bluuebunny/crossref_metadata_2025 huggingface dataset:
To what extent is severe osteoarthritis preventable? Occupational and non-occupational risk factors for knee and hip osteoarthritis
Authors: Kontio Tea , Heliövaara Markku , Viikari-Juntura Eira , Solovieva Svetlana
Published: April 2020

Objectives

To explore the relative contribution of cumulative physical workload, sociodemographic and lifestyle factors, as well as prior injury to hospitalization due to knee and hip OA.

Methods

We examined a nationally representative sample of persons aged 30–59 years, who participated in a comprehensive health examination (the Health 2000 Study). A total of 4642 participants were followed from mid-2000 to end-2015 for the first hospitalization due to knee or hip OA using the National Hospital Discharge Register. We examined the association of possible risk factors with the outcome using a competing risk regression model (death was treated as competing risk) and calculated population attributable fractions for statistically significant risk factors.

Results

Baseline age and BMI as well as injury were associated with the risk of first hospitalization due to knee and hip OA. Composite cumulative workload was associated with a dose–response pattern with hospitalizations due to knee OA and with hospitalizations due to hip OA at a younger age only. Altogether, prior injury, high BMI and intermediate to high composite cumulative workload accounted for 70% of hospitalizations due to knee OA. High BMI alone accounted for 61% and prior injury only for 6% of hospitalizations due to hip OA.

Conclusion

Our results suggest that overweight/obesity, prior injury and cumulative physical workload are the most important modifiable risk factors that need to be targeted in the prevention of knee OA leading to hospitalization. A substantial proportion of hospitalizations due to hip OA can be reduced by controlling excess body weight.
Systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome due to a CASP1 variant causing inflammasome hyperactivation
Authors: Jørgensen Sofie E , Christiansen Mette , Høst Christian , Glerup Mia , Mahler Birgitte , Lausten Mira M , Gad Hans Henrik , Hartmann Rune , Herlin Troels , Mogensen Trine H
Published: April 2020

Objectives

We investigated a patient with systemic juvenile idiopathic arthritis (sJIA) and recurrent macrophage activation syndrome (MAS) to discover genetic and immunological contributing factors.

Methods

Severe recurrent MAS motivated whole exome sequencing (WES) to identify genetic variants potentially involved in disease pathogenesis. In vitro peripheral blood mononuclear cell (PBMC) stimulations for cytokine expression and caspase-1 activity assays as well as NF-κB reporter luciferase assays were performed to functionally characterize variants.

Results

WES revealed an extremely rare heterozygous missense variant, c.482G>A, p.R161H in the CASP1 gene encoding pro-caspase-1. Lipopolysaccharide (LPS) stimulation of patient PBMCs induced high levels of IL-6 compared to controls, and activation of the NLRP3 inflammasome resulted in increased production of IL-1β and IL-18 as well as significantly elevated caspase-1 activity. Constitutive and inducible levels of IL-18 and IFNγ in whole blood were markedly elevated. Expression of the CASP1 variant in an NF-κB reporter luciferase assay induced increased NF-κB activation in a RIP2-dependent manner. The disease course of the patient was complicated by severe recurrent MAS. However, dual IL-1 and IL-6 blockade caused disease remission.

Conclusion

For the first time, we demonstrate the involvement of a CASP1 variant in sJIA and recurrent MAS. This variant is gain-of-function for both inflammasome and NF-κB activation leading to increased production of IL-6, IL-1β and IL-18. Although dual IL-1 and IL-6 blockade may be beneficial in patients, in whom single treatment is not sufficient to control MAS, caution should be practiced, since interstitial lung disease may progress despite apparent clinical and biochemical remission.
FvSTUA is a Key Regulator of Sporulation, Toxin Synthesis, and Virulence in Fusarium verticillioides
Authors: Rath M. , Crenshaw N. J. , Lofton L. W. , Glenn A. E. , Gold S. E.
Published: April 2020

Fusarium verticillioides is one of the most important pathogens of maize, causing rot and producing fumonisin mycotoxins during infection. Ingestion of fumonisin-contaminated corn causes underperformance and even fatal toxicity in livestock and is associated with neural tube birth defects, growth stunting in children, and some cancers. StuA, an APSES-class transcription factor, is a major developmental transcriptional regulator in fungi. It has been shown to regulate crucial developmental processes, such as sporulation, virulence, and mycotoxin synthesis among others. In this study, the role of FvSTUA in F. verticillioides was examined by characterizing ∆FvstuA deletion mutants functionally and transcriptomally. The deletion mutants exhibited reduced vegetative growth, stunted aerial hyphae, and significant reductions in microconidiation. Macroconidiation and hydrophobicity of the deletion strains were reduced as well. Additionally, fumonisin production and virulence of the deletion mutants were greatly reduced. Transcriptomic analysis revealed downregulation of expression of several genes in the fumonisin and fusarin C biosynthetic clusters and differential expression of genes involved in conidiation and virulence. Nuclear localization of FvSTUA supported its likely function as a transcription factor. Together, our results indicate that FvSTUA plays a global role in transcriptional regulation in F. verticillioides influencing morphogenesis, toxin production, and virulence.
Population Dynamics of Wheat Root Pathogens Under Different Tillage Systems in Northeast Oregon
Authors: Yin Chuntao , McLaughlin Katherine , Paulitz Timothy C. , Kroese Duncan R. , Hagerty Christina H.
Published: April 2020

