injected with Sad23L-GFP and Ad49L-GFP vectorial viruses as negative controls. Both mice and macaques tolerated well the vaccine inoculations without detectable clinical or pathologic changes. In macaques, prime-boost vaccination regimen induced high titers of 103.16S-binding antibody (S-BAb), 102.75cell receptor binding domain (RBD)-BAb and 102.38neutralizing antibody (NAb) to pseudovirus a week after boosting injection, followed by sustained high levels over 10 weeks of observation. Robust IFN-γ secreting T-cell response (712.6 SFCs/106cells), IL-2 secreting T-cell response (334 SFCs/106cells) and intracellular IFN-γ expressing CD4+/CD8+T cell response (0.39%/0.55%) to S peptides were detected in the vaccinated macaques. It was concluded that prime-boost immunization with Sad23L-nCoV-S and Ad49L-nCoV-S vaccines can safely elicit strong immunity in animals in preparation of clinical phase 1/2 trials.
Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure
Authors: Connelly Sean V. , Manzella-Lapeira Javier , Levine Zoë C. , Brzostowski Joseph , Krymskaya Ludmila , Rahman Rifat S. , Ellis Angela C. , Amin Shuchi N. , Sá Juliana M. , Wellems Thomas E.
Published: September 2020

Artemisinin and its semi-synthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstreamPlasmodiumparasites that enter into and later reactivate from a dormant persister state. Here we provide evidence that the mitochondria of dihydroartemisinin (DHA)-exposed persisters are dramatically altered and enlarged relative to the mitochondria of young, actively replicating ring forms. Restructured mitochondrial-nuclear associations and an altered metabolic state are consistent with stress from reactive oxygen species. New contacts between the mitochondria and nuclei may support communication pathways of mitochondrial retrograde signaling, resulting in transcriptional changes in the nucleus as a survival response. Further characterization of the organelle communication and metabolic dependencies of persisters may suggest strategies to combat recrudescences of malaria after treatment.

IMPORTANCE

The major first-line treatment for malaria, especially the deadliest form caused byPlasmodium falciparum, is combination therapy with an artemisinin-based drug (ART) plus a partner drug to assure complete cure. Without an effective partner drug, ART administration alone can fail because of the ability of small populations of blood-stage malaria parasites to enter into a dormant state and survive repeated treatments for a week or more. Understanding the nature of parasites in dormancy (persisters), and their ability to wake and reestablish actively-propagating parasitemias (recrudesce) after ART exposure, may suggest strategies to improve treatment outcomes and counter the threats posed by parasites that develop resistance to partner drugs. Here we show that persisters have dramatically altered mitochondria and mitochondrial-nuclear interactions associated with features of metabolic quiescence. Restructured associations between the mitochondria and nuclei may support signaling pathways that enable the ART survival responses of dormancy.
Inoculation by mosquito induces durable differences in serological profile in non-human primates infected with DENV1
Authors: Rajan Jayant V. , McCracken Michael , Mandel-Brehm Caleigh , Gromowski Greg , Pollett Simon , Jarman Richard , DeRisi Joseph L.
Published: September 2020

Natural dengue virus (DENV) infections are delivered by mosquito bite but how the route of inoculation route could shape the humoral immune response is not well understood. Here, we serologically profiled 20 non-human primates (NHP) from a prior study of DENV1 infection in which the animals were inoculated by mosquito (N=10) or subcutaneous injection (N=10). Using a comprehensive, densely tiled and highly redundant pan-flavivirus programmable phage library containing 91,562 overlapping 62 amino acid peptides, we produced a high-resolution map of linear peptide sequences enriched during DENV seroconversion. We found that serological profiles in mosquito-inoculated and subcutaneously-inoculated animals were similar up to 90 days after primary infection, but diverged at 1 year. We found differences in sero-reactivity, as indicated by the median area under the curve (AUC) in the Envelope (E; residues 215-406; p < 0.08), and Nonstructural-3 (NS3; residues 549-615; p < 0.05) proteins in mosquito-inoculated versus subcutaneously-inoculated animals. Within the E protein, residues 339-384 in domain III accounted for >99% of the total AUC difference across residues 215-406. Antibody breadth did not vary by mode of inoculation. The differential reactivity to E domain III (EDIII) seen by phage display validated orthogonally by ELISA, but did not correlate with late neutralization titers. Serological profiling of humoral immune responses to DENV infection in NHP by programmable phage display demonstrated durable differences in sero-reactivity by route of inoculation. These findings could have implications for DENV diagnostics and evaluation of vaccines.

