bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncogene inference optimization using constraint-based modelling incorporated with protein expression in normal and tumour tissues
Authors: Wu Wu-Hsiung , Li Fan-Yu , Shu Yi-Chen , Lai Jin-Mei , Chang Peter Mu-Hsin , Huang Chi-Ying F. , Wang Feng-Sheng
Published: March 2020

Cancer cells are known to exhibit unusual metabolic activity, and yet few metabolic cancer driver genes are known. Genetic alterations and epigenetic modifications of cancer cells result in the abnormal regulation of cellular metabolic pathways that are different when compared with normal cells. Such a metabolic reprogramming can be simulated using constraint-based modelling approaches towards predicting oncogenes. We introduced the tri-level optimization problem to use the metabolic reprogramming towards inferring oncogenes. The algorithm incorporated Recon 2.2 network with the Human Protein Atlas to reconstruct genome-scale metabolic network models of the tissue-specific cells at normal and cancer states, respectively. Such reconstructed models were applied to build the templates of the metabolic reprogramming between normal and cancer cell metabolism. The inference optimization problem was formulated to use the templates as a measure towards predicting oncogenes. The nested hybrid differential evolution algorithm was applied to solve the problem to overcome solving difficulty for transferring the inner optimization problem into the single one. Head and neck squamous cells were applied as a case study to evaluate the algorithm. We detected 13 of the top-ranked one-hit dysregulations and 17 of the top-ranked two-hit oncogenes with high similarity ratios to the templates. According to the literature survey, most inferred oncogenes are consistent with the observation in various tissues. Furthermore, the inferred oncogenes were highly connected with the TP53/AKT/IGF/MTOR signalling pathway through PTEN, which is one of the most frequently detected tumour suppressor genes in human cancer.
Releases of Asian houbara must respect genetic and geographic origin to preserve inherited migration behaviour: evidence from a translocation experiment
Authors: Burnside Robert J. , Buchan Claire , Salliss Daniel , Collar Nigel J. , Dolman Paul M.
Published: March 2020

Maintaining appropriate migratory strategies is important in conservation; however, translocations of migratory animals may alter locally evolved migration behaviours of recipient populations if these are different and heritable. We used satellite telemetry and experimental translocation to quantify differences and assess heritability in migration behaviours between three migratory Asian houbara (Chlamydotis macqueenii) breeding populations (640 km range across eastern, central and western Uzbekistan). Adults from the eastern population migrated twice as far (mean = 1184 km ± 44 s.e.) as the western population (656 km ± 183 s.e.) and showed significantly less variation in migration distance than the central population (1030 km ± 127 s.e.). The western and central populations wintered significantly further north (mean: +8.32° N ± 1.70 s.e. and +4.19° N ± 1.16 s.e., respectively) and the central population further west (−3.47° E ± 1.46 s.e.) than individuals from the eastern population. These differences could arise from a differing innate drive, or through learnt facultative responses to topography, filtered by survival. Translocated birds from the eastern population (wild-laid and captive-reared,n= 5) migrated further than adults from either western or central recipient populations, particularly in their second migration year. Translocated birds continued migrating south past suitable wintering grounds used by the recipient populations despite having to negotiate mountain obstacles. Together, this suggests a considerable conserved heritable migratory component with local adaptation at a fine geographic scale. Surviving translocated individuals returned to their release site, suggesting that continued translocations would lead to introgression of the heritable component and risk altering recipient migration patterns. Conservation biologists considering translocation interventions for migratory populations should evaluate potential genetic components of migratory behaviour.
Scattering on a square lattice from a crack with a damage zone
Authors: Lal Sharma Basant , Mishuris Gennady
Published: March 2020

A semi-infinite crack in an infinite square lattice is subjected to a wave coming from infinity, thereby leading to its scattering by the crack surfaces. A partially damaged zone ahead of the crack tip is modelled by an arbitrarily distributed stiffness of the damaged links. While an open crack, with an atomically sharp crack tip, in the lattice has been solved in closed form with the help of the scalar Wiener–Hopf formulation (Sharma 2015
SIAM J. Appl. Math.
,
75
, 1171–1192 (
doi:10.1137/140985093
); Sharma 2015
SIAM J. Appl. Math.
75
, 1915–1940. (
doi:10.1137/15M1010646
)), the problem considered here becomes very intricate depending on the nature of the damaged links. For instance, in the case of a partially bridged finite zone it involves a 2 × 2 matrix kernel of formidable class. But using an original technique, the problem, including the general case of arbitrarily damaged links, is reduced to a scalar one with the exception that it involves solving an auxiliary linear system of
N
 × 
N
equations, where
N
defines the length of the damage zone. The proposed method does allow, effectively, the construction of an exact solution. Numerical examples and the asymptotic approximation of the scattered field far away from the crack tip are also presented.
Terrestrial habitats decouple the relationship between species and subspecies diversification in mammals
Authors: van Holstein Laura , Foley Robert A.
Published: March 2020

