bluuebunny/crossref_metadata_2025 huggingface dataset:
Present knowledge, attitude, practice, and fear level of Bangladeshi people towards covid-19 after a year of the pandemic situation: a web-based cross-sectional study
Authors: Rupok Tahsin Ahmed , Dey Sunandan , Agarwala Rashni , Islam Md. Nurnobi , Bostami Bayezid
Published: July 2021

In the earlier phase of the pandemic situation, the governments of Bangladesh badly suffered to adhere their people to preventive measures probably due to less knowledge and attitude towards covid-19. To tackle the second wave of coronavirus, the governments again enforced an array of preventive measures, but still encountering the same problem after a year of the pandemic situation. In an attempt to find out the reasons behind this, our study aimed to assess the present knowledge, attitude, practice, and fear level of the people. A cross-sectional study was conducted from 15th to 25th April 2021. A total of 402 participants met all the inclusion criteria and were considered for performing all statistical analyses (Descriptive statistics, Mann-Whitney U test, Kruskal-Wallis H test, Multiple logistic regression, Spearman rank-order correlation). Out of 402 participants, more than 90% participants were students and all were adults aged 16 to 30. 84.6%, 65.7%, 54%, and 21.6% participants had more adequate knowledge, more positive attitude, more frequent practice, and moderate to high fear towards covid-19, respectively. Knowledge, attitude, practice, and fear were interrelated directly or indirectly. It was found knowledgeable participants were more likely to have more positive attitude (OR = 2.12, 95% CI = 1.14-3.95, P < 0.05) and very less fear (OR = 1.98, 95% CI = 1.02-3.82, P < 0.05). More positive attitude was found as a good predictor of more frequent practice (OR = 4.33, 95% CI = 2.66-7.04, P < 0.001), and very less fear had same negative impact on both attitude (OR = 0.48, 95% CI = 0.25-0.91, P < 0.05) and practice (OR = 0.48, 95% CI = 0.27-0.85, P < 0.05). Our findings reflect that knowledge level has elevated but attitude level subsided, and practice level stayed same as was in the earlier phase of pandemic and people are no longer panicked.
Integrative Metabolomic and Proteomic Signatures Define Clinical Outcomes in Severe COVID-19
Authors: Buyukozkan Mustafa , Alvarez-Mulett Sergio , Racanelli Alexandra C. , Schmidt Frank , Batra Richa , Hoffman Katherine L. , Sarwath Hina , Engelke Rudolf , Gomez-Escobar Luis , Simmons Will , Benedetti Elisa , Chetnik Kelsey , Zhang Guoan , Schenck Edward , Suhre Karsten , Choi Justin J. , Zhao Zhen , Racine-Brzostek Sabrina , Yang He S. , Choi Mary E. , Choi Augustine M.K. , Cho Soo Jung , Krumsiek Jan
Published: July 2021

The novel coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2 has ravaged global healthcare with previously unseen levels of morbidity and mortality. To date, methods to predict the clinical course, which ranges from the asymptomatic carrier to the critically ill patient in devastating multi-system organ failure, have yet to be identified. In this study, we performed large-scale integrative multi-omics analyses of serum obtained from COVID-19 patients with the goal of uncovering novel pathogenic complexities of this disease and identifying molecular signatures that predict clinical outcomes. We assembled a novel network of protein-metabolite interactions in COVID-19 patients through targeted metabolomic and proteomic profiling of serum samples in 330 COVID-19 patients compared to 97 non-COVID, hospitalized controls. Our network identified distinct protein-metabolite cross talk related to immune modulation, energy and nucleotide metabolism, vascular homeostasis, and collagen catabolism. Additionally, our data linked multiple proteins and metabolites to clinical indices associated with long-term mortality and morbidity, such as acute kidney injury. Finally, we developed a novel composite outcome measure for COVID-19 disease severity and created a clinical prediction model based on the metabolomics data. The model predicts severe disease with a concordance index of around 0.69, and furthermore shows high predictive power of 0.83-0.93 in two previously published, independent datasets.
Role of Multi-resolution Vulnerability Indices in COVID-19 spread: A Case Study in India
Authors: Bhattacharyya Rupam , Burman Anik , Singh Kalpana , Banerjee Sayantan , Maity Subha , Auddy Arnab , Rout Sarit Kumar , Lahoti Supriya , Panda Rajmohan , Baladandayuthapani Veerabhadran
Published: July 2021

