bluuebunny/crossref_metadata_2025 huggingface dataset:
Nocardioides jishulii sp. nov.,isolated from faeces of Tibetan gazelle (Procapra picticaudata)
Authors: Dong Kui , Lu Shan , Yang Jing , Pu Ji , Lai Xin-He , Jin Dong , Li Junqin , Zhang Gui , Wang Xiaoxia , Liang Junrong , Tian Zhi , Zhang Sihui , Huang Yuyuan , Ge Yajun , Zhou Juan , Ren Zhihong , Wu Xiaomin , Huang Ying , Wang Suping , Xu Jianguo
Published: May 2020

Two novel Gram-stain-positive, irregular rod-shaped bacterial strains, dk3136Tand dk3543, were isolated from the faeces of Tibetan gazelle (Procapra picticaudata) in the Qinghai–Tibet Plateau of PR China. The cells were aerobic, oxidase-negative and catalase-positive. Colonies were yellowish, circular without any observable aerial mycelium after culturing at 28 ℃ for 3 days on brain–heart infusion (BHI) agar with 5 % sheep blood. The cells grew optimally at 28 °C, pH 7.5 and with 1 % (w/v) NaCl on BHI agar supplemented with 5 % sheep blood. Phylogenetic analysis of the 16S rRNA gene sequences revealed that their nearest phylogenetic relative wasNocardioides solisilvaeKa25T(97.9 % similarity). The results of 16S rRNA gene sequence and phylogenetic/phylogenomic analyses illustrated thatN. solisilvaeKa25T,Nocardioides gilvusXZ17T,Nocardioides houyundeii78TandNocardioides daphniaeD287Twere their nearest phylogenetic neighbours. The DNA G+C contents of strains dk3136Tand dk3543 were 70.3 mol% and 70.4 mol%, respectively. Their genomes exhibit lower than threshold (95–96 %) average nucleotide identity to known species of the genusNocardioides.ll-2,6-diaminopimelic acid was the diagnostic diamino acid and MK-8(H4) was the predominant respiratory quinone. The major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The two strains had C18 : 1ω9c,iso-C16 : 0and C17 : 1ω8cas the major fatty acids, and rhamnose and galactose as the main whole-cell sugars. On the basis of the results of our genotypic, phenotypic and biochemical analyses, we conclude that strains dk3136Tand dk3543 represent a novel species in genusNocardioides, for which the nameNocardioides jishuliisp. nov. is proposed. The type strain is dk3136T(=CGMCC 4.7570T=JCM 33496T=KCTC 49314T).
Glaesserella australis sp. nov., isolated from the lungs of pigs
Authors: Turni Conny , Wu Yunchen , Omaleki Lida , Giang Nhan , Blackall P.J. , Christensen Henrik
Published: May 2020

Twenty-nine isolates of an unknown haemophilic organism were isolated from the lungs of pigs from 14 farms in Australia. Phylogenetic analyses based on the 16S rRNA gene,recNandrpoAshowed a monophyletic group that was most closely related toGlaesserella parasuisand [Actinobacillus]indolicus. Whole genome sequence analysis indicated that theGlaesserella parasuisand this group, using the type strain HS4635Tfor comparison, showed a similarity of 30.9 % DNA–DNA renaturation. The isolates were Gram-stain-negative, NAD-dependent, CAMP-negative and were oxidase-positive, catalase-negative and produced indole but not urease. The isolates could be separated from all currently recognized haemophilic and non-haemophilic members of the familyPastuerellaceae. Key phenotypic properties were the production of indole, the lack of urease activity, production of β-galactosidase but not α-fucosidase, acid formation from (−)-d-arabinose, (+)-d-galactose, maltose and trehalose and a failure to produce acid from (−)-d-mannitol. Taken together, these data indicate that the isolates belong to a novel species for which the nameGlaesserella australissp. nov. is proposed. The type strain is HS4635T(=CCUG 71931Tand LMG 30645T).
Novel yeast taxa from the cold: description of Cryolevonia giraudoae sp. nov. and Camptobasidium gelus sp. nov.
Authors: de Garcia Virginia , Trochine Andrea , Uetake Jun , Bellora Nicolas , Libkind Diego
Published: May 2020

Twenty-one psychrophilic yeast isolates related to theCamptobasidiaceaefamily in theMicrobotryomycetesclass were obtained from ice collected from cold environments worldwide. A new psychrophilic species from the recently described genusCryolevonia, Cryolevania giraudoaeis proposed to accommodate 18 isolates from Patagonia (Argentina) and Antarctica (holotype CRUB 2086T). In addition, a new psychrophilic species in the genusCamptobasidiumis described asCamptobasidium gelussp. nov. (holotype CBS 8941T), based on three isolates from glacial ice in the Russel glacier (Greenland ice sheet) and Antarctica. The strict psychrophilic profile is the salient feature of both novel species.
Using a mouse-adapted A/HK/01/68 influenza virus to analyse the impact of NS1 evolution in codons 196 and 231 on viral replication and virulence
Authors: Eiden Sebastian , Dijkman Ronald , Zell Roland , Fuchs Jonas , Kochs Georg
Published: May 2020