IMPORTANCE

Dengue virus (DENV) infections are transmitted by mosquito bite, but how being infected by mosquito bite affects the immune response is not known. In this study, we analyzed antibodies produced by rhesus macaques infected with DENV using programmable phage display, a high-throughput method for characterizing what viral protein derived peptides serum antibodies bind to. We found that while there was no difference in antibody binding profiles at early timepoints post-infection, at one year post-infection, there were substantial differences in the antibody binding profiles of macaques who were infected by mosquito bite versus those that were infected by injection. In general, antibodies in the macaques inoculated by mosquito maintained higher levels of sero-reactivity, with a strong signal still present one year post-infection. The findings we report could have implications for DENV diagnostics and evaluation of DENV vaccines.
Zinc-binding motif acts as an oxidative stress sensor to regulate TRPM7 channel activity
Authors: Inoue Hana , Murayama Takashi , Kobayashi Takuya , Konishi Masato , Yokoyama Utako
Published: September 2020

TRPM7 channel activity is negatively regulated by intracellular Mg2+. We previously reported that TRPM7 was inhibited by oxidative stress due to an enhancement of the inhibition by intracellular Mg2+. In the present study, we aimed to clarify the precise mechanism underlying the TRPM7 inhibition by oxidative stress induced by hydrogen peroxide (H2O2). Site-directed mutagenesis on full-length TRPM7 revealed that none of the cysteines other than C1809 and C1813 within the zinc-binding motif of the TRPM7 kinase domain were involved in the H2O2-induced TRPM7 inhibition. When C1809 or C1813 was mutated, full-length TRPM7 was not expressed on the plasma membrane. We, therefore, developed a novel approach in which the full-length TRPM7 is functionally reconstituted by co-expressing the TRPM7 channel domain (M7cd) and the TRPM7 kinase domain (M7kd) as separate individual proteins in HEK293 cells. When M7cd was expressed alone, the current was inhibited by intracellular Mg2+more strongly than in full-length TRPM7. Co-expression of M7cd and M7kd attenuated the current inhibition by intracellular Mg2+, and the current was sensitive to oxidative stress, indicating successful reconstitution of a full-length TRPM7-like current. A similar current reconstitution was observed when M7cd was co-expressed with the kinase inactive mutant M7kd-K1645R. Thus, it is suggested that the kinase activity is not essential for the reconstitution. Co-expression of M7cd and M7kd carrying a mutation at C1809 or C1813 failed to restore the full-length TRPM7-like current. No reconstitution was also observed with M7kd carrying a mutation at H1750 and H1807, which are involved in the zinc-binding motif formation together with C1809 and C1813. These data suggest that the zinc-binding motif is essential for the intracellular Mg2+-dependent regulation of the TRPM7 channel activity by M7kd, and the cysteines in the zinc-binding motif might play a role in the oxidative stress response of TRPM7.
Pinching the cortex of live cells reveals thickness instabilities caused by Myosin II motors
Authors: Laplaud V. , Levernier N. , Pineau J. , Roman M. San , Barbier L. , Saez P. J. , Lennon A. M. , Vargas P. , Kruse K. , du Roure O. , Piel M. , Heuvingh J.
Published: September 2020

The cell cortex is a contractile actin meshwork, which determines cell shape and is essential for cell mechanics, migration and division. Because the cortical thickness is below optical resolution, it has been generally considered as a thin uniform two-dimensional layer. Using two mutually attracted magnetic beads, one inside the cell and the other in the extracellular medium, we pinch the cortex of dendritic cells and provide an accurate and time resolved measure of its thickness. Our observations draw a new picture of the cell cortex as a highly dynamic layer, harboring large fluctuations in its third dimension due to actomyosin contractility. We propose that the cortex dynamics might be responsible for the fast shape changing capacity of highly contractile cells that use amoeboid-like migration.
Phenology and function in lycopod-Mucoromycotina symbiosis
Authors: Hoysted Grace A. , Bidartondo Martin I. , Duckett Jeffrey G. , Pressel Silvia , Field Katie J.
Published: September 2020