Introduction
The outbreak of COVID-19 has differentially affected countries in the world, with health infrastructure and other related vulnerability indicators playing a role in determining the extent of the COVID-19 spread. Vulnerability of a geographical region/country to COVID-19 has been a topic of interest, particularly in low- and middle-income countries like India to assess the multi-factorial impact of COVID-19 on the incidence, prevalence or mortality data.
Datasets and Methods
Based on publicly reported socio-economic, demographic, health-based and epidemiological data from national surveys in India, we compute contextual, COVID-19 Vulnerability Indices (cVIs) across multiple thematic resolutions for different geographical and spatial administrative regions. These multi-resolution cVIs were used in regression models to assess their impact on indicators of the spread of COVID-19 such as the average time-varying instantaneous reproduction number.
Results
Our observational study was focused on 30 districts of the eastern Indian state of Odisha. It is an agrarian state, prone to natural disasters and one of the largest contributors of an unprotected migrant workforce. Our analyses identified housing and hygiene conditions, availability of health care and COVID preparedness as important spatial indicators.
Conclusion
Odisha has demonstrated success in containing the COVID-19 infection to a reasonable level with proactive measures to contain the spread of the virus during the first wave. However, with the onset of the second wave of COVID, the virus has been making inroads into the hinterlands and peripheral districts of the state, burdening the already deficient public health system in these areas. The vulnerability index presented in this paper identified vulnerable districts in Odisha. While some of them may not have a large number of COVID-19 cases at a given point of time, they could experience repercussions of the pandemic. Improved understanding of the factors driving COVID-19 vulnerability will help policy makers prioritise resources and regions leading to more effective mitigation strategies for the COVID-19 pandemic and beyond.
Exploring predictive frameworks for malaria in Burundi
Authors: Mfisimana Lionel Divin , Nibayisabe Emile , Badu Kingsley , Niyukuri David
Published: July 2021

Malaria is a major public health concern in Burundi. The infection has been increasing in the last decade despite efforts to increase access to health services, and the deployment of several intervention programs. The use of different data sources can help to build predictive models of malaria cases in different sub-populations. We built predictive frameworks using generalized linear model (GLM), and artificial neural network to predict malaria cases in four sub-populations (pregnant women and children under 5 years, pregnant women, children between 0 and 11 months, children between 12 and 59 months), and the overall general population. The results showed that almost half malaria infections are observed in pregnant women and children under 5 years, but children between 12 and 59 months carry the highest burden. Neural network model performed better in predicting total cases compared to GLM. But the latter provided information on the effect of predictors, which is an important source of information to mainstream target interventions. Early prediction of cases can provide timely information needed to be proactive for intervention strategies, and it can help to mitigate the epidemics and reduce its impact on populations and the economy.
Time trends, factors associated with, and reasons for COVID-19 vaccine hesitancy in a massive online survey of US adults: January-May 2021
Authors: King Wendy C , Rubinstein Max , Reinhart Alex , Mejia Robin
Published: July 2021

Importance

COVID-19 vaccine hesitancy has become a leading barrier to increasing the US vaccination rate.

Objective

To evaluate time trends in COVID-19 vaccine intent during the US vaccine rollout, and identify key factors related to and self-reported reasons for COVID-19 vaccine hesitancy in May 2021.

Design, participants and setting

A COVID-19 survey was offered to US adult Facebook users in several languages yielding 5,088,772 qualifying responses from January 6 to May 31, 2021. Data was aggregated by month. Survey weights matched the sample to the age, gender, and state profile of the US population.

Exposure

Demographics, geographic factors, political/COVID-19 environment, health status, beliefs, and behaviors.

Main outcome measures

“If a vaccine to prevent COVID-19 were offered to you today, would you choose to get vaccinated.” Hesitant was defined as responding probably or definitely would not choose to get vaccinated (versus probably or definitely would, or already vaccinated).

Results

COVID-19 vaccine hesitancy decreased by one-third from 25.4% (95%CI, 25.3, 25.5) in January to 16.6% (95% CI, 16.4, 16.7) in May, with relatively large decreases among participants with Black, Pacific Islander or Hispanic race/ethnicity and ≤high school education. Independent risk factors for vaccine hesitancy in May (N=525,644) included younger age, non-Asian race, < 4 year college degree, living in a more rural county, living in a county with higher Trump vote share in the 2020 election, lack of worry about COVID-19, working outside the home, never intentionally avoiding contact with others, and no past-year flu vaccine. Differences in hesitancy by race/ethnicity varied by age (e.g., Black adults more hesitant than White adults <35 years old, but less hesitant among adults ≥45 years old). Differences in hesitancy by age varied by race/ethnicity. Almost half of vaccine hesitant respondents reported fear of side effects (49.2% [95%CI, 48.7, 49.7]) and not trusting the COVID-19 vaccine (48.4% [95%CI, 48.0, 48.9]); over one-third reported not trusting the government, not needing the vaccine, and waiting to see if safe. Reasons differed by degree of vaccine intent and by race/ethnicity.