No-till or direct seeding can be described as seeding directly into the crop stubble from the previous season without use of tillage. A reduction in tillage can result in many benefits, including increased soil organic matter, increased water holding capacity, and reduced fuel costs. However, the effect of no-till and reduced tillage on crop root disease profiles is poorly understood. To study the effect of tillage on disease dynamics, soil samples were collected from commercial wheat fields representing a wide range of tillage strategies in fall 2016 and fall 2017. Because precipitation might affect soilborne diseases, wheat fields located across a diverse gradient of precipitation zones of the dryland Pacific Northwest were selected. Fusarium spp., Pythium spp., and Rhizoctonia spp. were quantified from soil samples using soil dilution plating and quantitative PCR (qPCR) assays. Results of dilution plating showed that the colony counts of Fusarium, Pythium, and Rhizoctonia at the genus level were negatively associated with tillage. However, the same patterns were not observed when specific causal agents of Fusarium, Pythium, and Rhizoctonia that are known to be pathogenic on wheat were quantified with qPCR. Furthermore, precipitation affected the population density of some fungal pathogens (F. culmorum, P. ultimum, and R. solani AG 8). Within the scope of inference of this study, results of this study indicate that the benefits of adopting reduced tillage likely outweigh potential risk for increased root disease.
Cancer cell lines show high heritability for motility but not generation time
Authors: Wass Anastasia V. , Butler George , Taylor Tiffany B. , Dash Philip R. , Johnson Louise J.
Published: April 2020

Tumour evolution depends on heritable differences between cells in traits affecting cell survival or replication. It is well established that cancer cells are genetically and phenotypically heterogeneous; however, the extent to which this phenotypic variation is heritable is far less well explored. Here, we estimate the broad-sense heritability (
H
2
) of two cell traits related to cancer hallmarks––cell motility and generation time––within populations of four cancer cell lines
in vitro
and find that motility is strongly heritable. This heritability is stable across multiple cell generations, with heritability values at the high end of those measured for a range of traits in natural populations of animals or plants. These findings confirm a central assumption of cancer evolution, provide a first quantification of the evolvability of key traits in cancer cells and indicate that there is ample raw material for experimental evolution in cancer cell lines. Generation time, a trait directly affecting cell fitness, shows substantially lower values of heritability than cell speed, consistent with its having been under directional selection removing heritable variation.
Uncovering the behaviour of road accidents in urban areas
Authors: Cabrera-Arnau C. , Prieto Curiel R. , Bishop S. R.
Published: April 2020

Different patterns in the incidence of road accidents are revealed when considering areas with increased levels of urbanization. To understand these patterns, road accident data from England and Wales is explored. In particular, the data are used to (i) generate time series for comparison of the incidence of road accidents in urban as opposed to rural areas, (ii) analyse the relationship between the number of road accidents and the population size of a set of urban areas, and (iii) model the likelihood of suffering an accident in an urban area and its dependence with population size. It is observed that minor and serious accidents are more frequent in urban areas, whereas fatal accidents are more likely in rural areas. It is also shown that, generally, the number of accidents in an urban area depends on population size superlinearly, with this superlinear behaviour becoming stronger for lower degrees of severity. Finally, given an accident in an urban area, the probability that the accident is fatal or serious decreases with population size and the probability that it is minor, increases sublinearly. These findings promote the question as to why such behaviours exist, the answer to which will lead to more sustainable urban policies.
Social structure and relatedness in the fringe-lipped bat (Trachops cirrhosus)
Authors: Flores Victoria , Carter Gerald G. , Halczok Tanja K. , Kerth Gerald , Page Rachel A.
Published: April 2020

General insights into the causes and effects of social structure can be gained from comparative analyses across socially and ecologically diverse taxa, such as bats, but long-term data are lacking for most species. In the neotropical fringe-lipped bat,Trachops cirrhosus, social transmission of foraging behaviour is clearly demonstrated in captivity, yet its social structure in the wild remains unclear. Here, we used microsatellite-based estimates of relatedness and records of 157 individually marked adults from 106 roost captures over 6 years, to infer whether male and femaleT. cirrhosushave preferred co-roosting associations and whether such associations were influenced by relatedness. Using a null model that controlled for year and roosting location, we found that both male and femaleT. cirrhosushave preferred roosting partners, but that only females demonstrate kin-biased association. Most roosting groups (67%) contained multiple females with one or two reproductive males. Relatedness patterns and recapture records corroborate genetic evidence for female philopatry and male dispersal. Our study adds to growing evidence that many bats demonstrate preferred roosting associations, which has the potential to influence social information transfer.
Design and tailoring of inks for inkjet patterning of metal oxides
Authors: Fang Mei , Li Tianli , Zhang Sangjian , Rao K. V. , Belova Lyubov
Published: April 2020