Darwin proposed that lineages with higher diversification rates should evidence this capacity at both the species and subspecies level. This should be the case if subspecific boundaries are evolutionary faultlines along which speciation is generally more likely to occur. This pattern has been described for birds, but remains poorly understood in mammals. To investigate the relationship between species richness (SR) and subspecies richness (SSR), we calculated the strength of the correlation between the two across all mammals. Mammalian taxonomic richness correlates positively, but only very weakly, between the species and subspecies level, deviating from the pattern found in birds. However, when mammals are separated by environmental substrate, the relationship between generic SR and average SSR in non-terrestrial taxa is stronger than that reported for birds (Kendall'stau= 0.31,p< 0.001). By contrast, the correlation in terrestrial taxa alone weakens compared to that for all mammals (Kendall'stau= 0.11,p< 0.001). A significant interaction between environmental substrate and SR in phylogenetic regressions confirms a role for terrestrial habitats in disrupting otherwise linked dynamics of diversification across the taxonomic hierarchy. Further, models including species range size as a predictor show that range size affects SSR more in terrestrial taxa. Taken together, these results suggest that the dynamics of diversification of terrestrial mammals are more affected by physical barriers or ecological heterogeneity within ranges than those of non-terrestrial mammals, at two evolutionary levels. We discuss the implication of these results for the equivalence of avian and mammalian subspecies, their potential role in speciation and the broader question of the relationship between microevolution and macroevolution.
Fast diversification through a mosaic of evolutionary histories characterizes the endemic flora of ancient Neotropical mountains
Authors: Vasconcelos Thais N. C. , Alcantara Suzana , Andrino Caroline O. , Forest Félix , Reginato Marcelo , Simon Marcelo F. , Pirani José R.
Published: March 2020

Mountains are among the most biodiverse areas on the globe. In young mountain ranges, exceptional plant species richness is often associated with recent and rapid radiations linked to the mountain uplift itself. In ancient mountains, however, orogeny vastly precedes the evolution of vascular plants, so species richness has been explained by species accumulation during long periods of low extinction rates. Here we evaluate these assumptions by analysing plant diversification dynamics in thecampo rupestre, an ecosystem associated with pre-Cambrian mountaintops and highlands of eastern South America, areas where plant species richness and endemism are among the highest in the world. Analyses of 15 angiosperm clades show that radiations of endemics exhibit fastest rates of diversification during the last 5 Myr, a climatically unstable period. However, results from ancestral range estimations using different models disagree on the age of the earliestin situspeciation events and point to a complex floristic assembly. There is a general trend for higher diversification rates associated with these areas, but endemism may also increase or reduce extinction rates, depending on the group. Montane habitats, regardless of their geological age, may lead to boosts in speciation rates by accelerating population isolation in archipelago-like systems, circumstances that can also result in higher extinction rates and fast species turnover, misleading the age estimates of endemic lineages.
Ancient mitogenomes show plateau populations from last 5200 years partially contributed to present-day Tibetans
Authors: Ding Manyu , Wang Tianyi , Ko Albert Min-Shan , Chen Honghai , Wang Hui , Dong Guanghui , Lu Hongliang , He Wei , Wangdue Shargan , Yuan Haibing , He Yuanhong , Cai Linhai , Chen Zujun , Hou Guangliang , Zhang Dongju , Zhang Zhaoxia , Cao Peng , Dai Qingyan , Feng Xiaotian , Zhang Ming , Wang Hongru , Yang Melinda A. , Fu Qiaomei
Published: March 2020

The clarification of the genetic origins of present-day Tibetans requires an understanding of their past relationships with the ancient populations of the Tibetan Plateau. Here we successfully sequenced 67 complete mitochondrial DNA genomes of 5200 to 300-year-old humans from the plateau. Apart from identifying two ancient plateau lineages (haplogroups D4j1b and M9a1a1c1b1a) that suggest some ancestors of Tibetans came from low-altitude areas 4750 to 2775 years ago and that some were involved in an expansion of people moving between high-altitude areas 2125 to 1100 years ago, we found limited evidence of recent matrilineal continuity on the plateau. Furthermore, deep learning of the ancient data incorporated into simulation models with an accuracy of 97% supports that present-day Tibetan matrilineal ancestry received partial contribution rather than complete continuity from the plateau populations of the last 5200 years.
A review and meta-analysis of collaborative research prioritization studies in ecology, biodiversity conservation and environmental science
Authors: Dey Cody J. , Rego Adam I. , Midwood Jonathan D. , Koops Marten A.
Published: March 2020

Collaborative research prioritization (CRP) studies have become increasingly popular during the last decade. By bringing together a diverse group of stakeholders, and using a democratic process to create a list of research priorities, these methods purport to identify research topics that will better meet the needs of science users. Here, we review 41 CRP studies in the fields of ecology, biodiversity conservation and environmental science that collectively identify 2031 research priorities. We demonstrate that climate change, ecosystem services and protected areas are common terms found in the research priorities of many CRP studies, and that identified research priorities have become less unique over time. In addition, we show that there is a considerable variation in the size and composition of the groups involved in CRP studies, and that at least one aspect of the identified research priorities (lexical diversity) is related to the size of the CRP group. Although some CRP studies have been highly cited, the evidence that CRP studies have directly motivated research is weak, perhaps because most CRP studies have not directly involved organizations that fund science. We suggest that the most important impact of CRP studies may lie in their ability to connect individuals across sectors and help to build diverse communities of practice around important issues at the science–policy interface.
Direct and indirect effects of noise pollution alter biological communities in and near noise-exposed environments
Authors: Senzaki Masayuki , Kadoya Taku , Francis Clinton D.
Published: March 2020