Conclusion

COVID-19 vaccine hesitancy varied by demographics, geography, beliefs, and behaviors, indicating a need for a range of messaging and policy options to target high-hesitancy groups.
Apathy: an underestimated feature in GBA and LRRK2 non-manifesting mutation carriers
Authors: Pachi Ioanna , Koros Christos , Simitsi Athina M , Papadimitriou Dimitra , Bougea Anastasia , Prentakis Andreas , Papagiannakis Nikolaos , Bozi Maria , Antonelou Roubina , Angelopoulou Efthalia , Beratis Ion , Stamelou Maria , Trapali Xenia Geronicola , Papageorgiou Sokratis G. , Stefanis Leonidas
Published: July 2021

Background

Higher prevalence of motor and non-motor features has been observed in non-manifesting mutation carriers of Parkinson’s Disease (PD) compared to Healthy Controls (HC).

Objectives

The aim was to detect the differences between GBA and LRRK2 mutation carriers without PD and HC on neuropsychiatric symptoms.

Methods

This is a cross-sectional retrospective study of non-manifesting GBA and LRRK2 mutation carriers and HC enrolled into Parkinson’s Progression Markers Initiative (PPMI). Data extracted from the PPMI database contained: demographics and performance in MoCA scale and MDS-UPDRS scale part 1A (neuropsychiatric symptoms). All six features were treated as both continuous (MDS-UPDRS individual scores) and categorical variables (MDS-UPDRS individual score>0 and MDS-UPDRS individual score=0). Logistic regression analyses were applied to evaluate the association between mutation carrying status and neuropsychiatric symptoms.

Results

We found that non-manifesting mutation carriers as a whole (total N=654, GBA: n=285, LRRK2: n=369) were 2.3 times more likely to present apathy compared to HC, even after adjustment for covariates (adjusted OR=2.3, 95% CI=1.1-5.0, p-value=0.027). The effect was mainly driven by GBA mutation carriers (adjusted OR= 2.6, 95% CI=1.1-6.3, p=0.031), while the higher percentage of apathy for LRRK2 carriers compared to HC was marginally non-significant. Other neuropsychiatric symptoms, such as psychotic or depressive manifestations, did not differ between groups.

Conclusions

Symptoms of apathy could be present in the premotor period of LRRK2 and, especially, GBA mutation carriers. Longitudinal data, including detailed neuropsychiatric evaluation and neuroimaging, would be essential to further investigate the pathophysiological basis of this finding.
BNT162b2 Vaccination efficacy is marginally affected by the SARS-CoV-2 B.1.351 variant in fully vaccinated individuals
Authors: Mor Orna , Zuckerman Neta S. , Hazan Itay , Fluss Ronen , Ash Nachman , Ginish Netanel , Mendelson Ella , Alroy-Preis Sharon , Freedman Laurence , Huppert Amit
Published: July 2021

Background

Israeli has vaccinated over 80% of its adult population, with two doses of the Pfizer BNT162b2 vaccine. This intervention has been highly successful in curtailing the coronavirus 2 outbreak. One major concern is the ability of the virus to mutate which potentially can cause SARS-CoV-2 to partially escape from the immune system. Here we evaluate the efficacy of the Pfizer vaccine against the B.1.351 variant.

Methods

The Ministry of Health, initiated sequencing of selected positive swab samples identified as being of interest. We used logistic regression, with variant type as the dependent variable, vaccination status as the main explanatory variable, controlling for age, sex, subpopulation, place of residence and time of sample, to estimate the odds ratio for a vaccinated case to have the B. 1.351 versus the B.1.1.7 variant, within vaccinated and unvaccinated persons who tested positive.

Findings

There were 19 cases of B.1.351 variant (3.2%) among those vaccinated more than 14 days before the positive sample and 88 (3.5%) among the unvaccinated. The estimated odds ratio was 1.29 [95% CI: 0.66-2.50]. From this result, assuming the efficacy against the B.1.1.7 variant to be 95%, the estimated efficacy against the B.1.351 variant was 94% [95% CI: 87-97%].