Inkjet printing has become a promising, efficient, inexpensive, scalable technique for materials deposition, mask-less and digital patterning in many device applications. Meanwhile, the ink preparation remains a challenge especially for printing functional oxide materials. Based on the principles of inkjet printing (especially relevant for piezoelectric drop-on-demand inkjet printer) and the process of the conversion of liquid ink into solid thin films of oxide materials, we present two approaches to the design and tailoring of inks: (i) oxide particle suspensions (e.g. SiO
2
, TiO
2
, Fe
3
O
4
) and (ii) metal-acetates precursor solutions for directly printing oxide thin films (e.g. ZnO, MgO, ITO and so forth). The solution inks are stable and produce tunable oxide films with high density and smooth surface. For some of the inks containing multi-type acetates with possible phase separation even before calcinations, we have developed a chelating procedure in order to tailor the films into single-phase homogeneity. The work lays a foundation for inkjet printing of oxides films for functional applications in electronic, photonic and energy devices.
Evolutionary dynamics of culturally transmitted, fertility-reducing traits
Authors: Wodarz Dominik , Stipp Shaun , Hirshleifer David , Komarova Natalia L.
Published: April 2020

Human populations in many countries have undergone a phase of demographic transition, characterized by a major reduction in fertility at a time of increased resource availability. A key stylized fact is that the reduction in fertility is preceded by a reduction in mortality and a consequent increase in population density. Various theories have been proposed to account for the demographic transition process, including maladaptation, increased parental investment in fewer offspring, and cultural evolution. None of these approaches, including formal cultural evolutionary models of the demographic transitions, have addressed a possible direct causal relationship between a reduction in mortality and the subsequent decline in fertility. We provide mathematical models in which
low mortality
favours the cultural selection of low-fertility traits. This occurs because reduced mortality slows turnover in the model, which allows the cultural transmission advantage of low-fertility traits to outrace their reproductive disadvantage. For mortality to be a crucial determinant of outcome, a cultural transmission bias is required where slow reproducers exert higher social influence. Computer simulations of our models that allow for exogenous variation in the death rate can reproduce the central features of the demographic transition process, including substantial reductions in fertility within only one to three generations. A model assuming continuous evolution of reproduction rates through imitation errors predicts fertility to fall below replacement levels if death rates are sufficiently low. This can potentially explain the very low preferred family sizes in Western Europe.
Development and testing of a novel killer–rescue self-limiting gene drive system in
Drosophila melanogaster
Authors: Webster Sophia H. , Vella Michael R. , Scott Maxwell J.
Published: April 2020

Here we report the development and testing of a novel self-limiting gene drive system, Killer–Rescue (K–R), in
Drosophila melanogaster
. This system is composed of an autoregulated Gal4 Killer (K) and a Gal4-activated Gal80 Rescue (R). Overexpression of Gal4 is lethal, but in the presence of R activation of Gal80 leads to much lower levels of Gal4 and rescue of lethality. We demonstrate that with a single 2 : 1 engineered to wild-type release, K drives R through the population and after nine generations, more than 98% of the population carry R and less than 2% of the population are wild-type flies. We discuss how this simple K–R gene drive system may be readily adapted for population replacement in a human health pest,
Aedes aegypti
, or for population suppression in an agricultural pest,
Drosophila suzukii
.
Robust functional mapping of layer-selective responses in human lateral geniculate nucleus with high-resolution 7T fMRI
Authors: Qian Yazhu , Zou Jinyou , Zhang Zihao , An Jing , Zuo Zhentao , Zhuo Yan , Wang Danny J. J. , Zhang Peng
Published: April 2020

The lateral geniculate nucleus (LGN) of the thalamus is the major subcortical relay of retinal input to the visual cortex. It plays important roles in visual perception and cognition and is closely related with several eye diseases and brain disorders. Primate LGNs mainly consist of six layers of monocular neurons with distinct cell types and functions. The non-invasive measure of layer-selective activities of the human LGN would have broad scientific and clinical implications. Using high-resolution functional magnetic resonance imaging (fMRI) at 7 Tesla (T) and carefully designed visual stimuli, we achieved robust functional mapping of eye-specific and also magnocellular/parvocellular-specific laminar patterns of the human LGN. These laminar patterns were highly reproducible with different pulse sequences scanned on separate days, between different subjects, and were in remarkable consistency with the simulation from high-resolution histology of the human LGNs. These findings clearly demonstrate that 7T fMRI can robustly resolve layer-specific responses of the human LGN. This paves the way for future investigation of the critical roles of the LGN in human visual perception and cognition, as well as the neural mechanisms of many developmental and neurodegenerative diseases.
The secretome of a parasite alters its host's behaviour but does not recapitulate the behavioural response to infection
Authors: Berger Chloé Suzanne , Aubin-Horth Nadia
Published: April 2020