Noise pollution is pervasive across every ecosystem on Earth. Although decades of research have documented a variety of negative impacts of noise to organisms, key gaps remain, such as how noise affects different taxa within a biological community and how effects of noise propagate across space. We experimentally applied traffic noise pollution to multiple roadless areas and quantified the impacts of noise on birds, grasshoppers and odonates. We show that acoustically oriented birds have reduced species richness and abundance and different community compositions in experimentally noise-exposed areas relative to comparable quiet locations. We also found both acoustically oriented grasshoppers and odonates without acoustic receptors to have reduced species richness and/or abundance in relatively quiet areas that abut noise-exposed areas. These results suggest that noise pollution not only affects acoustically oriented animals, but that noise may reverberate through biological communities through indirect effects to those with no clear links to the acoustic realm, even in adjacent quiet environments.
Hydroxyethoxy phenyl butanone, a new cosmetic preservative, does not cause bacterial cross-resistance to antimicrobials
Authors: Wesgate Rebecca , Menard-Szczebara Florence , Khodr Ahmad , Cupferman Sylvie , Maillard Jean-Yves
Published: March 2020

Introduction. Biocide-induced cross-resistance to antimicrobials in bacteria has been described and is a concern for regulators. We have recently reported on a new protocol to predict the propensity of biocide to induce phenotypic resistance in bacteria.

Aim. To measure bacterial propensity to develop antimicrobial resistance following exposure to a new cosmetic preservative developed by L’Oréal R and I.

Methodology. Well-established antimicrobials including triclosan (TRI) and benzalkonium chloride (BZC) and a new molecule hydroxyethoxy phenyl butanone (HEPB) were investigated for their antimicrobial efficacy, effect on bacterial growth, and their potential to induce resistance to chemotherapeutic antibiotics using a new predictive protocol.

Results. The use of this predictive protocol with

Staphylococcus aureus

,

Escherichia coli

and

Pseudomonas aeruginosa

showed that TRI and BZC significantly affected bacterial growth, MICs and minimum bactericidal concentrations (MBCs). There was no change in antibiotic susceptibility profile following exposure to BZC, but

E. coli

became intermediate resistant to tobramycin following treatment with TRI (0.00002 % w/v). HEPB did not change the antimicrobial susceptibility profile in

P. aeruginosa

and

S. aureus

but

E. coli

became susceptible to gentamicin. TRI exposure resulted in bacterial susceptibility profile alteration consistent with the literature and confirmed the use of TRI as a positive control in such a test.

Conclusion. Data produced on the propensity of a molecule to induce bacterial resistance is useful and appropriate when launching a new preservative.
Decreased bioefficacy of long-lasting insecticidal nets and the resurgence of malaria in Papua New Guinea
Authors: Vinit Rebecca , Timinao Lincoln , Bubun Nakei , Katusele Michelle , Robinson Leanne , Kaman Peter , Sakur Muker , Makita Leo , Reimer Lisa , Schofield Louis , Pomat Willie , Mueller Ivo , Laman Moses , Freeman Tim , Karl Stephan
Published: March 2020

Background

Papua New Guinea (PNG) has the highest malaria transmission outside of Africa and long-lasting insecticidal nets (LLINs) are the only vector-control tool distributed country-wide. LLINs were introduced into PNG in about 2006 and have been attributed to have had a huge impact on malaria transmission, with reductions in observed average malaria prevalence from 15.7% (2008) to 1% (2014). However, since 2015 malaria indicators in PNG have risen significantly. Similar trends have been observed in several African nations. In the present study, we observed a drastic reduction in bioefficacy of LLINs collected both from households as used nets and prior to use in original, unopened packaging. We hypothesise that decreased bioefficacy of LLIN is a major contributor to the observed malaria resurgence in PNG and possibly in other parts of the world.

Methods

New LLINs in original and unopened packaging (n=192) manufactured between 2007-2019 were collected in 15 PNG provinces. Used LLIN (n=40) manufactured between 2008 and 2017 were collected in 2 provinces. LLIN were subjected to standard WHO cone bioassays using fully susceptible An. farauti mosquitoes. A subset of LLIN was re-tested using fully susceptible An. gambiae G3 mosquitoes in order to ensure reproducibility of results.

Results

Only 7% (95% CI 4-12%) of new LLINs manufactured between 2013-2019 exhibited 100% mortality. However, 84% (95%CI: 65-84%) new nets manufactured in 2012 or before exhibited 100% mortality. Only 29 % of used LLIN less than 3 years old exhibited > 80% 24h-mortality. Results obtained in tests using An. farauti corresponded well with confirmatory tests conducted using An. gambiae.

