bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetically-proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers
Authors: Yarmolinsky James , Díez-Obrero Virginia , Richardson Tom G , Pigeyre Marie , Sjaarda Jennifer , Paré Guillaume , Walker Venexia M , Vincent Emma E , Tan Vanessa Y , Obón-Santacana Mireia , Albanes Demetrius , Hampe Jochen , Gsur Andrea , Hampel Heather , Kampman Ellen , Pai Rish K , Jenkins Mark , Gallinger Steven , Casey Graham , Zheng Wei , Amos Christopher I ,   the International Lung Cancer Consortium,   the PRACTICAL consortium, Smith George Davey , Martin Richard M , Moreno Victor
Published: March 2021

Background

Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes.

Methods

Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 x 10-8) with systolic blood pressure in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Inverse-variance weighted random- effects models were used to examine associations between genetically-proxied inhibition of these drug targets and risk of cancer. Multivariable Mendelian randomization and colocalisation analyses were employed to examine robustness of findings to violations of Mendelian randomization assumptions.

Results

Genetically-proxied ACE inhibition equivalent to a 1 mmHg reduction in systolic blood pressure was associated with increased odds of colorectal cancer (OR 1.13, 95% CI 1.06-1.22; P = 3.6 x 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02-1.92; P = 0.035). There was little evidence of association of genetically-proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94-1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92-1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99-1.13; P = 0.08). Genetically-proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers.

Conclusion

Genetically-proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomised controlled trials for these medications.
Evolution of antibodies against SARS-CoV-2 over seven months: experience of the Nationwide Seroprevalence ENE-COVID Study in Spain
Authors: Pérez-Olmeda Mayte , Saugar José María , Fernández-García Aurora , Pérez-Gómez Beatriz , Pollán Marina , Avellón Ana , Pastor-Barriuso Roberto , Fernández-de Larrea Nerea , Martín Mariano , Cruz Israel , Sanmartín Jose L , Fedele Giovanni , León Paniagua Jose , Muñoz-Montalvo Juan F , Blanco Faustino , Yotti Raquel , Oteo-Iglesias Jesús
Published: March 2021

Objectives

To analyse temporal trends in SARS-CoV-2 anti-nucleocapsid IgG throughout the four rounds of the nationwide seroepidemiologic study ENE-COVID (April-November 2020), and to compare the fourth-round results of two immunoassays detecting antibodies against nucleocapsid and to S protein receptor-binding domain (RBD).

Methods

A chemiluminescent microparticle immunoassay (CMIA) was offered to all participants in the first three rounds (Abbott; anti-nucleocapsid IgG). In the fourth round we offered this test and a chemiluminescence immunoassay (CLIA) (Beckman; anti-RBD IgG) to i) a randomly selected sub-cohort, ii) participants who were IgG-positive in any of the three first rounds; and iii) participants who were IgG-positive in the fourth round by point-of-care immunochromatography.

Results

Immunoassays involving 10,153 participants (82.2% of people invited to donate samples) were performed in the fourth round. A total of 2595 participants (35.1% of participants with immunoassay results in the four rounds) were positive for anti-nucleocapsid IgG in at least one round. Anti-nucleocapsid IgG became undetectable in 43.3% of participants with positive first-round results. Pneumonia was more frequent in participants with anti-nucleocapsid IgG in all four rounds (11.2%) than those in which IgG became undetectable (2.4%).

In fourth round, anti-nucleocapsid and anti-RBD IgG were detected in 5.5% and 5.4% participants of the randomly selected sub-cohort, and in 26.6% and 25.9% participants with at least one previous positive result, respectively. Agreement between techniques was 90.3% (kappa: 0.72).

Conclusions

The response of IgG to SARS-CoV-2 is heterogeneous and conditioned by infection severity. A substantial proportion of the SARS-CoV-2 infected population may have negative serologic results in the post-infection months.
Quantifying Contact Patterns in Response to COVID-19 Public Health Measures in Canada
Authors: Brankston Gabrielle , Merkley Eric , Fisman David N. , Tuite Ashleigh R. , Poljak Zvonimir , Loewen Peter J. , Greer Amy L.
Published: March 2021

Background

A variety of public health measures have been implemented during the COVID-19 pandemic in Canada to reduce contact between individuals.

Objective

The objective of this study was to construct contact patterns to evaluate the degree to which social contacts rebounded to normal levels, as well as direct public health efforts toward age- and location-specific settings.

Design

Four population-based cross-sectional surveys.

Setting

Canada.

Participants

Members of a paid panel representative of Canadian adults by age, gender, official language, and region of residence.

Methods

Respondents provided information about the age and setting for each direct contact made in a 24-hour period. Contact matrices were constructed and contacts for those under the age of 18 years imputed. The next generation matrix approach was used to estimate the reproduction number (Rt) for each survey. Respondents with children estimated the number of contacts their children made in school and extracurricular settings.