Lycopodiella inundatais a lycophyte with a complex life cycle. The gametophytes and the juvenile, mature and retreating sporophytes form associations with Mucoromycotina fine root endophyte (MFRE) fungi, being mycoheterotrophic as gametophytes and mutualistic as mature sporophytes. However, the function of the symbiosis across juvenile and retreating sporophyte life stages remains unknown. We measured carbon-for-nutrient exchanges betweenL. inundataand MFRE across the transition from newly emerging sporophytes to mature sporophytes and in retreating adult sporophytes. We show MFRE fungi play distinct functional roles at each plant life stage, with evidence of bidirectional exchange of plant C for fungal acquired nutrients (N and P) between mature adult and retreating adult sporophytes and fungi, but no transfer of plant C to fungi and little fungal-acquired nutrient gain in juvenile sporophytes. Furthermore, we show that these functional stages correspond with different cytologies of colonisation. Our results show that MFRE have considerable plasticity in their interactions with the host plant which is related to the developmental stage of the host. This highlights the need for further research into symbiotic fungal function across plant life histories.
Combining computational controls with natural text reveals new aspects of meaning composition
Authors: Toneva Mariya , Mitchell Tom M. , Wehbe Leila
Published: September 2020

To study a core component of human intelligence—our ability to combine the meaning of words—neuroscientists have looked to theories from linguistics. However, linguistic theories are insufficient to account for all brain responses that reflect linguistic composition. In contrast, we adopt a data-driven computational approach to study the combined meaning of words beyond their individual meaning. We term this product “supra-word meaning” and investigate its neural bases by devising a computational representation for it and using it to predict brain recordings from two imaging modalities with complementary spatial and temporal resolutions. Using functional magnetic resonance imaging, we reveal that hubs that are thought to process lexical-level meaning also maintain supra-word meaning, suggesting a common substrate for lexical and combinatorial semantics. Surprisingly, we cannot detect supra-word meaning in magnetoencephalography, which suggests the hypothesis that composed meaning might be maintained through a different neural mechanism than the synchronized firing of pyramidal cells. This sensitivity difference has implications for past neuroimaging results and future wearable neurotechnology.
Luxotonic signals in human prefrontal cortex as a possible substrate for effects of light on mood and cognition
Authors: Sabbah Shai , Worden Michael S. , Laniado Dimitrios D. , Berson David M. , Sanes Jerome N.
Published: September 2020

Animal studies revealed a mood-regulating neural pathway linking intrinsically photosensitive retinal ganglion cells (ipRGCs) and the prefrontal cortex (PFC), involved in the pathophysiology of mood disorders. As humans too have luminance-encoding ipRGCs, we asked whether a similar pathway exist in humans. Here, fMRI was used to identify PFC regions and other areas exhibiting luminance-dependent signals. We report 29 human brain regions where activation either monotonically decreased or increased with luminance. Luxotonic activity was identified across the cerebral cortex, in diverse subcortical structures, and in the cerebellum, regions that have functions related to visual image formation, motor control, cognition, emotion, and reward processing. Light suppressed PFC activation level, the activation monotonically decreasing with increasing luminance. The sustained time course of light-evoked PFC responses, and their susceptibility to prior light exposure, most closely resembled those of ipRGCs. These findings offer a functional link between light exposure and PFC-mediated cognitive and affective phenomena.
Metabolomic signature of the maternal microbiota in the fetus
Authors: Pessa-Morikawa Tiina , Husso Aleksi , Kärkkäinen Olli , Koistinen Ville , Hanhineva Kati , Iivanainen Antti , Niku Mikael
Published: September 2020