Seasonal influenza viruses circulating between 1918 and 2009 harboured two prevalent genetic variations in the NS1 coding region. A glutamic acid (E)-to-lysine (K) exchange at position 196 was reported to diminish the capacity of NS1 to control interferon induction. Furthermore, alterations at position 231 determine a carboxy-terminal extension of seven amino acids from 230 to 237 residues. Sequence analyses of NS1 of the last 90 years suggest that variations at these two positions are functionally linked. To determine the impact of the two positions on viral replicationin vivo, we used a mouse-adapted variant of A/Hong Kong/01/68 (maHK68) (H3N2). maHK68 encodes an NS1 of 237 amino acids with lysine at position 196. A panel of recombinant maHK68 viruses was generated encoding NS1 variants that differed at positions 196 and 231. Our analyses showed a clear effect of the K-196-to-E exchange on interferon induction and virus virulence. These effects were further modulated by the loss of the seven-amino-acid extension. We propose that the combination of NS1 E-196 with the short C-terminal variant conferred a fitness advantage that is reflected by increased virulencein vivo. Notably, this particular NS1 constellation was observed for the pandemic 1918 H1N1 virus.
Functional analysis of the baculovirus per os infectivity factors 3 and 9 by imaging the interaction between fluorescently labelled virions and isolated midgut cells
Authors: Boogaard Bob , van Lent Jan W. M. , van Oers Monique M.
Published: May 2020

Baculovirus occlusion-derived viruses (ODVs) contain ten known per os infectivity factors (PIFs). These PIFs are crucial for midgut infection of insect larvae and form, with the exception of PIF5, an ODV entry complex. Previously, R18-dequenching assays have shown that PIF3 is dispensable for binding and fusion with midgut epithelial cells. Oral infection nevertheless fails in the absence of PIF3. PIF9 has not been analysed in much depth yet. Here, the biological role of these two PIFs in midgut infection was examined by monitoring the fate of fluorescently labelled ODVs when incubated with isolated midgut cells from Spodoptera exigua larvae. Confocal microscopy showed that in the absence of either PIF3 or PIF9, the ODVs bound to the brush borders, but the nucleocapsids failed to enter the cells. Finally, we discuss how the results obtained for PIF3 with dequenching assays and confocal microscopy can be explained by a two-phase fusion process.
The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential for reinfection
Authors: Kellam Paul , Barclay Wendy
Published: May 2020

SARS-CoV-2 is a novel coronavirus that is the causative agent of coronavirus infectious disease 2019 (COVID-19). As of 17 April 2020, it has infected 2 114 269 people, resulting in 145 144 deaths. The timing, magnitude and longevity of humoral immunity is not yet understood for SARS-CoV-2. Nevertheless, understanding this is urgently required to inform the likely future dynamics of the pandemic, to guide strategies to allow relaxation of social distancing measures and to understand how to deploy limiting vaccine doses when they become available to achieve maximum impact. SARS-CoV-2 is the seventh human coronavirus to be described. Four human coronaviruses circulate seasonally and cause common colds. Two other coronaviruses, SARS and MERS, have crossed from animal sources into humans but have not become endemic. Here we review what is known about the human humoral immune response to epidemic SARS CoV and MERS CoV and to the seasonal, endemic coronaviruses. Then we summarize recent, mostly non-peer reviewed, studies into SARS-CoV-2 serology and reinfection in humans and non-human primates and summarize current pressing research needs.
Computational genomic discovery of diverse gene clusters harbouring Fe-S flavoenzymes in anaerobic gut microbiota
Authors: Pascal Andreu Victòria , Fischbach Michael A. , Medema Marnix H.
Published: May 2020

The gut contains an enormous diversity of simple as well as complex molecules from highly diverse food sources, together with host-secreted molecules. This presents a large metabolic opportunity for the gut microbiota, but little is known about how gut microbes are able to catabolize this large chemical diversity. Recently, Fe-S flavoenzymes were found to be key in the transformation of bile acids, catalysing the key step in the 7α-dehydroxylation pathway that allows gut bacteria to transform cholic acid into deoxycholic acid, an exclusively microbe-derived molecule with major implications for human health. While this enzyme family has also been implicated in a limited number of other catalytic transformations, little is known about the extent to which it is of more global importance in gut microbial metabolism. Here, we perform a large-scale computational genomic analysis to show that this enzyme superfamily has undergone a remarkable expansion in Clostridiales, and occurs throughout a diverse array of >1000 different families of putative metabolic gene clusters. Analysis of the enzyme content of these gene clusters suggests that they encode pathways with a wide range of predicted substrate classes, including saccharides, amino acids/peptides and lipids. Altogether, these results indicate a potentially important role of this protein superfamily in the human gut, and our dataset provides significant opportunities for the discovery of novel pathways that may have significant effects on human health.
Nutrient-dependent morphological variability of Bacteroides thetaiotaomicron
Authors: Rangarajan Aathmaja Anandhi , Koropatkin Nicole M. , Biteen Julie S.
Published: May 2020