Results

Estimated Rt values were 0.49 (95% CI: 0.29-0.69) for May, 0.48 (95% CI: 0.29-0.68) for July, 1.06 (95% CI: 0.63-1.52) for September, and 0.81 (0.47-1.17) for December. The highest proportion of reported contacts occurred within the home (51.3% in May), in ‘other’ locations (49.2% in July) and at work (66.3% and 65.4% in September and December). Respondents with children reported an average of 22.7 (95% CI: 21.1-24.3) (September) and 19.0 (95% CI 17.7-20.4) (December) contacts at school per day per child in attendance.

Conclusion

The skewed distribution of reported contacts toward workplace settings in September and December combined with the number of reported school-related contacts suggest that these settings represent important opportunities for transmission emphasizing the need to ensure infection control procedures in both workplaces and schools.
SARS-CoV-2 specific immune-signature in direct contacts of COVID-19 cases protect them from contracting disease: A Retrospective Study
Authors: Raghav Sunil K. , Sen Kaushik , Ghosh Arup , Datta Sudeshna , Ahad Abdul , Jha Atimukta , Chatterjee Sanchari , Suranjika Sandhya , Sengupta Soumya , Bhattacharya Gargee , Shriwas Omprakash , Avula Kiran , Kshatri Jayasingh , Prasad Punit , Parida Ajay K.
Published: March 2021

The response to SARS-CoV-2 is largely impacted by the level of exposure and the status of immunity. The nature of protection shown by direct contacts of COVID-19 positive patients is quite intriguing to note. We aimed to study the immune differences reinforcing contact individuals in circumventing the disease. Our observation showed direct contacts of PCR positive patients developed elevated neutralizing antibody titres and cytokine levels. On the other hand, single cell data revealed differential usage of V(D)J genes and unique BCR clonotypes imparting protective immune signatures.

Topics

serologic tests, immunoglobulin a, immunoglobulin g, immunoglobulin m, antibody titre; cytokine levels; virus neutralization; V(D)J sequencing; BCR clonotypes
Comparing COVID-19 risk factors in Brazil using machine learning: the importance of socioeconomic, demographic and structural factors
Authors: Baqui Pedro , Marra Valerio , Alaa Ahmed M. , Bica Ioana , Ercole Ari , van der Schaar Mihaela
Published: March 2021

Background

The COVID-19 pandemic continues to have a devastating impact on Brazil. Brazil’s social, health and economic crises are aggravated by strong societal inequities and persisting political disarray. This complex scenario motivates careful study of the clinical, socioeconomic, demographic and structural factors contributing to increased risk of mortality from SARS-CoV-2 in Brazil specifically.

Methods

We consider the Brazilian SIVEP-Gripe catalog, a very rich respiratory infection dataset which allows us to estimate the importance of several non-laboratorial and socio-geographic factors on COVID-19 mortality. We analyze the catalog using machine learning algorithms to account for likely complex interdependence between metrics.

Findings

The XGBoost algorithm achieved excellent performance, producing an AUC-ROC of 0.813 (95%CI 0.810–0.817), and outperforming logistic regression. Using our model we found that, in Brazil, socioeconomic, geographical and structural factors are more important than individual comorbidities. Particularly important factors were: The state of residence and its development index; the distance to the hospital (especially for rural and less developed areas); the level of education; hospital funding model and strain. Ethnicity is also confirmed to be more important than comorbidities but less than the aforementioned factors.

Interpretation

Socioeconomic and structural factors are as important as biological factors in determining the outcome of COVID-19. This has important consequences for policy making, especially on vaccination/non-pharmacological preventative measures, hospital management and healthcare network organization.

Funding

None.
Airborne Transmission of COVID-19 and Mitigation Using Box Fan Air Cleaners in a Poorly Ventilated Classroom
Authors: He Ruichen , Liu Wanjiao , Elson John , Vogt Rainer , Maranville Clay , Hong Jiarong
Published: March 2021

Many indoor places, including aged classrooms and offices, prisons, homeless shelters, etc., are poorly ventilated but resource-limited to afford expensive ventilation upgrade or commercial air purification systems, raising concerns on the safety of opening activities in these places in the era of COVID-19 pandemic. To address this challenge, using computational fluid dynamics, we conducted a systematic investigation of airborne transmission in a classroom equipped with a single horizontal unit ventilator (HUV) and evaluate the performance of low-cost box fan air cleaner for risk mitigation. Our study shows that placing box fan air cleaners in the classroom results in a substantial reduction of airborne transmission risk across the entire space. The air cleaner can achieve optimal performance when placed near the asymptomatic patient. However, without knowing the location of the patient, the performance of the cleaner is optimal near the HUV with the air flowing downwards. In addition, we find that it is more efficient in reducing aerosol concentration and spread in the classroom by adding air cleaners in comparison with raising the flow rate of HUV alone. The number and placement of air cleaners need to be adjusted to maintain its efficacy for larger classrooms and to account for the thermal gradient associated with human thermal plume and hot ventilation air during cold seasons. Overall, our study shows that box fan air cleaners can serve as an effective low-cost alternative for mitigating airborne transmission risks in poorly ventilated spaces.
A rapid review of COVID-19 vaccine prioritization in the U.S.: alignment between Federal guidance and State practice
Authors: Jain Vageesh , Schwarz Lara , Lorgelly Paula
Published: March 2021

Background

Population groups to be prioritized for COVID-19 vaccinations in the U.S. have been determined at the Federal level. Evidence suggests that there is variation in how States have implemented this guidance. This review examines how the position of population groups in vaccine priority lists varies between Federal guidance and State practice.