Parasites with complex life cycles have been proposed to manipulate the behaviour of their intermediate hosts to increase the probability of reaching their final host. The cause of these drastic behavioural changes could be manipulation factors released by the parasite in its environment (the secretome), but this has rarely been assessed. We studied a non-cerebral parasite, the cestode
Schistocephalus solidus
, and its intermediate host, the threespine stickleback (
Gasterosteus aculeatus
), whose response to danger becomes significantly diminished when infected. These altered behaviours appear only during late infection, when the worm is ready to reproduce in its final avian host. Sympatric host–parasite pairs show higher infection success for parasites, suggesting that the secretome effects could differ for allopatric host–parasite pairs with independent evolutionary histories. We tested the effects of secretome exposure on behaviour by using secretions from the early and late infection of
S. solidus
and by injecting them in healthy sticklebacks from a sympatric and allopatric population. Contrary to our prediction, secretome from late infection worms did not result in more risky behaviours, but secretome from early infection resulted in more cautious hosts, only in fish from the allopatric population. Our results suggest that the secretome of
S. solidus
contains molecules that can affect host behaviour, that the causes underlying the behavioural changes in infected sticklebacks are multifactorial and that local adaptation between host–parasite pairs may extend to the response to the parasite's secretome content.
A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae
Authors: Zheng Jinshui , Wittouck Stijn , Salvetti Elisa , Franz Charles M.A.P. , Harris Hugh M.B. , Mattarelli Paola , O’Toole Paul W. , Pot Bruno , Vandamme Peter , Walter Jens , Watanabe Koichi , Wuyts Sander , Felis Giovanna E. , Gänzle Michael G. , Lebeer Sarah
Published: April 2020

The genus

Lactobacillus

comprises 261 species (at March 2020) that are extremely diverse at phenotypic, ecological and genotypic levels. This study evaluated the taxonomy of

Lactobacillaceae

and

Leuconostocaceae

on the basis of whole genome sequences. Parameters that were evaluated included core genome phylogeny, (conserved) pairwise average amino acid identity, clade-specific signature genes, physiological criteria and the ecology of the organisms. Based on this polyphasic approach, we propose reclassification of the genus

Lactobacillus

into 25 genera including the emended genus

Lactobacillus

, which includes host-adapted organisms that have been referred to as the

Lactobacillus delbrueckii

group,

Paralactobacillus

and 23 novel genera for which the names Holzapfelia, Amylolactobacillus, Bombilactobacillus, Companilactobacillus, Lapidilactobacillus, Agrilactobacillus, Schleiferilactobacillus, Loigolactobacilus, Lacticaseibacillus, Latilactobacillus, Dellaglioa, Liquorilactobacillus, Ligilactobacillus, Lactiplantibacillus, Furfurilactobacillus, Paucilactobacillus, Limosilactobacillus, Fructilactobacillus, Acetilactobacillus, Apilactobacillus, Levilactobacillus, Secundilactobacillus and Lentilactobacillus are proposed. We also propose to emend the description of the family

Lactobacillaceae

to include all genera that were previously included in families

Lactobacillaceae

and

Leuconostocaceae

. The generic term ‘lactobacilli’ will remain useful to designate all organisms that were classified as

Lactobacillaceae

until 2020. This reclassification reflects the phylogenetic position of the micro-organisms, and groups lactobacilli into robust clades with shared ecological and metabolic properties, as exemplified for the emended genus

Lactobacillus

encompassing species adapted to vertebrates (such as

Lactobacillus delbrueckii

,

Lactobacillus iners

,

Lactobacillus crispatus

, Lactobacillus jensensii,

Lactobacillus johnsonii

and

Lactobacillus acidophilus

) or invertebrates (such as

Lactobacillus apis

and

Lactobacillus bombicola

).
CoV Genome Tracker: tracing genomic footprints of Covid-19 pandemic
Authors: Akther Saymon , Bezrucenkovas Edgaras , Sulkow Brian , Panlasigui Christopher , Li Li , Qiu Weigang , Di Lia
Published: April 2020

Genome sequences constitute the primary evidence on the origin and spread of the 2019-2020 Covid-19 pandemic. Rapid comparative analysis of coronavirus SARS-CoV-2 genomes is critical for disease control, outbreak forecasting, and developing clinical interventions. CoV Genome Tracker is a web portal dedicated to trace Covid-19 outbreaks in real time using a haplotype network, an accurate and scalable representation of genomic changes in a rapidly evolving population. We resolve the direction of mutations by using a bat-associated genome as outgroup. At a broader evolutionary time scale, a companion browser provides gene-by-gene and codon-by-codon evolutionary rates to facilitate the search for molecular targets of clinical interventions.

Availability and Implementation

CoV Genome Tracker is publicly available athttp://cov.genometracker.organd updated weekly with the data downloaded from GISAID (http://gisaid.org). The website is implemented with a custom JavaScript script based on jQuery (https://jquery.com) and D3-force (https://github.com/d3/d3-force).