Unique morphologies can enable bacteria to survive in their native environment. Furthermore, many bacteria change their cell shape to adapt to different environmental conditions. For instance, some bacteria increase their surface area under carbon or nitrogen starvation. Bacteriodes thetaiotaomicron is an abundant human gut species; it efficiently degrades a number of carbohydrates and also supports the growth of other bacteria by breaking down complex polysaccharides. The gut provides a variable environment as nutrient availability is subject to the diet and health of the host, yet how gut bacteria adapt and change their morphologies under different nutrient conditions has not been studied. Here, for the first time, we report an elongated

B. thetaiotaomicron

morphology under sugar-limited conditions using live-cell imaging; this elongated morphology is enhanced in the presence of sodium bicarbonate. Similarly, we also observed that sodium bicarbonate produces an elongated-length phenotype in another Gram-negative gut bacterium,

Escherichia coli

. The increase in cell length might provide an adaptive advantage for cells to survive under nutrient-limited conditions.
Visual statistical learning and integration of perceptual priors are intact in Attention Deficit Hyperactivity Disorder
Authors: Richards Katie L. , Karvelis Povilas , Lawrie Stephen M. , Seriès Peggy
Published: May 2020

Deficits in statistical learning and predictive processing could in principle explain inattention and distractibility in attention deficit hyperactivity disorder (ADHD).

To test this, we evaluated whether adults diagnosed with ADHD (n = 17) differed from controls (n = 30) in implicitly learning and using low-level perceptual priors to guide sensory processing. We used a visual statistical learning task in which participants had to estimate the direction of coherently moving dots. Unbeknown to the participants, two directions were more frequently presented than the others, creating an implicit bias (prior) towards those directions. This task had previously revealed differences in autistic spectrum disorder and schizophrenia.

Both groups acquired the prior expectations for the most frequent directions and, except for some subtle differences over time, there were no group difference in how much the priors influenced performance. This suggests that ADHD symptoms do not stem from difficulties in developing and/or using perceptual priors.

Statement of Relevance

Schizophrenia, autistic spectrum disorder (ASD), and more recently anxiety and depression have all been described in terms of disturbances in predictive coding or Bayesian inference – a general mechanism for how incoming sensory information is integrated with prior knowledge and how such prior knowledge is learnt. In theory, Attention deficit hyperactivity disorder (ADHD) is also associated with a range of sensory processing differences that could be understood within the Bayesian inference framework. However, to our knowledge, there has been no experimental work explicitly testing differences in Bayesian inference in ADHD so far.

Here we found the acquisition and use of the low-level perceptual priors to be intact in ADHD, compared to controls.

Our study shows for the first time that the learning and use of low-level Bayesian priors are not impaired in ADHD, contrary to what has been described in other neurodevelopmental disorders.
Childhood-onset of primary Sjogren syndrome Phenotypic characterization at diagnosis of 158 children
Authors: Ramos-Casals Manuel , Acar-Denizli Nihan , Vissink Arjan , Brito-Zerón Pilar , Li Xiaomei , Carubbi Francesco , Priori Roberta , Toplak Nataša , Baldini Chiara , Faugier-Fuentes Enrique , Kruize Aike A. , Mandl Thomas , Tomiita Minako , Gandolfo Saviana , Hashimoto Kunio , Hernandez-Molina Gabriela , Hofauer Benedikt , Mendieta-Zerón Samara , Rasmussen Astrid , Sandhya Pulukool , Sene Damien , Trevisani Virginia Fernandes Moça , Isenberg David , Sundberg Erik , Pasoto Sandra G. , Sebastian Agata , Suzuki Yasunori , Retamozo Soledad , Xu Bei , Giacomelli Roberto , Gattamelata Angelica , Bizjak Masa , Bombardieri Stefano , Loor-Chavez Richard-Eduardo , van der Heijden Eefje , Olsson Peter , Bootsma Hendrika , Lieberman Scott M. ,   the Sjogren Big Data Consortium
Published: May 2020

OBJECTIVES. To characterize the phenotypic presentation at diagnosis of childhood-onset primary Sjogren syndrome (SjS).
METHODS. The Big Data Sjogren Project Consortium is an international, multicentre registry using worldwide data-sharing cooperative merging of pre-existing clinical SjS databases from the five continents. For this study, we selected those patients in whom the disease was diagnosed below the age of 19 according to the fulfilment of the 2002/2016 classification criteria.
RESULTS. Among the 12,083 patients included in the Sjogren Big Data Registry, 158 (1.3%) patients had a childhood-onset diagnosis (136 girls, mean age of 14.2 years): 126 (80%) reported dry mouth, 111 (70%) dry eyes, 52 (33%) parotid enlargement, 118/122 (97%) positive minor salivary gland biopsy and 60/64 (94%) abnormal salivary US study, 140/155 (90%) positive ANA, 138/156 (89%) anti-Ro/La antibodies and 86/142 (68%) positive RF. The systemic ESSDAI domains containing the highest frequencies of active patients included the glandular (47%), articular (26%) and lymphadenopathy (25%) domains. Patients with childhood-onset primary SjS showed the highest mean ESSDAI score and the highest frequencies of systemic disease in 5 (constitutional, lymphadenopathy, glandular, cutaneous and haematological) of the 12 ESSDAI domains, and the lowest frequencies in 4 (articular, pulmonary, peripheral nerve and central nervous system) in comparison with patients with adult-onset disease.
CONCLUSIONS. Childhood-onset primary SjS involves around 1% of patients with primary SjS, with a clinical phenotype dominated by sicca features, parotid enlargement and systemic disease. Age at diagnosis plays a key role on modulating the phenotypic expression of the disease.
Multilevel Integrated Model with a Novel Systems Approach (MIMANSA) for Simulating the Spread of COVID-19
Authors: Welling Arpita , Patel Abhilasha , Kulkarni Padmaj , Vaidya Vinay G.
Published: May 2020