Interpretation

Despite the concerns caused by the B.1.351 variant, the BNT162b2 vaccine seems to provide substantial immunity against both that variant and the B.1.1.7. Our results suggest that from 14 days following the second vaccine dose the efficacy of BNT162b2 vaccine is at most marginally affected by the B.1.351 variant.

Funding

No funding
Parsing Genetically Influenced Risk Pathways: Genetic Loci Impact Problematic Alcohol Use Via Externalizing and Specific Risk
Authors: Barr Peter B. , Mallard Travis T. , Sanchez-Roige Sandra , Poore Holly E. , Linnér Richard Karlsson ,   COGA Collaborators, Waldman Irwin D. , Palmer Abraham A. , Harden K. Paige , Dick Danielle M.
Published: July 2021

Importance

Characterizing whether genetic variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk, and, potentially, allows us to design more targeted prevention and interventions.

Objective

Employ multivariate methods to tease apart variants associated with problematic alcohol use through either general or specific pathways and compare results to standard univariate genetic analysis of problematic alcohol use.

Design

We compared results from a univariate genome wide association study (GWAS) of problematic alcohol use to those from a previous multivariate GWAS of externalizing phenotypes. We identified genetic variants associated with problematic alcohol use through a broad liability to externalizing, and those that remain after removing shared variance with externalizing. We compared these results across SNP overlap, bioannotations, genetic correlations, and polygenic scores.

Setting

We included GWAS summary statistics from existing GWAS, and two US based hold out samples: The National Longitudinal Study of Adolescent to Adult Health (Add Health) and the Collaborative Study on the Genetics of Alcoholism (COGA).

Participants

Publicly available GWAS of externalizing behaviors and participants in Add Health (N=5,107) and COGA (N=7,483), limited to individuals of European ancestries.

Exposure(s)

N/A

Main Outcome(s) and Measure(s)

Outcomes included problematic alcohol use (ALCP-O), shared risk for externalizing (EXT), and problematic alcohol use-specific risk (ALCP-S) for the GWASs; a preregistered list of 99 available phenotypes for genetic correlations; and substance use, substance use disorder criteria, and alcohol misuse in the polygenic score analyses.

Results

The analysis differentiated SNPs operating through common versus specific risk pathways. While ALCP-O was associated with multiple phenotypes, ALCP-S was predominantly associated with alcohol use and other forms of psychopathology. Polygenic scores for ALCP-O were associated with a variety of other forms of substance use and substance use disorders, polygenic scores for ALCP-S were only associated with alcohol phenotypes. Polygenic scores for both ALCP-S and EXT show differential patterns of associations with alcohol misuse across development.

Conclusions and Relevance

Focusing on the differential impacts of shared and specific risk can better characterize pathways of risk for alcohol use disorders. Multivariate methods can be a useful tool for studying many psychiatric conditions. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice for psychiatric outcomes.
NO INCREASE IN RELATIVE MORTALITY RATES FOR THOSE WITHOUT A COLLEGE DEGREE DURING COVID-19: AN ANOMALY
Authors: Case Anne , Deaton Angus
Published: July 2021

American mortality rates have diverged in recent years between those with and without a four-year college degree, and there are many reasons to expect the education-mortality gradient to have steepened during the pandemic. Those without a BA are more likely to work in frontline occupations, to rely on public transportation, and to live in crowded quarters, all of which are associated with an increase in infection risk, a risk that was zero prior to the pandemic. We use publicly available data from the National Center for Health Statistics on deaths by age, sex, education and race/ethnicity to assess the protective effect of a BA in 2020 compared to 2019. While the BA was strongly protective during 2020, the ratio of mortality rates between those with and without a degree was little changed relative to pre-pandemic years. Among 60 groups (gender by race/ethnicity by age) that are available in the data, the relative risk reduction associated with a BA fell for more than half the groups between 2019 and 2020, and increased by more than 5 percentage points for only five groups. Our main finding is not that the BA was protective against death in 2020, which has long been the case, but that the protective effect was little different than in 2019 and earlier years, in spite of the change in the pattern of risk by occupation and income. The virus maintained the mortality-education gradient that existed pre-pandemic, at least through the end of 2020. Our results suggest that changes in the risk of infection were less important in structuring mortality than changes in the risk of death conditional on infection.
Associations between forensic loci and neighboring gene expression levels may compromise medical privacy
Authors: Bañuelos Mayra M. , Zavaleta Jhony A. , Roldan Alennie , Reyes Rochelle-Jan , Guardado Miguel , Rojas Berenice Chavez , Nyein Thet , Vega Ana Rodriguez , Santos Maribel , Sanchez Emilia Huerta , Rohlfs Rori
Published: July 2021