Methods

An online search of State vaccination prioritization plans was conducted. Data were extracted on each population group included and their relative position. A standardized ranking method was applied to provide a directional measure of variability in prioritization between State and Federal guidance, for each population group.

Results

Healthcare workers and those in long-term care facilities were largely prioritized in line with Federal guidance. Aside from early education staff, essential workers were often excluded at State level. Of the 37 States including frontline essential workers, 12 assigned them to a lower priority than recommended. Almost all States included the 65-74 year age group and most assigned them to a higher position than recommended in Federal guidance. Those with underlying medical conditions were similarly highly prioritized, although there was more variability across States. Some socially vulnerable groups (not included in Federal guidance) were highly prioritized by many States.

Conclusions

Across the U.S, the prioritization of groups for COVID-19 vaccination has been highly variable. Essential workers were the most often excluded or less highly prioritised group compared to Federal guidance. Some socially vulnerable groups were highly prioritized in State plans, whilst others were mentioned in only a few States. Future guidance must be relevant to local needs and values, to minimise any unwarranted heterogeneity in vaccine access across populations.
Exposure to SARS-CoV-2 within the household is associated with greater symptom severity and stronger antibody responses in a community-based sample of seropositive adults
Authors: Schrock Joshua M. , Ryan Daniel T. , Saber Rana , Benbow Nanette , Vaught Lauren A. , Reiser Nina , Velez Matthew P. , Hsieh Ryan , Newcomb Michael , Demonbreun Alexis R. , Mustanski Brian , McNally Elizabeth M. , D’Aquila Richard , McDade Thomas W.
Published: March 2021

Magnitude of SARS-CoV-2 virus exposure may contribute to symptom severity. In a sample of seropositive adults (n=1101), we found that individuals who lived with a known COVID-19 case exhibited greater symptom severity and IgG concentrations compared to individuals who were seropositive but did not live with a known case (P<0.0001).
Sex ratios and ‘missing women’ among Asian minority and migrant populations in Aotearoa/New Zealand: A retrospective cohort analysis
Authors: Simon-Kumar Rachel , Paynter Janine , Chiang Annie , Chabba Nimisha
Published: March 2021

Background

Recent research from the UK, USA, Australia, and Canada point to male-favouring Sex Ratios at Birth (SRB) among their Asian minority populations, attributed to son preference and sex-selective abortion within these cultural groups. The present study conducts a similar investigation of SRBs among New Zealand’s Asian minority and migrant populations, who comprise 15% of the population.

Methods

The New Zealand historical census series between 1976-2013 was used to examine SRBs between ages 0-5 by ethnicity. A retrospective birth cohort in New Zealand was created using the Stats NZ Integrated Data Infrastructure from 2003-2018. A logistic regression was conducted and adjusted for selected variables of interest including visa group, parity, maternal age and deprivation. Finally, associations between family size, ethnicity and family gender composition were examined in a subset of this cohort (families with 2 or 3 children).

Results

There was no evidence of ‘missing women’ or gender bias as indicated by a deviation from the biological norm in New Zealand’s Asian population. However, Indian and Chinese families were significantly more likely to have a third child if their first two children were females compared to two male children.

Conclusion

The analyses did not reveal male-favouring SRBs or any conclusive evidence of sex-selective abortion among Indian and Chinese populations. Based on this data, we conclude that in comparison to other western countries, New Zealand’s Asian migrant populations presents as an anomaly. The larger family sizes for Indian and Chinese populations where the first two children were girls suggested potentially ‘soft’ practices of son preference.

WHAT IS ALREADY KNOWN ON THIS SUBJECT

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There are discrepancies in Sex Ratios at Birth (SRB) among the Asian minority migrant populations – particularly Indian and Chinese populations –in countries like Canada, UK, USA. SRBs show a pronounced number of males over female children, suggesting a widespread practice of sex-selective abortions in these communities since the 1970s.

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These trends implicitly reflect social norms of gender bias through son preference, and daughter devaluation.

WHAT IS BEING ADDED

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The present study did not find evidence of skewed SRBs that favour boys over girls among Asian ethnicities. The analyses however did find a tendency for Indian and Chinese families to have larger families especially when the first two children were girls.