Discussion

Bioefficacy of LLIN in PNG appears to have been highly variable since 2013, with few nets manufactured since 2013 meeting WHO standards. This time-frame coincides with malaria resurgence in the country. These results may have ramifications for LLIN-based malaria control that go beyond the local PNG scenario.
Deficient uracil base excision repair leads to persistent dUMP in HIV proviruses during infection of monocytes and macrophages
Authors: Meshesha Mesfin , Esadze Alexandre , Cui Junru , Churgulia Natela , Sahu Sushil Kumar , Stivers James T.
Published: March 2020

Non-dividing cells of the myeloid lineage such as monocytes and macrophages are target cells of HIV that have low dNTP pool concentrations and elevated levels of dUTP, which leads to frequent incorporation of dUMP opposite to A during reverse transcription (“uracilation”). One factor determining the fate of dUMP in proviral DNA is the host cell uracil base excision repair (UBER) system. Here we explore the relative UBER capacity of monocytes (MC) and monocyte-derived macrophages (MDM) and the fate of integrated uracilated viruses in both cell types to understand the implications of viral dUMP on HIV diversification and infectivity. We find that monocytes are almost completely devoid of functional UBER, while macrophages are mainly deficient in the initial enzyme uracil DNA glycosylase (hUNG2). Accordingly, dUMP persists in viral DNA during the lifetime of a MC and can only be removed after differentiation of MC into MDM. Overexpression of human uracil DNA glycosylase in MDM prior to infection resulted in rapid removal of dUMP from HIV cDNA and near complete depletion of dUMP-containing viral copies. This finding establishes that the low hUNG2 expression level in these cells limits UBER but that hUNG2 is restrictive against uracilated viruses. In contrast, overexpression of hUNG2 after viral integration did not accelerate the excision of uracils, suggesting that they may poorly accessible in the context of chromatin. We found that viral DNA molecules with incorporated dUMP contained unique (+) strand transversion mutations that were not observed when dUMP was absent (G→T, T→A, T→G, A→C). These observations and other considerations suggest that dUMP introduces errors predominantly during (-) strand synthesis when the template is RNA. These mutations may arise from the increased mispairing and duplex destabilizing effects of dUMP relative to dTMP during reverse transcription. Overall, the likelihood of producing a functional virus fromin vitroinfection of MC is about 50-fold and 300-fold reduced as compared to MDM and activated T cells. The results implicate viral dUMP incorporation in MC and MDM as a potential viral diversification and restriction pathway during human HIV infection.
Germline and Tumor Whole Genome Sequencing as a Diagnostic Tool to Resolve Suspected Lynch Syndrome
Authors: Pope Bernard J. , Clendenning Mark , Rosty Christophe , Mahmood Khalid , Georgeson Peter , Joo Jihoon E. , Walker Romy , Hutchinson Ryan A. , Jayasekara Harindra , Joseland Sharelle , Como Julia , Preston Susan , Spurdle Amanda B. , Macrae Finlay A. , Win Aung K. , Hopper John L. , Jenkins Mark A. , Winship Ingrid M. , Buchanan Daniel D.
Published: March 2020

Background

People who develop mismatch repair (MMR) deficient cancer in the absence of a germline MMR gene pathogenic variant or hypermethylation of theMLH1gene promoter in their tumor are classified as having suspected Lynch syndrome (SLS). We applied germline whole genome sequencing (WGS) and targeted and genome-wide tumor sequencing approaches to identify the underlying cause of tumor MMR-deficiency in SLS.

Methods

Germline WGS was performed on 14 cancer-affected people with SLS, including two sets of first-degree relatives. Tumor tissue was sequenced for somatic MMR gene mutations by targeted, whole exome sequencing or WGS. Germline pathogenic variants, including complex structural rearrangements and non-coding variants, were assessed for the MMR genes. Tumor mutation burden and mutational signatures.

Results

Germline WGS identified pathogenic MMR variants in 3 of the 14 (21.4%) SLS cases including a 9.5Mb inversion disrupting exons 1-7 ofMSH2in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8/11 (72.7%) tumors tested, supporting a non-inherited cause of tumor MMR-deficiency. In the second mother-daughter pair, the combined analysis of germline and tumor by WGS supported a somatic rather than inherited cause of their tumor MMR-deficiency, through presence of double somaticMSH2mutations in their respective tumors.

Conclusion

Germline WGS of people with SLS improved the identification of Lynch syndrome. When coupled with tumor sequencing, >70% of the people with SLS were resolved as having double somatic MMR mutations and a non-inherited cause for their tumor MMR-deficiency.
From work stress to disease: A computational model
Authors: de Grave Remco Benthem , Hasselman Fred , Bijleveld Erik
Published: March 2020

In modern society, work stress is highly prevalent. Problematically, work stress can cause disease. To help understand the causal relationship between work stress and disease, we present a computational model of this relationship. That is, drawing from allostatic load theory, we captured the link between work stress and disease in a set of mathematical formulas. With simulation studies, we then examined our model’s ability to reproduce key findings from previous empirical research. Specifically, results from Study 1 suggested that our model could accurately reproduce established findings on daily fluctuations in cortisol levels (both on the group level and the individual level). Results from Study 2 suggested that our model could accurately reproduce established findings on the relationship between work stress and cardiovascular disease. Finally, results from Study 3 yielded new predictions about the relationship between workweek configurations (i.e., how working hours are distributed over days) and the subsequent development of disease. Together, our studies suggest a new, computational approach to studying the causal link between work stress and disease. We suggest that this approach is fruitful, as it aids the development of falsifiable theory, and as it opens up new ways of generating predictions about why and when work stress is (un)healthy.
The effects of border control and quarantine measures on global spread of COVID-19
Authors: Hossain M. Pear , Junus Alvin , Zhu Xiaolin , Jia Pengfei , Wen Tzai-Hung , Pfeiffer Dirk , Yuan Hsiang-Yu
Published: March 2020

The rapid expansion of coronavirus (COVID-19) has been observed in many parts of the world. Many newly reported cases of this new coronavirus during early outbreak phases have been associated with travel history from an epidemic region (identified as imported cases). For those cases without travel history, the risk of wider spreads through community contact is even higher. However, most population models assume a homogeneous infected population without considering that the imported and secondary cases contracted by the imported cases can pose a different risk to community spread.