The maternal microbiota affects the development of the offspring by microbial metabolites translocating to the fetus. We investigated samples of placenta, fetal intestine and brain from germ-free (GF) and specific pathogen free (SPF) mouse dams by non-targeted metabolic profiling. One hundred one annotated metabolites and altogether 3680 molecular features were present in significantly different amounts in the placenta and/or fetal organs of GF and SPF mice. The concentrations of more than half of the annotated and differentially expressed metabolites were lower in the GF organs, suggesting their microbial origin or a metabolic response of the host to the presence of gut microbiota. The clearest separation was observed in the placenta. Metabolites that were detected in lower amounts in the fetal organs in the GF mice included 5-aminovaleric acid betaine, trimethylamine N-oxide, catechol-O-sulphate, hippuric and pipecolic acid. Derivatives of the amino acid tryptophan, such as kynurenine, 3-indolepropionic acid and hydroxyindoleacetic acid, were also decreased in the absence of microbiota. Several metabolites had higher levels in the GF mice. These could be precursors of microbial metabolites or indicators of host metabolic response to the absence of gut microbiota. Ninety-nine molecular features were only detected in the SPF mice, suggesting the existence of yet unidentified microbially modified metabolites that potentially influence fetal development.
Predicting age and clinical risk from the neonatal connectome
Authors: Taoudi-Benchekroun Yassine , Christiaens Daan , Grigorescu Irina , Gale-Grant Oliver , Schuh Andreas , Pietsch Maximilian , Chew Andrew , Harper Nicholas , Falconer Shona , Poppe Tanya , Hughes Emer , Hutter Jana , Price Anthony N , Tournier J-Donald , Cordero-Grande Lucilio , Counsell Serena J , Rueckert Daniel , Arichi Tomoki , Hajnal Joseph V , Edwards A David , Deprez Maria , Batalle Dafnis
Published: September 2020

The development of perinatal brain connectivity underpins motor, cognitive and behavioural abilities in later life. Diffusion MRI allows the characterisation of subtle inter-individual differences in structural brain connectivity. Individual brain connectivity maps (connectomes) are by nature high in dimensionality and are complex to interpret. Machine learning methods are a powerful tool to uncover properties of the connectome which are not readily visible, and can give us clues as to how and why individual developmental trajectories differ.

In this manuscript we used Deep Neural Networks and Random Forests to predict demographic and neurodevelopmental characteristics from neonatal structural connectomes in a large sample of babies (n = 524) from the developing Human Connectome Project. We achieved an accurate prediction of post menstrual age (PMA) at scan in term-born infants (Mean absolute error (MAE) = 0.72 weeks, r = 0.83 and p<0.001). We also achieved good accuracy when predicting gestational age at birth in a cohort of term and preterm babies scanned at term equivalent age (MAE = 2.21 weeks, r = 0.82, p<0.001). We subsequently used sensitivity analysis to obtain feature relevance from our prediction models, with the most important connections for prediction of PMA and GA found to be predominantly thalamocortical. From our models of PMA at scan for infants born at term, we computed a brain maturation index (predicted age minus actual age) of individual preterm neonates and found a significant correlation between this index and motor outcome at 18 months corrected age. Our results demonstrate the applicability of machine learning techniques in analyses of the neonatal connectome, and suggest that a neural substrate for later developmental outcome is detectable at term equivalent age.
A Probabilistic and Anisotropic Failure Metric for Ascending Thoracic Aortic Aneurysm Risk Stratification
Authors: Liu Minliang , Liang Liang , Zou Qing , Ismail Yasmeen , Lou Xiaoying , Iannucci Glen , Chen Edward P. , Leshnower Bradley G. , Elefteriades John A. , Sun Wei
Published: September 2020

Experimental studies have shown that aortic wall tensile strengths in circumferential and longitudinal directions are different (i.e., anisotropic), and vary significantly among patients with aortic aneurysm. To assess aneurysm rupture and dissection risk, material failure metric of the aortic wall needs to be accurately defined and determined. Previously such risk assessment methods have largely relied on deterministic or isotropic failure metric. In this study, we develop a novel probabilistic and anisotropic failure metric for risk stratification of ascending thoracic aortic aneurysm (ATAA). To this end, uniaxial tensile tests were performed using aortic tissue samples of 84 ATAA patients, from which a joint probability distribution of the anisotropic wall strengths was obtained. Next, the anisotropic failure probability (FP) based on the Tsai−Hill (TH) failure criterion was derived. The novel FP metric, which incorporates uncertainty in the anisotropic failure properties, can be evaluated after the aortic wall stresses are computed from patient-specific biomechanical analysis. For method validation, “ground-truth” risks of additional 41 ATAA patients were numerically-reconstructed using corresponding CT images and tissue testing data. Performance of different risk stratification methods (e.g., with and without patient-specific hyperelastic properties) was compared using p-value and receiver operating characteristic (ROC) curve. The results show that: (1) the probabilistic FP metric outperforms the deterministic TH metric; and (2) patient-specific hyperelastic properties can help to improve the performance of probabilistic FP metric in ATAA risk stratification.
Interconversion of unexpected thiol states affects stability, structure and dynamics in engineered antibody for site-specific conjugation
Authors: Orozco C. T. , Edgeworth M. J. , Devine P. W. A. , Hines A. R. , Cornwell O. , Wang X. , Phillips J. J. , Ravn P. , Jackson S. E. , Bond N. J.
Published: September 2020