Due to the spread of the coronavirus, public health officials grapple with multiple issues such as recommending a lockdown, contact tracing, promoting the use of masks, social distancing, frequent handwashing, as well as quarantining. It is even more challenging to find the optimal combination of these factors without the use of a suitable mathematical model.

In this paper, we discuss a novel systems approach to building a model for simulating the spread of COVID-19. The model, MIMANSA, divides an individual’s in-person social interactions into three areas, namely home, workplace, and public places. The model tracks the in-person interactions and follows the virus spread. When a new silent carrier is created, the model automatically expands and builds a new layer in the network.

MIMANSA has four control mechanisms, namely the exposure, infection rate, lockdown, and quarantining. MIMANSA differentiates between virus-infected patients, silent carriers, and healthy carriers. It can consider variations in virus activity levels of asymptomatic patients, varying the exposure to the virus, and varying the infection rate depending on the person’s immunity. MIMANSA can simulate scenarios to study the impact of many different conditions simultaneously. It could assist public health officials in complex decision making, enable scientists in projecting the SARS-CoV-2 virus spread and aid hospital administrators in the management of beds and equipment.

MIMANSA is trained and validated using the data from the USA and India. Our results show that MIMANSA forecasts the number of COVID-19 cases in the USA, and India within a 3% margin of error.
Atrophy of the Nucleus Basalis of Meynert predicts the progression of gait variability in Parkinson’s disease
Authors: Wilkins Kevin B. , Parker Jordan E. , Bronte-Stewart Helen M.
Published: May 2020

Parkinson’s disease (PD) is a systemic brain disorder where the cortical cholinergic network begins to degenerate early in the disease process. Readily accessible, quantitative, and specific behavioral markers of the cortical cholinergic network are lacking. Although degeneration of the dopaminergic network may be responsible for deficits in cardinal motor signs, the control of gait is a complex process and control of higher-order aspects of gait, such as gait variability, may be influenced by cognitive processes attributed to cholinergic networks. We investigated whether swing time variability, a metric of gait variability that is independent from gait speed, was a quantitative behavioral marker of cortical cholinergic network integrity in PD. Twenty-two individuals with PD and twenty-nine age-matched controls performed a validated stepping-in-place (SIP) task to assess swing time variability off all therapy. The PD cohort also underwent structural MRI scans to measure gray matter volume of the Nucleus Basalis of Meynert (NBM), the key node in the cortical cholinergic network. Swing time variability was also measured ON subthalamic nucleus (STN) deep brain stimulation (DBS) in PD individuals. A subset of eleven individuals with PD completed the SIP task again off all therapy after three years of continuous DBS. Clinical motor assessments were performed for each condition. Swing time variability was significantly greater (i.e., worse) in PD compared to controls and greater swing time variability was related to greater atrophy of the NBM. STN DBS significantly improved cardinal motor signs but did not improve swing time variability. Swing time variability worsened in PD, off therapy, after three years of continuous STN DBS, and NBM atrophy predicted the degree of increase. In contrast, cardinal motor signs did not progress. These results demonstrate that swing time variability is a reliable marker of cortical cholinergic health, and support a framework in which higher-order aspects of gait control in PD are reliant on the cortical cholinergic system, in contrast to other motor aspects of PD that rely on the dopaminergic network.
Physics of Virus Transmission by Speaking Droplets
Authors: Eaton William A , Bax Adriaan , Netz Roland R
Published: May 2020

Droplets of oral fluid emitted by speaking are a long-recognized mechanism of respiratory virus transmission. While there have been many simulations of droplet evaporation to determine whether droplets containing virions remain floating in air or rapidly fall to the ground, they typically conceal the fundamental mechanisms because of the use of numerics. To make the physics of emitted oral fluid droplets easily understood, we present simple and transparent algebraic equations that capture the essential physics of the problem. Calculations with these equations provide a straightforward way to determine the airborne lifetime of emitted droplets after accounting for the decrease in droplet size from water evaporation. At a relative humidity of 50%, droplets with initial radii larger than about 50 microns rapidly fall to the ground while smaller, potentially-virus containing droplets shrink in size and remain airborne for many minutes. Rough estimates of airborne virion emission rates while speaking support the proposal that covering the mouth can help end the pandemic more quickly.
SARS pandemic exposure impaired early childhood development: A lesson for COVID-19
Authors: Fan Yunfei , Wang Huiyu , Wu Qiong , Zhou Xiang , Zhou Yubo , Wang Bin , Han Yiqun , xue Tao , Zhu Tong
Published: May 2020