We have developed an “easy-to-use” mathematical framework extending from a meta-population model embedding city-to-city connections to stratify the dynamics of transmission waves caused by imported, secondary, and others from an outbreak source region when control measures are considered. Using the dynamics of the secondary cases, we are able to determine the probability of community spread.

Using the top 10 visiting cities from Wuhan in China as an example, we first demonstrated that the arrival time and the dynamics of the outbreaks at these cities can be successfully predicted under the reproductive number R0 = 2.92 and latent period τ = 5.2 days. Next, we showed that although control measures can gain extra 32.5 and 44.0 days in arrival time through a high intensive border control measure and a shorter time to quarantine under a low R0 (1.4), if the R0 is higher (2.92), only 10 extra days can be gained for each of the same measures. This suggests the importance of lowering the incidence at source regions together with infectious disease control measures in susceptible regions. The study allows us to assess the effects of border control and quarantine measures on the emergence and the global spread in a fully connected world using the dynamics of the secondary cases.
Serological immunochromatographic approach in diagnosis with SARS-CoV-2 infected COVID-19 patients
Authors: Pan Yunbao , Li Xinran , Yang Gui , Fan Junli , Tang Yueting , Zhao Jin , Long Xinghua , Guo Shuang , Zhao Ziwu , Liu Yinjuan , Hu Hanning , Xue Han , Li Yirong
Published: March 2020

An outbreak of new coronavirus SARS-CoV-2 was occurred in Wuhan, China and rapidly spread to other cities and nations. The standard diagnostic approach that widely adopted in the clinic is nuclear acid detection by real-time RT-PCR. However, the false-negative rate of the technique is unneglectable and serological methods are urgently warranted. Here, we presented the colloidal gold-based immunochromatographic (ICG) strip targeting viral IgM or IgG antibody and compared it with real-time RT-PCR. The sensitivity of ICG assay with IgM and IgG combinatorial detection in nuclear acid confirmed cases were 11.1%, 92.9% and 96.8% at the early stage (1-7 days after onset), intermediate stage (8-14 days after onset), and late stage (more than 15 days), respectively. The ICG detection capacity in nuclear acid-negative suspected cases was 43.6%. In addition, the consistencies of whole blood samples with plasma were 100% and 97.1% in IgM and IgG strips, respectively. In conclusion, serological ICG strip assay in detecting SARS-CoV-2 infection is both sensitive and consistent, which is considered as an excellent supplementary approach in clinical application.
Clinical Characteristics and Durations of Hospitalized Patients With COVID-19 in Beijing: A Retrospective Cohort Study
Authors: Zhao Wen , Zha Xiangyi , Wang Ning , Li Dongzeng , Li Aixin , Yu Shikai
Published: March 2020

Objective

To give the information on clinical characteristics and different durations of COVID-19 and to identify the potential risk factors for longer hospitalization duration.

Methods

In this retrospective study, we enrolled 77 patients (mean age: 52±20 years; 44.2% males) with laboratory-confirmed COVID-19 admitted to Beijing YouAn Hospital during 21st Jan and 8th February 2020. Epidemiological, clinical, and radiological data on admission were collected; complications and outcomes were followed up until 26th February 2020. The study’s endpoint was the discharge within two weeks. Cox proportional-hazards regression was performed to identify risk factors for longer hospitalization duration.

Results

Of 77 patients, there were 34 (44.2%) males, 24 (31.2%) with comorbidities, 22 (28.6%) lymphopenia, 20 (26.0%) categorized as severe patients, and 28 (36.4%) occurred complications. By the end of follow-up, 64 (83.1%) patients were discharged home, 8 remained in hospital and 5 died. 36 (46.8%) patients were discharged within 14 days and thus reached the study endpoint, including 34 (59.6%) of 57 non-severe patients and 2 (10%) of 20 severe patients. The overall cumulative probability of the endpoint was 48.3%. Hospital length of stay and duration of exposure to discharge for 64 discharged patients were 13 (10-16.5) and 23 (18-24.5) days, respectively. Multivariable stepwise Cox regression model showed that bilateral pneumonia on CT scan, shorter time from the illness onset to admission, severity of disease and lymphopenia were independently associated with longer duration of hospitalization.

Conclusions

COVID-19 has significantly shorter duration of disease and hospital length of stay than SARS. Bilateral pneumonia on CT scan, shorter period of illness onset to admission, lymphopenia, severity of disease are the risk factors for longer hospitalization duration of COVID-19.