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Overall, the findings suggest the absence of widespread practices of sex-selective abortion making New Zealand an anomaly relative to other migrant-receiving countries. However, there are still vestiges of son preference that are seen through decisions around family size and gender composition.
Ancestrally and Temporally Diverse Analysis of Penetrance of Clinical Variants in 72,434 Individuals
Authors: Forrest Iain S. , Chaudhary Kumardeep , Vy Ha My T. , Bafna Shantanu , Jordan Daniel M. , Rocheleau Ghislain , Loos Ruth J.F. , Cho Judy H. , Do Ron
Published: March 2021

A major goal of genomic medicine is to quantify the disease risk of genetic variants. Here, we report the penetrance of 37,772 clinically relevant variants (including those reported in ClinVar1 and of loss-of-function consequence) for 197 diseases in an analysis of exome sequence data for 72,434 individuals over five ancestries and six decades of ages from two large-scale population-based biobanks (BioMe Biobank and UK Biobank). With a high-quality set of 5,359 clinically impactful variants, we evaluate disease prevalence in carriers and non-carriers to interrogate major determinants and implications of penetrance. First, we associate biomarker levels with penetrance of variants in known disease-predisposition genes and illustrate their clear biological link to disease. We then systematically uncover large numbers of ClinVar pathogenic variants that confer low risk of disease, even among those reviewed by experts, while delineating stark differences in variant penetrance by molecular consequence. Furthermore, we ascertain numerous variants present in non-European ancestries and reveal how increasing carrier age modifies penetrance estimates. Lastly, we examine substantial heterogeneity of penetrance among variants in known disease-predisposition genes for conditions such as familial hypercholesterolemia and breast cancer. These data indicate that existing categorical systems for variant classification do not adequately capture disease risk and warrant consideration of a more quantitative system based on population-based penetrance to evaluate clinical impact.
Prediction of severe COVID-19 cases requiring a ventilator in Tokyo, Japan
Authors: Kurita Junko , Sugawara Tamie , Ohkusa Yasushi
Published: March 2021

Background

To avoid exhaustion of medical resources by COVID-19, policy-makers must predict care needs, specifically the proportion of severe cases likely to need ventilator care.

Objective

This study was designed to use a statistical model to elucidate dynamics of severe cases in Tokyo and to discuss the timing of effective policy activation.

Methods

The study extended from April 27 through October 18, 2020 in Japan’s Tokyo Metropolitan area. Medical exhaustion was defined as use of more than half of the ventilator capacity available before the COVID-19 outbreak. We regressed the number of severe cases on the newly onset patients of more than 14 days prior. As earlier research indicated, the COVID-19 severity changed at the end of May. Therefore, we added dummy variables to reflect changing severity from June and its product with newly onset patients as the explanatory variable. Then we calculated the threshold using R(t): R(t)=0.99 for the number of patients 14 days prior was used as a threshold at which strong countermeasures should be activated to keep to avoid medical exhaustion.

Results

The critical number signaling medical exhaustion in Tokyo was defined as 655 cases. We selected 15, 30, 60 and 90 days prior as explanatory variables for explaining the number of severe cases. A coefficient of determination larger than 0.95 was inferred as indicating good fit. The threshold was estimated as more than 4500 cases for R(t)=1.1 and monotonically decreasing by R(t) to be 600 cases for R(t)=2.5.

Discussion and Conclusion

Results showed that newly onset patients reported more than 14 days prior can explain the number of severe cases very well. We also confirmed the threshold number of patients 14 days prior by R(t) for which strong countermeasures should be activated to avoid medical exhaustion with R(t)=0.99. This method is expected to be useful for countermeasure activation policies for Tokyo.
Relationships Between Parental Involvement and Suicidal Ideation among In-school Adolescents in Vietnam: A Multilevel Analysis of the Global School-Based Student Health Survey 2019
Authors: Long Khuong Quynh , Hanh Tran Thi Tuyet , Anh Hoang Thi Ngoc , Park Kidong , Takeuchi Momoe , Lam Nguyen Tuan , Nga Pham Thi Quynh , Anh Le Phuong , Van Tuan Le , Bao Tran Quoc , Nguyet Van Nguyen Hang , Thanh Pham Quoc , Phi Nguyen Hong , Anh Le Duong Minh , Phuong Nguyen Hong , Van Minh Hoang
Published: March 2021

Youth suicide is a leading cause of death among adolescents, but evidence about the influences of parental involvement on adolescent suicidal behaviors is inconsistent and have not been well studied. We used nationally representative data from the Vietnam Global School-based Student Health Survey (GSHS) 2019 (n = 7796 students aged 13–18 years). Using the 2-level random intercept logistic regressions, we evaluated the relationship between parental involvement (high expectation, monitoring, and understanding) and suicidal ideation and identified related factors of suicidal ideation. The overall prevalence of suicidal ideation was 15.6%. While high level of parental monitoring and understanding were associated with lower odds of suicidal ideation among adolescents (OR: 0.63; 95% CI: 0.52–0.77 and OR: 0.60; 95% CI: 0.49–0.73, respectively), high parental expectation was linked to higher odds of suicidal ideation (OR: 1.42; 95% CI: 1.24–1.63). Other risk factors at the individual- and school-level for suicidal ideation included being girls, living in urban areas, having mental health problems, involving in risk behaviors, suffering from bullying and violence, and poor school quality. Targeted suicide prevention initiatives should take into account comprehensive aspects of parent-child bonding, student, and school factors to mitigate the burden of suicidal behaviors among adolescents.
Computational Elucidation of Recombinant Fusion Protein Effect on Peptide-Directed Nanoparticles
Authors: Polasa Adithya , Mosleh Imann , Losey James , Abbaspourrad Alireza , Beitle Robert , Moradi Mahmoud
Published: March 2021