Social and mental stressors associated with the COVID-19 pandemic may promote long-term effects on child development. However, reports aimed at identifying the relationship between pandemics and child health are limited. We conducted a retrospective study to evaluate the severe acute respiratory syndrome (SARS) pandemic in 2003 and its relationship to child development indicators using a representative sample across China. Our study involved longitudinal measurements of 14,647 children, 36% of whom (n = 5216) were born before or during the SARS pandemic. Cox models were utilized to examine the effects of SARS on preterm birth and four milestones of development: age to (1) walk independently, (2) say a complete sentence, (3) count from 0 to 10, and (4) undress him/herself for urination. Mixed effect models were utilized to associate SARS with birthweight, body weight and height. Our results show that experiencing SARS during early childhood was significantly associated with delayed milestones, with adjusted hazard ratios of 3.17 [95% confidence intervals (CI): 2.71, 3.70], 3.98 (3.50, 4.53), 4.96 (4.48, 5.49), or 5.57 (5.00, 6.20) for walking independently, saying a complete sentence, counting from 0 to 10, and undressing him/herself for urination, respectively. Experiencing SARS was also associated with reduced body weight. This effect was strongest for preschool children [a weight reduction of 4.86 (0.36, 9.35) kg, 5.48 (-0.56, 11.53) kg or 5.09 (-2.12, 12.30) kg for 2, 3, 4 year-olds, respectively]. We did not identify a significant effect of maternal SARS exposure on birthweight or gestational length. Collectively, our results showed that the SARS pandemic was associated with delayed child development and provided epidemiological evidence to support the association between infectious disease epidemics and impaired child health. These results provide a useful framework to investigate and mitigate relevant impacts from the COVID-19 pandemic.
Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates
Authors: Pons-Faudoa Fernanda P. , Sizovs Antons , Shelton Kathryn A. , Momin Zoha , Bushman Lane R. , Xu Jiaqiong , Chua Corrine Ying Xuan , Nichols Joan E. , Hawkins Trevor , Rooney James F. , Marzinke Mark A. , Kimata Jason T. , Anderson Peter L. , Nehete Pramod N. , Arduino Roberto C. , Ferrari Mauro , Sastry K. Jagannadha , Grattoni Alessandro
Published: May 2020

Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 fmol/106peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIVSF162P3challenge, the nTAF cohort had a 62.50% reduction (95% CI: 1.72% to 85.69%;p=0.068) in risk of infection per exposure compared to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60.00% protective efficacy was observed in macaques, and clinically, 67.00% reduction in risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.
DCI: Learning Causal Differences between Gene Regulatory Networks
Authors: Belyaeva Anastasiya , Squires Chandler , Uhler Caroline
Published: May 2020

Designing interventions to control gene regulation necessitates modeling a gene regulatory network by a causal graph. Currently, large-scale expression datasets from different conditions, cell types, disease states and developmental time points are being collected. However, application of classical causal inference algorithms to infer gene regulatory networks based on such data is still challenging, requiring high sample sizes and computational resources. Here, we propose an algorithm that efficiently learns the differences in gene regulatory mechanisms between different conditions. Our difference causal inference (DCI) algorithm infers changes (i.e., edges that appeared, disappeared or changed weight) between two causal graphs given gene expression data from the two conditions. This algorithm is efficient in its use of samples and computation since it infers the differences between causal graphs directly without estimating each possibly large causal graph separately. We provide a user-friendly Python implementation of DCI and also enable the user to learn the most robust difference causal graph across different tuning parameters via stability selection. Finally, we show how to apply DCI to bulk and single-cell RNA-seq data from different conditions and cell states, and we also validate our algorithm by predicting the effects of interventions.

Availability and implementation

All algorithms are freely available as a Python package athttp://uhlerlab.github.io/causaldag/dci

Contact

cuhler@mit.edu
A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin-associated histone modifications
Authors: Levine Morgan , McDevitt Ross , Meer Margarita , Perdue Kathy , Di Francesco Andrea , Meade Theresa , Farrell Colin , Thrush Kyra , Wang Meng , Dunn Christopher , Pellegrini Matteo , de Cabo Rafael , Ferrucci Luigi
Published: May 2020