Significance Statement

In this study, we reported that the average hospital length of stay for discharged patients with COVID-19 is 13 days and the average time of clinical course of COVID-19 is 23 days, both of which are significantly shorter than that of SARS. The risk factors for longer hospitalization duration of COVID-19 include bilateral pneumonia on CT scan, shorter period of illness onset to admission, lymphopenia, and severity of disease. There findings might be helpful for the countries or territories facing the threat of COVID-19 to well prepare and rebalance their medical resources.
Lower DNA methylation levels in CpG island shores of CR1, CLU, and PICALM genes in the blood of Alzheimer’s disease patients
Authors: Mitsumori Risa , Sakaguchi Kazuya , Niida Shumpei , Shimoda Nobuyoshi
Published: March 2020

The aim of the present study was to (1) investigate the relationship between late onset AD and DNA methylation levels in the top six Alzheimer’s disease (AD)-related genes in blood and (2) examine its applicability to the diagnosis of AD. We examined methylation differences at CpG island shores in the top six genes using Sanger sequencing, and one of two groups of 48 AD patients and 48 elderly controls was used for a test or replication analysis. We found that methylation levels in three out of the six genes, CR1, CLU, and PICALM, were lower in AD subjects. The combination of CLU methylation levels and the APOE genotype classified AD patients with AUC=0.84 and 0.80 in the test and replication analyses, respectively. Our results implicate methylation differences at the CpG island shores of AD-related genes in the onset of AD and suggest their diagnostic value.
Excess cases of Influenza like illnesses in France synchronous with COVID19 invasion
Authors: Boëlle Pierre-Yves ,   the Sentinelles syndromic and viral surveillance group
Published: March 2020

Several French regions where COVID19 has been reported currently show a renewed increase in ILI cases in the general practice based Sentinelles network. Here we computed the number of excess cases by region and found correlation with the number of reported COVID19 cases so far. These data suggest larger circulation of SARS-CoV-2 in the French population than apparent from confirmed cases.
Expected impact of COVID-19 outbreak in a major metropolitan area in Brazil
Authors: Rocha Filho Tarcísio M. , dos Santos Fabiana Sherine Ganem , Gomes Victor Bertollo , Rocha Thiago Augusto Hernandes , Croda Julio Henrique Rosa , Ramalho Walter Massa , de Araújo Wildo Navegantes
Published: March 2020

In January 2020 China reported to the World Health Organization an outbreak of pneumonia of undetermined origin in the city of Wuhan, Hubei. In January 30, 2020, the World Health Organization declared the outbreak of COVID-19 as a Public Health Emergency of International Interest (PHEI).

Objectives

The aim of this study is to assess the impact of a COVID-19 epidemic in the metropolitan region of São Paulo, Brazil.

Methods

We used a generalized SEIR (Susceptibles, Exposed, Infectious, Recovered) model, with additional Hospitalized variables (SEIHR model) and age-stratified structure to analyze the expected time evolution during the onset of the epidemic in the metropolitan area of São Paulo. The model allows to determine the evolution of the number of cases, the number of patients admitted to hospitals and deaths caused by COVID-19. In order to investigate the sensibility of our results with respect to parameter estimation errors we performed Monte Carlo analysis with 100 000 simulations by sampling parameter values from an uniform distribution in the confidence interval.

Results

We estimate 1 368 (IQR: 880, 2 407) cases, 301 (22%) in older people (≥60 years), 81 (50, 143) hospitalizations, and 14 (9, 26) deaths in the first 30 days, and 38 583 (IQR: 16 698, 113, 163) cases, 8 427 (21.8%) in older people (≥60 years), 2181 (914, 6392) hospitalizations, and 397(166, 1205) deaths in the first 60 days.

Limitations

We supposed a constant transmission probability Pc among different age-groups, and that every severe and critic case will be hospitalized, as well as that the detection capacity in all the primary healthcare services does not change during the outbreak.

Conclusion

Supposing the reported parameters in the literature apply in the city of São Paulo, our study shows that it is expected that the impact of a COVID-19 outbreak will be important, requiring special planning from the authorities. This is the first study for a major metropolitan center in the south hemisphere, and we believe it can provide policy makers with a prognosis of the burden of the pandemic not only in Brazil, but also in other tropical zones, allowing to estimate total cases, hospitalization and deaths, in support to the management of the public health emergence caused by COVID-19.
Indications for healthcare surge capacity in European countries facing an exponential increase in COVID19 cases
Authors: Verelst Frederik , Kuylen Elise , Beutels Philippe
Published: March 2020

European healthcare systems face extreme pressure from COVID-19. We estimate such pressure by relating both country-specific accumulated COVID-19 deaths (intensity-approach) and active COVID-19 cases (magnitude-approach) to measures of healthcare system capacity: hospital beds, healthcare workers and healthcare expenditure. On March 25, 2020 - relative to Italy on March 11- we found Spain, The Netherlands and France to experience the highest pressure using the intensity-approach with a composite measure for healthcare capacity. For updates see www.covid-hcpressure.org
Propagation analysis and prediction of the COVID-19
Authors: Li Lixiang , Yang Zihang , Dang Zhongkai , Meng Cui , Huang Jingze , Meng Hao Tian , Wang Deyu , Chen Guanhua , Zhang Jiaxuan , Peng Haipeng
Published: March 2020