Nanoparticles synthesized using various peptides have optimized properties and functional abilities which can be achieved via peptide flexibility and site specificity. Using peptide Pd4 and other alanine substitution combinations of Pd4 attached to a green fluorescent protein (GFPuv), nanoparticles with well-defined sizes that are soluble in aqueous solutions can be produced. In this study, extensive molecular dynamics simulations explored the structural and functional differences between the free peptides and the peptides bound to the GFPuv used in nanoparticle production. Binding affinities of histidines of Pd4 peptide and its two mutants A6 and A11 to a palladium atom were calculated using the free energy perturbation method. Interestingly, the average particle sizes obtained from transmission electron microscopy (TEM) images correlated with our calculated free energies of different peptide sequences. Remarkably, when the peptide was bound to GFPuv, the free energies of histidine were very similar in the wild-type and other mutated peptides. However, this trend is not observed with free peptide simulations, where binding affinities differ by mutation of histidine residues. This study describes, at a molecular level, the role of amino acid sequence on binding affinity of the peptide to the surface of the palladium particles, and the functional ability of the GFPuv protein controlling these free energies irrespective of peptide sequence. Our study will provide a framework for designing free and protein attached peptides that facilitate peptide-mediated nanoparticle formation with well-regulated properties.
Emerging variants of concern in SARS-CoV-2 membrane protein: a highly conserved target with potential pathological and therapeutic implications
Authors: Shen Lishuang , Bard Jennifer Dien , Triche Timothy J. , Judkins Alexander R. , Biegel Jaclyn A. , Gai Xiaowu
Published: March 2021

Mutations in the SARS-CoV-2 Membrane (M) gene are relatively uncommon. The M gene encodes the most abundant viral structural protein, and is implicated in multiple viral functions, including initial attachment to the host cell via heparin sulfate proteoglycan, viral protein assembly in conjunction with the N and E genes, and enhanced glucose transport. We have identified a recent spike in the frequency of reported SARS-CoV-2 genomes carrying M gene mutations. This is associated with emergence of a new sub-B.1 clade defined by the previously unreported M:I82T mutation within TM3, the third of three membrane spanning helices implicated in glucose transport. The frequency of this mutation increased in the USA from 0.014% in October 2020 to 1.62% in February 2021, a 116-fold change. While constituting 0.7% of the isolates overall, M:I82T sub-B.1 lineage accounted for 14.4% of B.1 lineage isolates in February 2021, similar to the rapid initial increase previously seen with the B.1.1.7 and B.1.429 lineages, which quickly became the dominant lineages in Europe and California over a period of several months. A similar increase in incidence was also noted in another related mutation, V70L, also within the TM2 transmembrane helix. The rapid emergence of this sub-B.1 clade with recurrent I82T mutation suggests that this M gene mutation is more biologically fit, perhaps related to glucose uptake during viral replication, and should be included in ongoing genomic surveillance efforts and warrants further evaluation for potentially increased pathogenic and therapeutic implications.
Ras guanine nucleotide exchange factor RasGRP1 promotes acute inflammatory response and restricts inflammation-contributed cancer cell growth
Authors: Wang Cong , Li Xue , Yu Changping , Wang Luoling , Deng Rilin , Liu Hui , Chen Zihao , Zhang Yingdan , Fan Suping , Sun Hungyu , Zhu Haizhen , Wang Jianli , Tang Songqing
Published: March 2021

Acute inflammatory response needs to be tightly regulated for promoting the elimination of pathogens and preveting the risk of tumorigenesis, but the mechanism has not been fully elucidated. Here, we report that Ras guanine nucleotide releasing protein 1 (RasGRP1) plays a bifunctional regulator that promotes acute inflammation and inhibits inflammation-associated cancer. At the mRNA level,RasGRP1strengthens the inflammatory response by functioning as a competing endogenous RNA to specifically promote IL-6 expression by sponging let-7a.In vivooverexpression of theRasGRP13’ untranslated region significantly aggravated lipopolysaccharide-induced systemic inflammation and dextran sulphate sodium-induced colitis inIL-6+/+mice but not inIL-6-/-mice. At the protein level, RasGRP1 restricts the growth of inflammation-contributed cancer cells by impairing EGFR-SOS1-Ras-AKT signalling. Tumour patients with high RasGRP1 expression showed a better clinical outcome than those with low expression. Considering acute inflammation rarely leads to tumorigenesis, this work reveals that RasGRP1 is an essential bifunctional regulator for acute inflammatory response.
PBN-PVT projection modulates negative affective states in mice
Authors: Zhu Ya-Bing , Wang Yan , Hua Xiao-Xiao , Xu Ling , Liu Ming-Zhe , Zhang Rui , Liu Peng-Fei , Li Jin-Bao , Zhang Ling , Mu Di
Published: March 2021