Aging has been shown to be a strong driver of DNA methylation changes, leading to the development of robust biomarkers in humans and more recently, in mice. This study aimed to generate a novel epigenetic clock in rats—a model with unique physical, physiological, and biochemical advantages for studying mammalian aging. Additionally, we incorporated behavioral data, unsupervised machine learning, and network analysis to identify epigenetic signals that not only track with age, but also relate to phenotypic aging and reflect higher-order molecular aging changes. We used DNAm data from reduced representation bisulfite sequencing (RRBS) to train an epigenetic age (DNAmAge) measure in Fischer 344 CDF (F344) rats. In an independent sample of n=32 F344 rats, we found that this measure correlated with age at (r=0.93), and related to physical functioning (5.9e-3), after adjusting for age and differential cell counts. DNAmAge was also found to correlate with age in C57BL/6 mice (r=0.79), and was decreased in response to caloric restriction (CR), such that the longer the animal was on a CR diet, the greater the decrease in DNAm. We also observed resetting of DNAm when kidney and lung fibroblasts when converted to induced pluripotent stem cells (iPSCs). Using weighted gene correlation network analysis (WGCNA) we identified two modules that appeared to drive our DNAmAge measure. These two modules contained CpGs in intergenic regions that showed substantial overlap with histone marks H3K9me3, H3K27me3, and E2F1 transcriptional factor binding. In moving forward, our ability to unravel the complex signals linking DNA methylation changes to functional aging would require experimental studies in model systems in which longitudinal epigenetic changes can be related to other molecular and physiological hallmarks of aging.
Chest MRI of patients with COVID-19: a retrospective case study
Authors: Vasilev Yu.A. , Sergunova K.A. , Bazhin A.V. , Masri A.G. , Vasileva Yu.N. , Semenov D.S. , Kudryavtsev N.D. , Panina O.Yu. , Khoruzhaya A.N. , Zinchenko V.V. , Akhmad E.S. , Petraikin A.V. , Vladzymyrskyy A.V. , Midaev A.V. , Morozov S.P.
Published: May 2020

During the pandemic of COVID-19, computed tomography showed its effectiveness in diagnosis of coronavirus infection. However, ionizing radiation during CT studies causes concern for patients who require dynamic observation, as well as for examination of children and young people. For this retrospective study, we included 15 suspected for COVID-19 patients who were hospitalized in April 2020, Russia. There were 4 adults with positive polymerase chain reaction (PCR) test for COVID-19. All patients underwent MRI examinations using MR-LUND PROTOCOL: Single-shot Fast Spin Echo (SSFSE), LAVA 3D and IDEAL 3D, EPI diffusion-weighted imaging (DWI) and Fast Spin Echo (FSE) T2WI without using respiratory or any other trigger. 3 patients also had CT scan performed. In 5 (33,3%) patients, detected lesioins were visualized on T2WI and DWI simultaneously. At the same time, 4 (26.7%) patients revealed lung tissue changes only on T2WI (P(McNemar)= 0,125, OR= 0,00 (95%), kappa=0,500). Pulmonary changes on MRI were also analyzed depending on their localization. In those patients who had CT scan, the changes were comparable to MRI. MRI of the lungs can detect features of viral pneumonia and assess severity of lung damage. The method can be used to diagnose COVID-19. These data may be applicable for interpreting other studies, such as thoracic spine MRI, detecting signs of viral pneumonia of asymptomatic patients. The current study was limited by a small sample size and absence of chest CT scans of all patients.
COVID-19 healthcare demand projections: Arizona
Authors: Gel Esma S. , Jehn Megan , Lant Timothy , Muldoon Anna R. , Nelson Trisalyn , Ross Heather M.
Published: May 2020

Beginning in March 2020, the United States emerged as the global epicenter for COVID-19 cases. In the ensuing weeks, American jurisdictions attempted to manage disease spread on a regional basis using non-pharmaceutical interventions (i.e., social distancing), as uneven disease burden across the expansive geography of the United States exerted different implications for policy management in different regions. While Arizona policymakers relied initially on state-by-state national modeling projections from different groups outside of the state, we sought to create a state-specific model using a mathematical framework that ties disease surveillance with the future burden on Arizona’s healthcare system. Our framework uses a compartmental system dynamics model using a SEIRD framework that accounts for multiple types of disease manifestations for the COVID-19 infection, as well as the observed time delay in epidemiological findings following public policy enactments. We use a bin initialization logic coupled with a fitting technique to construct projections for key metrics to guide public health policy, including exposures, infections, hospitalizations, and deaths under a variety of social reopening scenarios.
Improved survival outcome in SARs-CoV-2 (COVID-19) Acute Respiratory Distress Syndrome patients with Tocilizumab administration
Authors: Wadud Nafisa , Ahmed Naim , Mannu Shergil Mannu , Khan Maida , Krishna Murali G , Gilani Aamir , El Zarif Samer , Galaydick Jodi , Linga Karthika , Koor Shravan , Galea Julia , Stuczynski Lauren , Osundele Maria B
Published: May 2020

ABSTRACT
Background:
The novel human coronavirus, severe acute respiratory syndrome coronavirus-2 (SARs-CoV-2), was declared a global pandemic by the World Health Organization on March 11, 2020. Hence, there is an urgency to find effective treatment. Of those patients afflicted in the United States, many have required treatment with ventilator secondary to acute respiratory distress syndrome (ARDS). Data are needed regarding the benefit of treatment and prevention of the cytokine storms in COVID-19 patients with Tocilizumab.

Methods:
Clinical outcomes data for patients admitted to Orange Regional Medical Center with confirmed COVID-19 from Mar 15, 2020 to Apr 20, 2020 were identified through electronic health record chart review. We conducted a retrospective case-control study in confirmed COVID 19 positive patients with ARDS requiring mechanical ventilation and compared outcome in terms of mortality and length of stay amongst those who received Tocilizumab as treatment modality opposed to those that did not.