Contact

weigang@genectr.hunter.cuny.edu, City University of New York, Hunter College

Supplementary Information

All supporting scripts developed in JavaScript, Python, BASH, and PERL programming languages are available as Open Source at the GitHub repositoryhttps://github.com/weigangq/cov-browser.
A large decrease in the magnitude of seasonal fluctuations in mortality explains part of the increase in longevity in Sweden during the 20th century
Authors: Ledberg Anders
Published: April 2020

BACKGROUND

Mortality rates of are known to depend on the seasons and in temperate climates rates are highest during winter. The magnitude of these seasonal fluctuations in mortality have decreased substantially during the 20th century in many countries, but the extent to which this decrease has contributed to the concurrent increase in life expectancy, is not known. Here I describe how the seasonality of all-cause mortality among persons aged 60 years or more in Sweden has changed in the time period from 1860 to 1995, and furthermore investigate how this change has contributed to the increase in life expectancy observed during the same period.

METHODS

Yearly sex-specific birth cohorts consisting of all persons born in Sweden between 1800 and 1901, and who reached at least 59 years of age, were obtained from a genealogical database. The mortality rates of each cohort were modeled by an exponential function of age modulated by a sinusoidal function of time of year. The contribution of seasonal fluctuations to life expectancy was investigated by a novel decomposition of the total mortality rate into a seasonal part and a part independent of the seasons. Cohort life expectancy at 60 was used to quantify changes in lifespan during the time period.

RESULTS

The magnitude of seasonal variations of mortality rates decreased substantially over the time period. For cohorts born in 1800, the risk of dying during the winter season was almost twice that of dying during summer. For cohorts born in 1900, the relative increase in winter mortality was 10%. Cohort life expectancy at 60 increased with 4.3 years for men and 6.8 years for women and the decrease of seasonal variability accounted for approximately 40% of this increase in average lifespan.

CONTRIBUTION

By following a large number of extinct cohorts it was possible to show how the decrease in seasonal mortality fluctuations has contributed to an increase in life expectancy. The decomposition of total mortality introduced here might be useful to better understand the processes and mechanisms underlying the marked improvements in life expectancy seen over the last 150 years.
Estimate of the Maximum Limit of Total Cases of Infected Patients COVID-19
Authors: Dutra Carlos Maximiliano , de Melo Carlos Augusto Riella
Published: April 2020

In this work, we present a method to estimate the maximum limit of total cases COVID-19 cases considering that the time in which the maximum number of new daily cases occurs corresponds to the inflection point of the curve described by the total number of cases that assumed to have a growth according to a logistical function in which the number of total cases at the inflection point will correspond to half of the maximum limit of total cases COVID-19. We estimate this maximum limit for China and South Korea, obtaining results compatible with the observations. And we also estimate for Italy, Germany, United Kingdom, United States and Spain.
Delayed-Phase Thrombocytopenia in Patients of Coronavirus Disease 2019 (COVID-19)
Authors: Chen Wanxin , Li Ziping , Yang Bohan , Wang Ping , Zhou Qiong , Zhu Jianhua , Chen Xuexing , Yang Peng , Zhou Hao
Published: April 2020

The pandemic COVID-19 pneumonia has engulfed the entire world. Hematopoietic system can also be affected by COVID-19. Thrombocytopenia at admission was prevalent, while late-phase or delayed-phase thrombocytopenia is obscure. This retrospective single-center case series analyzed patients with COVID-19 at the Union Hospital, Wuhan, China, from January 25th to March 9th, 2020. Analysis began on March 11th, 2020. COVID-19 associated delayed-phase thrombocytopenia was occurred in 11.8% percent of enrolled patients. The delayed-phase thrombocytopenia in COVID-19 is prone to develop in elderly patients or patients with low lymphocyte count on admission. The delayed-phase thrombocytopenia is significantly associated with increased length of hospital stay and higher ICU admission rate. Delayed-phase nadir platelet counts demonstrated a high and significantly negative linear correlation with B cell percentages and serum IL-6 levels. We also presented bone marrow aspiration pathology of three patients with delayed-phase thrombocytopenia, showing impaired maturation of megakaryocytes. We speculated that the delayed-phase platelet destruction might be mediated by antibodies, and suggest immunoregulatory treatment in severe patients to improve outcomes. Besides, clinicians need to pay attention to the delayed-phase thrombocytopenia especially at 3-4 weeks after symptom onset.
Human agency and infection rates: implications for social distancing during epidemics
Authors: Ramsey Christopher Bronk
Published: April 2020

Social distancing is an important measure in controlling epidemics. This paper presents a simple theoretical model focussed on the implications of the wide range in interaction rates between individuals, both within the workplace and in the social setting. The model is based on well-mixed populations and so is not intended for studying geographic spread. The model shows that epidemic growth rate is largely determined by the upper interactivity quantiles of society, implying that the most efficient methods of epidemic control are interaction capping approaches rather than overall reductions in interaction.