Long-lasting negative affections dampen enthusiasm for life, and dealing with negative affective states is essential for individual survival. The parabrachial nucleus (PBN) and the thalamic paraventricular nucleus (PVT) are critical for modulating affective states in mice. However, the functional role of the PBN-PVT projection in modulating affective states remains elusive. Here, we show that the PBN neurons send dense projection fibers to the PVT and form direct excitatory synapses with the PVT neurons. Activation of the PBN-PVT projection or PVT-projecting PBN neurons induces robust anxiety-like, aversion-like, and fear-like behaviors without affecting nociceptive behaviors. Inhibition of the PBN-PVT projection or PVT-projecting PBN neurons reduces fear-like and aversion-like behaviors. Furthermore, the PVT neurons innervated by the PBN are activated by aversive stimulation, and activation of PBN-PVT projection enhances the neuronal activity of PVT neurons in response to the aversive stimulus. Activation of these downstream PVT neurons induces anxiety-like behavior behaviors. Thus, our study indicates that the PBN-PVT projection modulates negative affective states in mice.
On the generality and cognitive basis of base-rate neglect
Authors: Stengård Elina , Juslin Peter , Hahn Ulrike , van den Berg Ronald
Published: March 2021

Base rate neglect refers to people’s apparent tendency to underweight or even ignore base rate information when estimating posterior probabilities for events, such as the probability that a person with a positive cancer-test outcome actually does have cancer. While often replicated, almost all evidence for the phenomenon comes from studies that used problems with extremely low base rates, high hit rates, and low false alarm rates. It is currently unclear whether the effect generalizes to reasoning problems outside this “corner” of the entire problem space. Another limitation of previous studies is that they have focused on describing empirical patterns of the effect at the group level and not so much on the underlying strategies and individual differences. Here, we address these two limitations by testing participants on a broader problem space and modelling their responses at a single-participant level. We find that the empirical patterns that have served as evidence for base-rate neglect generalize to a larger problem space, albeit with large individual differences in the extent with which participants “neglect” base rates. In particular, we find a bi-modal distribution consisting of one group of participants who almost entirely ignore the base rate and another group who almost entirely account for it. This heterogeneity is reflected in the cognitive modeling results: participants in the former group were best captured by a linear-additive model, while participants in the latter group were best captured by a Bayesian model. We find little evidence for heuristic models. Altogether, these results suggest that the effect known as “base-rate neglect” generalizes to a large set of reasoning problems, but varies largely across participants and may need a reinterpretation in terms of the underlying cognitive mechanisms.
Rapid tissue-specific screening ofWolbachia,CardiniumandRickettsiain Flies (Diptera: Sepsidae; Drosophilidae)
Authors: Wei Yuan Cher , Huicong Ding , Puniamoorthy Nalini
Published: March 2021

Maternally transmitted endosymbionts can negatively influence the reproduction of their arthropod hosts (e.g. male-killing, cytoplasmic incompatibility). However, such infections are rarely assessed in insect models such as Sepsidae or Drosophilidae that are routinely used in sexual selection studies. To detect infection and bacterial localisation in the host, we developed and optimised a tissue-specific multiplex screening protocol forWolbachia,CardiniumandRickettsiathat can be completed in a day. The robustness of the protocol was tested with the screening of multiple species and populations of flies commonly used in reproductive studies (N=147 flies; n=426 tissues). With triplex PCRs and more effective duplex PCRs, we detected both single and co-infections in most individuals from both families (Drosophilidae | Sepsidae; Single infection: 51.4% | 62.7%; Dual infection: 29.2% | 9.3%; Triple infection: 4.2% | 0%). Surprisingly, we documented the presence of all three reproductive bacteria in 32 wild-caught drosophilids from Singapore. Also, we note that most sepsid populations (19 out of 22) tested positive forCardinium. We found that theRickettsiainfection was overall low, but it was predominantly detected in the gastrointestinal tract instead of the reproductive tract, suggesting a potential horizontal transmission. Finally, we found that amplicon sequences of equivalent sizes between the three tissues from the same individuals share at least 98.8% identity, which suggests that the same endosymbiont strain inhabits within the whole arthropod. Overall, we believe this protocol is effective in detecting co-infections and understanding the transmission of various reproductive endosymbionts. It can also be used to assess endosymbiont infections in other insects.
Functional characterization of a DNA-dependent AAA ATPase inSimranZ1, a F cluster mycobacteriophage
Authors: Das Ritam , Bajpai Urmi
Published: March 2021