Results:
A total of 94 patients with COVID-19 ARDS were analyzed. 44 were in the study group and 50 in the control group. We tried to match both group as close as possible in terms of age, sex, BMI and HS score- calculated using inflammatory markers- ferritin, triglycerides, AST and fibrinogen. The median age was 55.5 years in the study group and 66 in the control group, difference was not statistically significant. Average HS score was 114 in the Tocilizumab group and 92 in the control group, difference was statistically significant with P<0.0001. Also, the patients in the study group had elevated levels of IL-6, triglycerides, AST, ferritin which were statistically significant with p < 0.0001 when compared to the control group. Length of stay was longer, average 17.9 days in the Tocilizumab. Survival rate was much lower at 48 % in the control group and 61.36 % in patients who received Tocilizumab with significant P value of < 0.00001. The number needed to treat (NNT) was 7.48, if we treat 8 patients with Tocilizumab, 1 will not die.

Conclusions:
Cytokine Release Syndrome (CRS) occurs in a large number of patients with severe COVID-19, which is also an important cause of death. IL- 6 is the key molecule of CRS, so IL-6R antagonist Tocilizumab may be of value in improving outcomes. In our study Tocilizumab group seemed to have improved survival outcome. Results have to be interpreted with caution since this is a retrospective study and mortality is affected by multiple, confounding factors. We await the results of ongoing randomized controlled trials to definitely answer the question of whether Tocilizumab improves survival in COVID-19 ARDS patients.
Association of national Bacille Calmette-Guérin vaccination policy with COVID-19 epidemiology: an ecological study in 78 countries
Authors: Kuratani Norifumi
Published: May 2020

A possible association between national Bacille Calmette-Guérin (BCG) vaccination policy and lower COVID-19 incidence has been suggested in some preprint papers. Using publicly accessible databases, I explored associations of national BCG vaccination policy with COVID-19 epidemiology in 78 countries. Data collection was conducted from April 25 to May 5, 2020. I compared countries that have a current universal BCG vaccination policy (BCG countries), with countries that currently lack such a policy (non-BCG countries). The mixed effect model revealed national BCG policy decreases in the country-specific risk of death by COVID-19, correspond to odds ratio of 0.446 (95% confidence intervals 0.323 - 0.614, P =1×10-5). In BCG countries, the case increase rate was attenuated marginally by 25.4% (95% CI 3.0 to 42.7, P=0.029) as compared with those of the non-BCG countries. Although the protective mechanism of BCG vaccination against COVID-19 remains unknown, further laboratory and clinical research should be warranted.
Measuring brain integrity using MRI: a novel biomarker for Alzheimer’s disease using T2 relaxometry
Authors: Wearn Alfie R. , Nurdal Volkan , Saunders-Jennings Esther , Knight Michael J. , Isotalus Hanna K. , Dillon Serena , Tsivos Demitra , Kauppinen Risto A. , Coulthard Elizabeth J.
Published: May 2020

Early Alzheimer’s disease diagnosis is vital for development of disease-modifying therapies. Prior to significant loss of brain tissue, several microstructural changes take place as a result of Alzheimer’s pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. The different factors that affect T2 may cause it to increase, as in the case of free water, or decrease, as in the case of iron, amyloid and tau. Thus, tissue affected by early Alzheimer’s disease could become more heterogeneous yet show no change in average T2. We hypothesise that T2 heterogeneity in regions affected early in Alzheimer’s disease (hippocampus and thalamus) may present a sensitive early marker of microstructural changes in Alzheimer’s disease.

In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a diagnosis of Alzheimer’s disease. All participants underwent structural MRI including multi-echo sequence for assessing quantitative T2. Cognitive change over one year was assessed in participants with MCI. Hippocampus and thalamus were automatically masked using ASHS and Freesurfer, respectively. T2 distributions were modelled using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ).

We show an increase in heterogeneity (T2σ; p<.0001) in MCI compared to healthy controls, which was not seen with midpoint (T2μ; p=.149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over one year in MCI participants (p=.018), but midpoint (p=.132) and volume (p=.315) did not. Age affects T2, but the effects described here are significant even after correcting for age.

We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in prodromal Alzheimer’s disease. We describe a new model that takes into account the competing effects of factors that both increase and decrease T2. These two opposing forces act in opposition and mean that previous human literature focusing on midpoint T2 has obscured the true potential of T2 as an early marker of Alzheimer’s disease. In fact, T2 heterogeneity outperforms midpoint and volumetry in predicting cognitive decline in those with MCI. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of Alzheimer’s disease.
Derivation and validation of a prognostic model for predicting in-hospital mortality in patients admitted with COVID-19 in Wuhan, China: the PLANS (Platelet Lymphocyte Age Neutrophil Sex) model
Authors: Li Jiong , Chen Yuntao , Chen Shujing , Wang Sihua , Zhang Dingyu , Wang Junfeng , Postmus Douwe , Zeng Hesong , Qin Guoyou , Shen Yin , Jiang Jinjun , Yu Yongfu
Published: May 2020

OBJECTIVE

To develop and validate a prognostic model for in-hospital mortality in COVID-19 patients using routinely collected demographic and clinical characteristics.

DESIGN

Multicenter, retrospective cohort study.

SETTING

Jinyintan Hospital, Union Hospital, and Tongji Hosptial in Wuhan, China.