The theoretical model can also be applied to look at the dynamics of epidemic progression under various scenarios. The theoretical model suggests that with no intervention herd immunity would be achieved with a lower overall infection rate than if variation in interaction rate is ignored, because by this stage almost all the most interactive members of society would have had the infection; however the overall mortality with such an approach is very high. Scenarios for mitigation and suppression suggest that, by using interactivity capping, it should be possible to control an epidemic without extreme sanctions on the majority of the population if R0 of the uncontrolled infection is 2.4. However to control the infection rate to a specific level will always require the switching on and off of measures and for this reason eradication is likely to be a less costly policy in the long run. While social distancing alone can be used for eradication it is not be a good mechanism on its own to prevent reinfection. The use of robust testing, quarantining, and contact tracing would strengthen any social distancing measures, speed up eradication, and be a better tool for prevention of infection or reinfection.
Validation Study of HLA-B*13:01 as a Biomarker of Dapsone Hypersensitivity Syndrome in Leprosy Patients in Indonesia
Authors: Krismawati Hana , Irwanto Astrid , Pongtiku Arry , Irwan Ishak Darryl , Maldan Yustinus , Sitanggang Yuli Arisanti , Wahyuni Tri , Tanjung Ratna , Sun Yonghu , Liu Hong , Zhang Furen , Oktavian Antonius , Liu Jianjun
Published: April 2020

Importance

Leprosy is a stigmatizing, chronic infection which degenerates the nervous system and often leads to incapacitation. Multi-drug therapy (MDT) which consists of dapsone, rifampicin and clofazimine has been effective to combat this disease. In Indonesia, leprosy is still a problem. Furthermore, there had been reports of Dapsone Hypersensitivity Syndrome (DHS) which also challenges leprosy elimination in certain aspects. HLA-B*13:01 has been found to be associated with DHS and prospective screening has proven its ability to prevent DHS in the Chinese population, but has not been validated in Indonesians.

Objective

To validate HLA-B*13:01 as a biomarker for DHS in the Indonesian population.

Design

This is a case-control study.

Setting

Population-based, multi-district recruitment from primary care centers in two of the top 3 most prevalent provinces in Indonesia, Papua and West Papua.

Participants

Leprosy patients who presented themselves with DHS were recruited as case subjects (34 cases) and leprosy patients without DHS were recruited as control subjects (52 controls).

Exposure

Leprosy patients who had undergone multi-drug treatment for leprosy under the standard WHO guideline, consisting of rifampicin, dapsone and clofazamine.

Main Outcome and Measures

The association of HLA-B*13:01 to DHS based on difference in allele frequencies between cases and controls. HLA-B alleles were typed using the gold-standard Sequence Based Typing method. Results were analyzed using logistic regression and risk assessment was carried out.

Results

The results of HLA-typing showed that HLA-B*13:01 was the most significant allele associated with DHS, with odds ratio=247.6 and P-value=4.81E-9, confirming the strong association of HLA-B*13:01 to DHS in the Indonesian population. The sensitivity of this biomarker is 91.2% and specificity is 96.2%, with an area under the curve of 0.95.

Conclusions and Relevance

HLA-B*13:01 is validated as a biomarker for DHS in leprosy patients in Indonesia, and can potentially be a good predictor of DHS to help prevent this condition in the future.

KEY POINTS

Question

Can HLA-B*13:01 be a predictor of Dapsone Hypersensitivity Syndrome in Indonesians?

Findings

In this case control validation study, HLA-B*13:01 is significantly associated with DHS in Indonesians and can predict a person at risk of DHS 95% of the time.

Meaning

HLA-B*13:01 is validated as a biomarker for DHS in Indonesians and can be useful to screen and prevent further incidences of DHS in the population.
Processivity of molecular motors under vectorial loads
Authors: Khataee Hamid , Neufeld Zoltan , Mahamdeh Mohammed
Published: April 2020

Molecular motors are cellular machines that drive the spatial organisation of the cells by transporting cargoes along intracellular filaments. Although the mechanical properties of single molecular motors are relatively well characterised, it remains elusive how the three-dimensional geometry of a load imposed on a motor affects its processivity, i.e., the average distance that a motor moves per interaction with a filament. Here, we theoretically explore this question for a single kinesin molecular motor by analysing the load-dependence of the stepping and detachment processes. We find that the processivity of kinesin increases with lowering the load angle between kinesin and microtubule filament, due to the deceleration of the detachment rate. When the load angle is large, the processivity is predicted to enhance with accelerating the stepping rate, through an optimal distribution of the load over the kinetic transition rates underlying a mechanical step of the motor. These results provide new insights into understanding of the design of potential synthetic biomolecular machines that can travel long distances with high velocities.
Human organ chip-enabled pipeline to rapidly repurpose therapeutics during viral pandemics
Authors: Si Longlong , Bai Haiqing , Rodas Melissa , Cao Wuji , Oh Crystal Yuri , Jiang Amanda , Moller Rasmus , Hoagland Daisy , Oishi Kohei , Horiuchi Shu , Uhl Skyler , Blanco-Melo Daniel , Albrecht Randy A. , Liu Wen-Chun , Jordan Tristan , Nilsson-Payant Benjamin E. , Logue James , Haupt Robert , McGrath Marisa , Weston Stuart , Nurani Atiq , Kim Seong Min , Zhu Danni Y. , Benam Kambez H. , Goyal Girija , Gilpin Sarah E. , Prantil-Baun Rachelle , Powers Rani K. , Carlson Kenneth , Frieman Matthew , tenOever Benjamin R. , Ingber Donald E.
Published: April 2020