Mycobacteriophages are viruses ofMycobacteriumspp. with promising diagnostic and therapeutic potential. Phage genome exploration and characterization of their proteomes are essential to gain a better understanding of their role in phage biology. So far, about 2014 mycobacteriophages have been genomically defined and 1563 phage protein families (phamilies) are identified. However, the function of only a fraction (about 15%) is known and a majority of ORFs in phage genomes are hypothetical proteins. In this study, from the annotated genome of a F1 cluster mycobacteriophageSimranZ1, a putative AAA ATPase (Gp65, Pham 9410) is characterized as a DNA-dependent ATPase. Sequence-based functional annotation predicted Gp65 to belong to the P-loop NTPase superfamily, having AAA_24 and RecA/RadA domains which are known to be involved in ATP-dependent DNA repair/maintenance mechanism. On molecular docking, Gly21 and Ser23 of Gp65 showed specific binding with ATP. Using a microtiter plate assay, ATPase activity of Gp65 was experimentally verified which was found to increase in the presence of dsDNA. Gel electrophoresis under non-denaturing condition showed the oligomeric states of Gp65 and Transmission Electron Microscopy revealed it to exist as a hexamer having a prominent central pore with a diameter of 1.9 nm. In summary, functional characterization of Gp65 as a DNA dependent AAA ATPase indicates its role in DNA repair/maintenance mechanism in mycobacteriophages.
Direct Extraction of Signal and Noise Correlations from Two-Photon Calcium Imaging of Ensemble Neuronal Activity
Authors: Rupasinghe Anuththara , Francis Nikolas A , Liu Ji , Bowen Zac , Kanold Patrick O , Babadi Behtash
Published: March 2021

Neuronal activity correlations are key to understanding how populations of neurons collectively encode information. While two-photon calcium imaging has created a unique opportunity to record the activity of large populations of neurons, existing methods for inferring correlations from these data face several challenges. First, the observations of spiking activity produced by two-photon imaging are temporally blurred and noisy. Secondly, even if the spiking data were perfectly recovered via deconvolution, inferring network-level features from binary spiking data is a challenging task due to the non-linear relation of neuronal spiking to endogenous and exogenous inputs. In this work, we propose a methodology to explicitly model and directly estimate signal and noise correlations from two-photon fluorescence observations, without requiring intermediate spike deconvolution. We provide theoretical guarantees on the performance of the proposed estimator and demonstrate its utility through applications to simulated and experimentally recorded data from the mouse auditory cortex.
A Proposal of New Feature Selection Method Sensitive to Outliers and Correlation
Authors: Demirarslan Mert , Suner Aslı
Published: March 2021

In disease diagnosis classification, ensemble learning algorithms enable strong and successful models by training more than one learning function simultaneously. This study aimed to eliminate the irrelevant variable problem with the proposed new feature selection method and compare the ensemble learning algorithms’ classification performances after eliminating the problems such as missing observation, classroom noise, and class imbalance that may occur in the disease diagnosis data. According to the findings obtained; In the preprocessed data, it was seen that the classification performance of the algorithms was higher than the raw version of the data. When the algorithms’ classification performances for the new proposed advanced t-Score and the old t-Score method were compared, the feature selection made with the proposed method showed statistically higher performance in all data sets and all algorithms compared to the old t-Score method (p = 0.0001).
Extracellular matrix gene expression signatures as cell type and cell state identifiers
Authors: Sacher Fabio , Feregrino Christian , Tschopp Patrick , Ewald Collin Y.
Published: March 2021

Transcriptomic signatures based on cellular mRNA expression profiles can be used to categorize cell types and states. Yet whether different functional groups of genes perform better or worse in this process remains largely unexplored. Here we test the core matrisome - that is, all genes coding for structural proteins of the extracellular matrix - for its ability to delineate distinct cell types in embryonic single-cell RNA-sequencing (scRNA-seq) data. We show that even though expressed core matrisome genes correspond to less than 2% of an entire cellular transcriptome, their RNA expression levels suffice to recapitulate important aspects of cell type-specific clustering. Notably, using scRNA-seq data from the embryonic limb, we demonstrate that core matrisome gene expression outperforms random gene subsets of similar sizes and can match and exceed the predictive power of transcription factors. While transcription factor signatures generally perform better in predicting cell types at early stages of chicken and mouse limb development,i.e.,when cells are less differentiated, the information content of the core matrisome signature increases in more differentiated cells. Our findings suggest that each cell type produces its own unique extracellular matrix, or matreotype, which becomes progressively more refined and cell type-specific as embryonic tissues mature.

Highlights

Cell types produce unique extracellular matrix compositions

Dynamic extracellular matrix gene expression profiles hold predictive power for cell type and cell state identification
Pheniqs 2.0: accurate, high performance Bayesian decoding and confidence estimation for combinatorial barcode indexing
Authors: Galanti Lior , Shasha Dennis , Gunsalus Kristin C.
Published: March 2021

Background

Systems biology increasingly relies on deep sequencing with combinatorial index tags to associate biological sequences with their sample, cell, or molecule of origin. Accurate data interpretation depends on the ability to classify sequences based on correct decoding of these combinatorial barcodes. The probability of correct decoding is influenced by both sequence quality and the number and arrangement of barcodes. The rising complexity of experimental designs calls for a probability model that accounts for both sequencing errors and random noise, generalizes to multiple combinatorial tags, and can handle any barcoding scheme. The needs for reproducibility and community benchmark standards demand a peer-reviewed tool that preserves decoding quality scores and provides tunable control over classification confidence that balances precision and recall. Moreover, continuous improvements in sequencing throughput require a fast, parallelized and scalable implementation.