PARTICIPANTS

A pooled derivation cohort of 1008 COVID-19 patients from Jinyintan Hospital, Union Hospital in Wuhan and an external validation cohort of 1031 patients from Tongji Hospital in Wuhan, China.

MAIN OUTCOME MEASURES

Outcome of interest was in-hospital mortality, treating discharged alive from hospital as the competing event. Fine-Gray models, using backward elimination for inclusion of predictor variables and allowing non-linear effects of continuous variables, were used to derive a prognostic model for predicting in-hospital mortality among COVID-19 patients. Internal validation was implemented to check model overfitting using bootstrap approach. External validation to a separate hospital was implemented to evaluate the generalizability of the model.

RESULTS

The derivation cohort was a case-mix of mild-to-severe hospitalized COVID-19 patients (n=1008, 43.6% females, median age 55). The final model (PLANS), including five predictor variables of platelet count, lymphocyte count, age, neutrophil count, and sex, had an excellent predictive performance (optimism-adjusted C-index: 0.85, 95% CI: 0.83 to 0.87; averaged calibration slope: 0.95, 95% CI: 0.82 to 1.08). Internal validation showed little overfitting. External validation using an independent cohort (n=1031, 47.8% female, median age 63) demonstrated excellent predictive performance (C-index: 0.87, 95% CI: 0.85 to 0.89; calibration slope: 1.02, 95% CI: 0.92 to 1.12). The averaged predicted survival curves were close to the observed survival curves across patients with different risk profiles.

CONCLUSIONS

The PLANS model based on the five routinely collected demographic and clinical characteristics (platelet count, lymphocyte count, age, neutrophil count, and sex) showed excellent discriminative and calibration accuracy in predicting in-hospital mortality in COVID-19 patients. This prognostic model would assist clinicians in better triaging patients and allocating healthcare resources to reduce COVID-19 fatality.
The SARS-CoV-2 T-cell immunity is directed against the spike, membrane, and nucleocapsid protein and associated with COVID 19 severity
Authors: Thieme Constantin J , Anft Moritz , Paniskaki Krystallenia , Blazquez-Navarro Arturo , Doevelaar Adrian , Seibert Felix S , Hoelzer Bodo , Konik Margarethe Justine , Brenner Thorsten , Tempfer Clemens , Watzl Carsten , Dolff Sebastian , Dittmer Ulf , Westhoff Timm H. , Witzke Oliver , Stervbo Ulrik , Roch Toralf , Babel Nina
Published: May 2020

Identification of immunogenic targets of SARS-CoV-2 is crucial for monitoring of antiviral immunity and vaccine design. Currently, mainly anti-spike (S)-protein adaptive immunity is investigated. However, also the nucleocapsid (N)- and membrane (M)-proteins should be considered as diagnostic and prophylactic targets.
The aim of our study was to explore and compare the immunogenicity of SARS-CoV-2 S-, M- and N-proteins in context of different COVID-19 manifestations. Analyzing a cohort of COVID-19 patients with moderate, severe, and critical disease severity, we show that overlapping peptide pools (OPP) of all three proteins can activate SARS-CoV-2-reactive T-cells with a stronger response of CD4+ compared to CD8+ T-cells. Although interindividual variations for the three proteins were observed, M protein induced the highest frequencies of CD4+ T-cells, suggesting its relevance as diagnostic and vaccination target. Importantly, patients with critical COVID-19 demonstrated the strongest T-cell response, including the highest frequencies of cytokine-producing bi- and trifunctional T-cells, for all three proteins. Although the higher magnitude and superior functionality of SARS-CoV-2-reactive T-cells in critical patients can also be a result of a stronger immunogenicity provided by severe infection, it disproves the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. To this end, activation of effector T-cells with differentiated memory phenotype found in our study could cause hyper-reactive response in critical cases leading to immunopathogenesis.
Conclusively, since the S-, M-, and N-proteins induce T-cell responses with individual differences, all three proteins should be evaluated for diagnostics and therapeutic strategies to avoid underestimation of cellular immunity and to deepen our understanding of COVID-19 immunity.
National estimates of critical care capacity in 54 African countries
Authors: Craig Jessica , Kalanxhi Erta , Hauck Stephanie
Published: May 2020

The COVID-19 pandemic is an emerging threat across the African continent where critical care capacity is underdeveloped or unknown. In this paper, we describe national critical care capacity including number of ICU beds, number of ventilators, and number of physician and non-physician anesthesia providers for 54 African countries. Data was compiled from a variety of resources including World Bank databases, local and international news media, government reports, local healthcare workers, and published scientific literature. Overall, data on number of physicians, hospital beds, and ICU beds were available for over 90% of countries. Data on number of ventilators, number of physician anesthesia providers (PAP) and non-PAP were available for 46 (85%), 47 (87%) and 37 (69%) countries, respectively. Across all 54 countries included in the analysis, there was an average of 3.10 ICU beds and 0.97 ventilators per 100,000 people, and an average of 2.42 total (physician and non-physician) anesthesia providers per 100,000 people. The purpose of this analysis was to fill in knowledge gaps around current critical care capacity across the African continent and to inform national, regional, and international pandemic preparation and response efforts.