Based on the official data modeling, this paper studies the transmission process of the Corona Virus Disease 2019 (COVID-19). The error between the model and the official data curve is within 3%. At the same time, it realized forward prediction and backward inference of the epidemic situation, and the relevant analysis help relevant countries to make decisions.
International expansion of a novel SARS-CoV-2 mutant
Authors: Wang Minjin , Li Mengjiao , Ren Ruotong , Bråve Andreas , van der Werf Sylvie , Chen En-Qiang , Zong Zhiyong , Li Weimin , Ying Binwu
Published: March 2020

Letter to the editor. There is no abstract. The summary was showed: SARS-CoV-2 has inevitably mutated during its pandemic spread to cause unpredictable effects on COVID-19 and complicate epidemic control efforts. Here we report that a novel SARS-CoV-2 mutation (ORF3a) appears to be spreading worldwide, which deserves close attention.
Examination of WHO/INRUD Core Drug Use Indicators at Public Primary Healthcare Centers in Kisii County, Kenya
Authors: Okalebo Faith A. , Guantai Eric M. , Nyabuti Aggrey O.
Published: March 2020

Background

Irrational drug use is a global problem. However, the extent of the problem is higher in low-income countries. This study set out to assess and characterize drug use at the public primary healthcare centers (PPHCCs) in a rural county in Kenya, using the World Health Organization/ International Network for the Rational Use of Drugs (WHO/INRUD) core drug use indicators methodology.

Methods

Ten PPHCCs were randomly selected. From each PPHCC, ninety prescriptions from October to December 2018 were sampled and data extracted. Three-hundred (30 per PPHCC) patients and ten (1 per PPHCC) dispensers were also observed and interviewed. The WHO/INRUD core drug use indicators were used to assess the patterns of drug use.

Results

The average number of drugs per prescription was 2.9 (SD 0.5) (recommended: 1.6– 1.8), percentage of drugs prescribed by generic names was 27.7% (recommended: 100%); the percentage of prescriptions with an antibiotic was 84.8% (recommended: 20.0–26.8%), and with an injection prescribed was 24.9% (recommended: 13.4–24.1%). The percentage of prescribed drugs from the Kenya Essential Medicines List was 96.7% (recommended: 100%). The average consultation time was 4.1 min (SD 1.7) (recommended: ≥10 min), the average dispensing time was 131.5 sec (SD 41.5) (recommended: ≥90 sec), the percentage of drugs actually dispensed was 76.3% (recommended: 100%), the percentage of drugs adequately labeled was 22.6% (recommended: 100%) and percentage of patients with correct knowledge of dispensed drugs was 54.7% (recommended: 100%). Only 20% of the PPHCCs had a copy of KEML available, and 80% of the selected essential drugs assessed were available.

Conclusion

The survey shows irrational drug use practices, particularly polypharmacy, non-generic prescribing, overuse of antibiotics, short consultation time and inadequacy of drug labeling. Effective programs and activities promoting the rational use of drugs are the key interventions suggested at all the health facilities.
Transmissibility of coronavirus disease 2019 (COVID-19) in Chinese cities with different transmission dynamics of imported cases
Authors: Chong Ka Chun , Cheng Wei , Zhao Shi , Ling Feng , Mohammad Kirran N. , Wang Maggie Haitian , Zee Benny Chung Ying , Wei Lei , Xiong Xi , Liu Hengyan , Wang Jingxuan , Chen Enfu
Published: March 2020

Background

Monitoring the time-varying reproduction number (Rt) of the disease is useful in determining whether there is sustained transmission in a population. In this study, we examinedRtof COVID-19 and compared its transmissibility between different intervention periods in Hangzhou and Shenzhen.

Methods

Daily aggregated counts of confirmed imported and local cases between January 1, 2020 and March 13, 2020 were analysed. A likelihood function was constructed to estimateRt, accounting for imported cases.

Results

Although Hangzhou had fewer number of cases than Shenzhen, Shenzhen had higher proportion of imported cases than Hangzhou (83% vs 29%). Since the epidemic of COVID-19 in Shenzhen was dominated by imported cases,Rtwas kept below unity through time. On the contrary,Rtwas greater than unity in Hangzhou from 16 January to 7 February due to the surge in local cases. Credits to the Wuhan lockdown and outbreak response measures following the local lockdown,Rtdecreased steadily and dropped below unity in mid-February.

Conclusion

The lockdown measures and local outbreak responses helped reduce the potential of local transmission in Hangzhou and Shenzhen. Meanwhile, cities with similar epidemic trend could have different transmission dynamics given the variation in imported cases.
Population-wide Screening for Germline Variants of Hereditary Cancer Genes in 12K Unselected Japanese Colorectal Cancers and 27K Controls
Authors: Fujita Masashi , Liu Xiaoxi , Iwasaki Yusuke , Terao Chikashi , Takata Sadaaki , Inai Chihiro , Aoi Tomomi , Maejima Kazuhiro , Hirata Makoto , Murakami Yoshinori , Kamatani Yoichiro , Kubo Michiaki , Akagi Kiwamu , Matsuda Koichi , Nakagawa Hidewaki , Momozawa Yukihide
Published: March 2020

Background & Aims

Colorectal cancer (CRC) is one of the most common cancers in Western countries and Japan. Currently, a few % of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes, predominantly the DNA mismatch repair genes. To establish a universal screening strategy for hereditary CRCs, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations.