Results

We developed a flexible, robustly engineered software that performs probabilistic decoding and supports arbitrarily complex barcoding designs. Pheniqs computes the full posterior decoding error probability of observed barcodes by consulting basecalling quality scores and prior distributions, and reports sequences and confidence scores in Sequence Alignment/Map (SAM) fields. The product of posteriors for multiple independent barcodes provides an overall confidence score for each read. Pheniqs achieves greater accuracy than minimum edit distance or simple maximum likelihood estimation, and it scales linearly with core count to enable the classification of >11 billion reads in 1h15m using <50 megabytes of memory. Pheniqs has been in production use for seven years in our genomics core facility.

Conclusions

We introduce a computationally efficient software that implements both probabilistic and minimum distance decoders and show that decoding barcodes using posterior probabilities is more accurate than available methods. Pheniqs allows fine-tuning of decoding sensitivity using intuitive confidence thresholds and is extensible with alternative decoders and new error models. Any arbitrary arrangement of barcodes is easily configured, enabling computation of combinatorial confidence scores for any barcoding strategy. An optimized multithreaded implementation assures that Pheniqs is faster and scales better with complex barcode sets than existing tools. Support for POSIX streams and multiple sequencing formats enables easy integration with automated analysis pipelines.
Plant generaCannabisandHumulusshare the same pair of well-differentiated sex chromosomes
Authors: Prentout D , Stajner N , Cerenak A , Tricou T , Brochier-Armanet C , Jakse J , Käfer J , Marais GAB
Published: March 2021

We recently described, inCannabis sativa, the oldest sex chromosome system documented so far in plants. Based on our estimate of its age, we predicted that it should be shared by its sister genusHumulus, which is known to also possess XY sex chromosomes.

Here, we used transcriptome sequencing of a F1 family ofHumulus lupulusto identify and study the sex chromosomes in this species using the probabilistic method SEX-DETector.

We identified 265 sex-linked genes inH. lupulus, located on the chromosome that is also theC. sativasex chromosome pair. Using phylogenies of sex-linked genes, we show that a region of these chromosomes had already stopped recombining in the common ancestor of the two species. Furthermore, as inC. sativa, Y gene expression was reduced in correlation to the position on the X chromosome, and strongly Y degenerated genes showed dosage compensation.

Here we report, for the first time in the Angiosperms, a sex chromosome system that is shared by two different genera. Recombination suppression started at least 21-25 My ago, and then (either gradually or step-wise) spread to a large part of the sex chromosomes, leading to a strongly degenerated Y.
THINGSvision: a Python toolbox for streamlining the extraction of activations from deep neural networks
Authors: Muttenthaler Lukas , Hebart Martin N.
Published: March 2021

Over the past decade, deep neural network (DNN) models have received a lot of attention due to their near-human object classification performance and their excellent prediction of signals recorded from biological visual systems. To better understand the function of these networks and relate them to hypotheses about brain activity and behavior, researchers need to extract the activations to images across different DNN layers. The abundance of different DNN variants, however, can often be unwieldy, and the task of extracting DNN activations from different layers may be non-trivial and error-prone for someone without a strong computational background. Thus, researchers in the fields of cognitive science and computational neuroscience would benefit from a library or package that supports a user in the extraction task.THINGSvisionis a new Python module that aims at closing this gap by providing a simple and unified tool for extracting layer activations for a wide range of pretrained and randomly-initialized neural network architectures, even for users with little to no programming experience. We demonstrate the general utility ofTHINGsvisionby relating extracted DNN activations to a number of functional MRI and behavioral datasets using representational similarity analysis, which can be performed as an integral part of the toolbox. Together,THINGSvisionenables researchers across diverse fields to extract features in a streamlined manner for their custom image dataset, thereby improving the ease of relating DNNs, brain activity, and behavior, and improving the reproducibility of findings in these research fields.
ChAdOx1 nCoV-19 (AZD1222) protects Syrian hamsters against SARS-CoV-2 B.1.351 and B.1.1.7
Authors: Fischer Robert J. , van Doremalen Neeltje , Adney Danielle R. , Yinda Claude Kwe , Port Julia R. , Holbrook Myndi G. , Schulz Jonathan E. , Williamson Brandi N. , Thomas Tina , Barbian Kent , Anzick Sarah L. , Ricklefs Stacy , Smith Brian J. , Long Dan , Martens Craig , Saturday Greg , de Wit Emmie , Gilbert Sarah C. , Lambe Teresa , Munster Vincent J.
Published: March 2021

We investigated ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy against SARS-CoV-2 variants of concern (VOCs) B.1.1.7 and B.1.351 in Syrian hamsters. We previously showed protection against SARS-CoV-2 disease and pneumonia in hamsters vaccinated with a single dose of ChAdOx1 nCoV-19. Here, we observed a 9.5-fold reduction of virus neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 did not lose weight compared to control animals. In contrast to control animals, the lungs of vaccinated animals did not show any gross lesions. Minimal to no viral subgenomic RNA (sgRNA) and no infectious virus was detected in lungs of vaccinated animals. Histopathological evaluation showed extensive pulmonary pathology caused by B.1.1.7 or B.1.351 replication in the control animals, but none in the vaccinated animals. These data demonstrate the effectiveness of the ChAdOx1 nCoV-19 vaccine against clinical disease caused by B.1.1.7 or B.1.351 VOCs.