Antibody drug conjugates have become one of the most actively developed classes of drugs in recent years. Their great potential comes from combining the strengths of large and small molecule therapeutics: the exquisite specificity of antibodies and the highly potent nature of cytotoxic compounds. More recently, the approach of engineering antibody drug conjugate scaffolds to achieve highly controlled drug to antibody ratios has focused on substituting or inserting cysteines to facilitate site-specific conjugation. Herein, we characterise an antibody scaffold engineered with an inserted cysteine that formed an unexpected disulfide bridge. A combination of mass spectrometry and biophysical techniques have been used to understand how the additional disulfide bridge forms, interconverts and changes the stability and structural dynamics of the antibody. Insight is gained into the local and global destabilisation associated with the engineering and subsequent disulfide bonded variant that will inform future engineering strategies.
A deep learning algorithm to translate and classify cardiac electrophysiology: From induced pluripotent stem cell-derived cardiomyocytes to adult cardiac cells
Authors: Aghasafari Parya , Yang Pei-Chi , Kernik Divya C. , Sakamoto Kauho , Kanda Yasunari , Kurokawa Junko , Vorobyov Igor , Clancy Colleen E.
Published: September 2020

The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability and immature phenotype of the iPSC-CM platform. It was trained using simulated action potential (AP) data and applied to classify cells into the drug-free and drugged categories and to predict the impact of electrophysiological perturbation across the continuum of aging from the immature iPSC-CMs to the adult ventricular myocytes. The phase of the AP extremely sensitive to perturbation due to a steep rise of the membrane resistance was found to contain the key information required for successful network multitasking. We also demonstrated successful translation of both experimental and simulated iPSC-CM AP data validating our network by prediction of experimental drug-induced effects on adult cardiomyocyte APs by the latter.
Identification of a unique ZIP transporter involved in zinc uptake via the arbuscular mycorrhizal fungal pathway
Authors: Watts-Williams Stephanie J , Wege Stefanie , Ramesh Sunita A , Berkowitz Oliver , Gilliham Matthew , Whelan James , Tyerman Stephen D
Published: September 2020

Low soil zinc (Zn) availability is a limiting factor for crop yield, and increasing Zn content is a major target for the biofortification of major crops. Arbuscular mycorrhizal (AM) fungi associate with the roots of most terrestrial plant species and improve the host plant’s growth and nutrition through the mycorrhizal pathway of nutrient uptake. Although the physiology of Zn uptake through the mycorrhizal pathway is well established, the identity of the molecular components responsible for Zn transport in the mycorrhizal pathway are unknown.

RNA-seq analysis identified the putative Zn transporter geneMtZIP14by its marked up-regulation inMedicago truncatularoots when colonised by the AM fungusRhizophagus irregularisunder varying soil Zn supply. Expression of GFP-tagged MtZIP14 in roots revealed that it is exclusively localised to the site of plant-fungal nutrient exchange in cortical cells, the peri-arbuscular membrane. Expression of MtZIP14 in a yeast mutant lacking Zn transport function restored growth under low Zn availability.M. truncatula MtZIP14loss-of-function mutants had reduced shoot biomass compared to the wild-type when colonised by AM fungi and grown under low Zn. Vesicular and arbuscular colonisation, but not hyphal colonisation, were also lower inmtzip14mutant plants.

Based on these results we propose that MtZIP14 plays a key role in the transport of Zn from AM fungus to plant across the peri-arbuscular membrane, andMtZIP14function is crucial to plant competitiveness in a low Zn soil.

Significance statement

Majority of crop plant species associate with arbuscular mycorrhizal fungi, which can increase plant nutrient uptake. Improving our knowledge of how Zn is taken up in mycorrhizal plants will lead to improved plant and human Zn nutrition outcomes. Here, we report a novel plant transporter with a major role in Zn nutrition of mycorrhizal plants. MtZIP14 is involved in Zn transport, is exclusively localised to the specialised plant-fungal interface in roots, and impairment ofMtZIP14gene function results in negative impacts on both plant growth and Zn nutrition.