Methods

We analyzed the coding regions of 27 cancer-predisposing genes, including mismatch repair genes,APC, andBRCA1/2, in 12,503 unselected Japanese CRC patients and 23,705 controls aged ≥ 60 years without any personal or family history of cancer by target sequencing and genome-wide SNP chip data. Their clinical significance was assessed using ClinVar and the guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP).

Results

We identified 4,804 variants in the 27 genes and annotated them as 397 pathogenic variants, 941 benign variants, and 3,466 variants of uncertain significance, of which 43.6% were registered in neither ClinVar nor dbSNP. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant of the 27 genes. The pathogenic variants ofMSH2(odds ratio (OR) =18.1),MLH1(OR=8.6),MSH6(OR=4.9),APC(OR=49.4),BRIP1(OR=3.6),BRCA1(OR=2.6),BRCA2(OR=1.9), andTP53(OR=1.7) were significantly associated with CRC development in the Japanese population (P-values < 0.01, FDR<0.05). Furthermore, we confirmed copy number variants (CNVs) ofMSH2/EPCAM, MLH1, andAPCby multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR in this cohort (n = 23), including whole gene duplications ofMSH2andAPC.These pathogenic variants were significantly associated with the diagnostic age and personal/family history of other types of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes.

Conclusions

This is the largest study of CRC heredity in the Asian population and would contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs. Universal screening for CRC risk should be assessed in multiple genes, includingBRCA1/2andBRIP1. These data would facilitate risk assessment of cancer and optimize the screening strategy.
Multimodal determinants of phase-locked dynamics across deep-superficial hippocampal sublayers during theta oscillations
Authors: Navas-Olive Andrea , Valero Manuel , Jurado-Parras Teresa , de Salas-Quiroga Adan , Averkin Robert G , Gambino Giuditta , Cid Elena , de la Prida Liset M
Published: March 2020

Theta oscillations play a major role in temporarily defining the hippocampal rate code by translating behavioural sequences into neuronal representations. However, mechanisms constraining phase timing and cell-type specific phase preference are unknown. Here, we employ computational models tuned with evolutionary algorithms to evaluate phase preference of individual CA1 pyramidal cells recorded in mice and rats not engaged in any particular memory task. We applied unbiased and hypothesis-free approaches to identify effects of intrinsic and synaptic factors, as well as cell morphology, in determining phase preference. We found that perisomatic inhibition delivered by complementary populations of basket cells interacts with input pathways to shape phase-locked specificity of deep and superficial pyramidal cells. Somatodendritic integration of fluctuating glutamatergic inputs defined cycle-by-cycle by unsupervised methods demonstrated that firing selection is tuneable across sublayers. Our data identify different mechanisms of phase-locking selectivity that are instrumental for high-level flexible dynamical representations.
Formation of uniform reaction volumes using concentric amphiphilic microparticles
Authors: Destgeer Ghulam , Ouyang Mengxing , Wu Chueh-Yu , Di Carlo Dino
Published: March 2020

Reactions performed in uniform microscale volumes have enabled numerous applications in the analysis of rare entities (e.g. cells and molecules), however, sophisticated instruments are usually required to form large numbers of uniform compartments. Here, uniform aqueous droplets are formed by simply mixing microscale multi-material particles, consisting of concentric hydrophobic outer and hydrophilic inner layers, with oil and water. The particles are manufactured in batch using a 3D printed device to co-flow four concentric streams of polymer precursors which are polymerized with UV light. The size of the particles is readily controlled by adjusting the fluid flow rate ratios and mask design; whereas the cross-sectional shapes are altered by microfluidic nozzle design in the 3D printed device. Once a particle encapsulates an aqueous volume, each “dropicle” provides uniform compartmentalization and customizable shape-coding for each sample volume to enable multiplexing of uniform reactions in a scalable manner. We implement an enzymatically-amplified affinity assay using the dropicle system, yielding a detection limit of <1 pM with a dynamic range of at least 3 orders of magnitude. Moreover, multiplexing using two types of shape-coded particles was demonstrated without cross talk, laying a foundation for democratized single-entity assays.
Autism and Williams syndrome: dissimilar socio-cognitive profiles with similar patterns of abnormal gene expression in the blood
Authors: Niego Amy , Benítez-Burraco Antonio
Published: March 2020

Autism Spectrum Disorders (ASD) and Williams Syndrome (WS) exhibit quite opposite features in the social domain, but also share some common underlying behavioral and cognitive deficits. It is not clear, however, which genes account for the attested differences (and similarities) in the socio-cognitive domain. In this paper we adopted a comparative-molecular approach and looked for genes that might be differentially (or similarly) regulated in the blood of people with these two conditions. We found a significant overlap between differentially-expressed genes compared to neurotypical controls, with most of them exhibiting a similar trend in both conditions, but with genes being more dysregulated in WS than in ASD. These genes are involved in aspects of brain development and function (particularly, dendritogenesis) and are expressed in brain areas (particularly, the cerebellum, the thalamus and the striatum) of relevance for the ASD and the WS etiopathogenesis.