The rising threat of pandemic viruses, such as SARS-CoV-2, requires development of new preclinical discovery platforms that can more rapidly identify therapeutics that are activein vitroand also translatein vivo. Here we show that human organ-on-a-chip (Organ Chip) microfluidic culture devices lined by highly differentiated human primary lung airway epithelium and endothelium can be used to model virus entry, replication, strain-dependent virulence, host cytokine production, and recruitment of circulating immune cells in response to infection by respiratory viruses with great pandemic potential. We provide a first demonstration of drug repurposing by using oseltamivir in influenza A virus-infected organ chip cultures and show that co-administration of the approved anticoagulant drug, nafamostat, can double oseltamivir’s therapeutic time window. With the emergence of the COVID-19 pandemic, the Airway Chips were used to assess the inhibitory activities of approved drugs that showed inhibition in traditional cell culture assays only to find that most failed when tested in the Organ Chip platform. When administered in human Airway Chips under flow at a clinically relevant dose, one drug – amodiaquine - significantly inhibited infection by a pseudotyped SARS-CoV-2 virus. Proof of concept was provided by showing that amodiaquine and its active metabolite (desethylamodiaquine) also significantly reduce viral load in both direct infection and animal-to-animal transmission models of native SARS-CoV-2 infection in hamsters. These data highlight the value of Organ Chip technology as a more stringent and physiologically relevant platform for drug repurposing, and suggest that amodiaquine should be considered for future clinical testing.
Dryland cropping system, weed communities, and disease status modulate the effect of climate conditions on wheat soil bacterial communities.
Authors: Ishaq Suzanne Lynn , Seipel Tim , Yeoman Carl , Menalled Fabian D
Published: April 2020

Little knowledge exists on whether soil bacteria are impacted by cropping systems and disease status in current and predicted climate scenarios. We assessed the impact of soil moisture and temperature, weed communities, and disease status on soil bacterial communities across three cropping systems: conventional no-till (CNT) utilizing synthetic pesticides and herbicides, 2) USDA-certified tilled organic (OT), and 3) USDA-certified organic with sheep grazing (OG). Sampling date within the growing season, and associated soil temperature and moisture, exerted the greatest effect on bacterial communities, followed by cropping system, Wheat streak mosaic virus (WSMV) infection status, and weed community. Soil temperature was negatively associated with bacterial richness and evenness, while soil moisture was positively associated with bacterial richness and evenness. Both soil temperature and moisture altered soil bacterial community similarity. Inoculation with WSMV altered community similarity, and there was a date x virus interaction on bacterial richness in CNT and OT systems, as well as an interaction between WSMV x climate. In May and July, cropping system altered the effect of climate change on the bacterial community composition in hotter, and hotter and drier conditions not treated with WSMV, as compared to ambient conditions. In areas treated with WSMV, there were interactions between cropping system, sampling date, and climate conditions, indicating the effect of multiple stressors on bacterial communities in soil. Overall, this study indicates that predicted climate modifications as well as biological stressors play a fundamental role in the impact of cropping systems on soil bacterial communities.
Longitudinal alterations in fronto-striatal glutamate are associated with functioning during inhibitory control in autism spectrum disorder and obsessive compulsive disorder
Authors: Hollestein Viola , Buitelaar Jan K. , Brandeis Daniel , Banaschewski Tobias , Kaiser Anna , Hohmann Sarah , Oranje Bob , Gooskens Bram , Durston Sarah , Lythgoe David J. , Naaijen Jilly
Published: April 2020

Background

Autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) are neurodevelopmental disorders with overlapping symptomatology. Both show deficits in inhibitory control, which are associated with altered functioning and glutamate concentrations in the fronto-striatal circuitry. These parameters have never been examined together. Here we, for the first time, used a multi-center, longitudinal approach to investigate fronto-striatal functioning during an inhibitory control task and its association with fronto-striatal glutamate concentrations across these two disorders.

Methods

74 adolescents with ASD (24) or OCD (15) and controls (35) aged 8-17 were recruited across three sites of the European TACTICS consortium. They underwent two magnetic resonance imaging (MRI) sessions with a one-year interval. This included proton magnetic resonance spectroscopy (1H-MRS; n=74) and functional MRI during an inhibitory control task (n=57). We used linear mixed effects models to investigate, over time, the relationship between fronto-striatal functioning and glutamate concentrations across these groups and continuous measures of overlapping compulsivity symptoms.

Results

During failed inhibitory control, in OCD increased striatal glutamate was associated with increased neural activation of ACC, an effect that decreased over time. During successful inhibitory control, higher ACC glutamate was positively associated with striatal activation in OCD and compulsivity across time. ACC glutamate levels decreased over time in the ASD group compared to controls, while striatal glutamate decreased over time, independent of diagnosis.

Conclusions

Significant differences in fronto-striatal glutamate were observed in ASD and OCD, affecting functional activity during failed- and successful inhibitory control differently, especially in OCD, with effects changing over time.
Visual attention modulates the integration of goal-relevant evidence and not value
Authors: Sepulveda Pradyumna , Usher Marius , Davies Ned , Benson Amy , Ortoleva Pietro , De Martino Benedetto
Published: April 2020

When choosing between options, such as food items presented in plain view, people tend to choose the option they spend longer looking at. The prevailing interpretation is that visual attention increases value. However, in previous studies, ‘value’ was coupled to a behavioural goal, since subjects had to choose the item they preferred. This makes it impossible to discern if visual attention has an effect on value, or, instead, if attention modulates the information most relevant for the goal of the decision-maker. Here we present the results of two independent studies—a perceptual and a value-based task—that allow us to decouple value from goal-relevant information using specific task-framing. Combining psychophysics with computational modelling, we show that, contrary to the current interpretation, attention doesnotboost value, but instead it modulates goal-relevant information. This work provides a novel and more general mechanism by which attention interacts with choice.
Inhibition of Wnt signalling by Notch via two distinct mechanisms
Authors: Acar Ahmet , Hidalgo-Sastre Ana , Leverentz Michael K. , Mills Christopher G. , Woodcock Simon , Baron Martin , Collu Giovanna M. , Brennan Keith
Published: April 2020

Notch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although, they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between the two pathways is important in generating the great diversity of cell types that we find in metazoans. However, several different mechanisms have been proposed that allow Notch to limit Wnt signalling, driving a Notch-ON/Wnt-OFF state. Here we explore these different mechanisms in vertebrate cells and demonstrate two distinct mechanisms by which Notch itself, can limit the transcriptional activity of β-catenin. At the membrane, independently of DSL ligands, Notch1 can antagonise β-catenin activity through an endocytosis mediated mechanism that is dependent upon its interaction with Deltex and sequesters β-catenin into the membrane fraction. Within the nucleus, the intracellular domain of Notch1 can also limit β-catenin induced transcription through the formation of a complex that requires its interaction with RBPjκ. We believe these mechanisms contribute to the robustness of cell-fate decisions by sharpening the distinction between opposing Notch/Wnt responses.
A modular microscale granuloma model for immune-microenvironment signaling studiesin vitro
Authors: Berry Samuel B. , Gower Maia S. , Su Xiaojing , Seshadri Chetan , Theberge Ashleigh B.
Published: April 2020

Tuberculosis (TB) is one of the most potent infectious diseases in the world, causing more deaths than any other single infectious agent. TB infection is caused by inhalation ofMycobacterium tuberculosis(Mtb) and subsequent phagocytosis and migration into the lung tissue by innate immune cells (e.g., alveolar macrophages, neutrophils, dendritic cells), resulting in the formation of a fused mass of immune cells known as the granuloma. Considered the pathological hallmark of TB, the granuloma is a complex microenvironment that is crucial for pathogen containment as well as pathogen survival. Disruption of the delicate granuloma microenvironmentvianumerous stimuli, such as variations in cytokine secretions, nutrient availability, and the makeup of immune cell population, can lead to an active infection. Herein, we present a novelin vitromodel to examine the soluble factor signaling between a mycobacterial infection and its surrounding environment. Adapting a newly developed suspended microfluidic platform, known as Stacks, we established a modular microscale infection model containing human immune cells and a model mycobacterial strain that can easily integrate with different microenvironmental cues through simple spatial and temporal “stacking” of each module of the platform. We validate the establishment of suspended microscale (4 μL) infection cultures that secrete increased levels of proinflammatory factors IL-6, VEGF, and TNFα upon infection and form 3D aggregates (granuloma model) encapsulating the mycobacteria. As a proof of concept to demonstrate the capability of our platform to examine soluble factor signaling, we cocultured anin vitroangiogenesis model with the granuloma model and quantified morphology changes in endothelial structures as a result of culture conditions (P < 0.05 when comparing infected vs. uninfected coculture systems). We envision our modularin vitrogranuloma model can be further expanded and adapted for studies focusing on the complex interplay between granulomatous structures and their surrounding microenvironment, as well as a complementary tool to augmentin vivosignaling and mechanistic studies.
Polyphosphate FunctionsIn Vivoas Iron Chelator and Fenton Inhibitor
Authors: Beaufay Francois , Quarles Ellen , Franz Allison , Katamanin Olivia , Wholey Wei-Yun , Jakob Ursula
Published: April 2020

Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequentin vitroandin vivostudies revealed that polyP provides a crucial iron reservoir under non-stress conditions, and effectively complexes free iron and blocks ROS formation during iron stress. These results demonstrate that polyP, a universally conserved biomolecule, plays a hitherto unrecognized role as an iron chelator and an inhibitor of the Fenton reaction.