A set of 20 short tandem repeats (STRs) is used by the United States criminal justice system to identify suspects, and to maintain a database of genetic profiles for individuals who have been previously convicted or arrested. Some of these STRs were identified in the 1990s, with a preference for markers in putative gene deserts to avoid forensic profiles revealing protected medical information. We revisit that assumption, investigating whether forensic genetic profiles reveal information about gene expression variation, or potential medical information. We find six significant correlations (FDR = 0.23) between the forensic STRs and the expression levels of neighboring genes in lymphoblastoid cell lines. We explore possible mechanisms for these associations, with evidence compatible with forensic STRs causing expression variation, or being in LD with a causal locus in three cases, and weaker or potentially spurious associations in the other three cases. Together, these results suggest that forensic genetic loci may reveal expression level and, perhaps, medical information.
Sex-specific effects of aging on the humoral immune response to repeat vaccination with the high-dose seasonal influenza vaccine in older adults
Authors: Shapiro Janna R. , Li Huifen , Morgan Rosemary , Chen Yiyin , Kuo Helen , Ning Xiaoxuan , Shea Patrick , Wu Cunjin , Merport Katherine , Saldanha Rayna , Liu Suifeng , Abrams Engle , Chen Yan , Kelly Denise C. , Sheridan-Malone Eileen , Wang Lan , Zeger Scott L. , Klein Sabra L. , Leng Sean X.
Published: July 2021

Older adults (≥65 years of age) bear a significant burden of severe disease and mortality associated with influenza, despite relatively high annual vaccination coverage and substantial pre-existing immunity to influenza. To test the hypothesis that host factors, including age and sex, play a role in determining the effect of repeat vaccination and levels of pre-existing humoral immunity to influenza, we evaluated pre- and post-vaccination strain-specific hemagglutination inhibition (HAI) titers in adults over 75 years of age who received a high-dose influenza vaccine in at least four out of six influenza seasons (NCT02200276). Neither age, sex, body mass index, frailty, nor repeat vaccination were significantly associated with post-vaccination HAI titer outcomes. Pre-vaccination titers, however, were significantly predictive of post-vaccination outcomes. Pre-vaccination titers to H1N1 remained constant with age, while those to H3N2 and influenza B decreased substantially with age in males but not in females. Our findings highlight the importance of pre-existing immunity in this highly vaccinated older adult population and suggest that older males are particularly vulnerable to reduced pre-existing humoral immunity to influenza from previous annual vaccination.
Cell-Mediated and Humoral Immune Response to 2-Dose SARS-CoV2 mRNA vaccination in Immunocompromised patient population
Authors: Ramanathan Muthukumar , Murugesan Kanagavel , Yang Lu M. , Costales Cristina , Bulterys Philip L. , Schroers-Martin Joseph , Alizadeh Ash A. , Boyd Scott D. , Brown Janice M. , Nadeau Kari C. , Nadimpalli Sruti S. , Wang Aileen X. , Busque Stephan , Pinsky Benjamin A. , Banaei Niaz
Published: July 2021

Characterization of cell-mediated and humoral immune responses to SARS-CoV2 mRNA vaccine has implications for protective immunity in immunocompromised patients. However, studies have demonstrated poor humoral response to SARS-CoV2 mRNA vaccine in immunocompromised patients and data on cellular immune response are currently lacking. Here we compared immune response after 2-dose vaccination in 100 immunocompromised patients (solid organ transplant recipients, hematologic malignancy, autoimmune condition, and primary immunodeficiency) and 16 immunocompetent healthy healthcare workers. We find that 100% (CI=80.6-100%) of immunocompetent individuals show positive cell-mediated and humoral immune response post vaccination while only 50% (CI=40.4-59.6%) of immunocompromised patients show humoral immune response and 69% (CI=59.4-77.2%) have a positive cell-mediated immune response. 21% of immunocompromised patients have no humoral immune response or cell-mediated immune response and thus are likely vulnerable to SARS-CoV2 infection. Monitoring of immune response in immunocompromised populations, particularly in high-risk immunocompromised patients (solid organ transplant recipients, patients with severe autoimmunity, and those ≥50 years), with clinical IGRA and serological assay after vaccination may identify patients who may benefit from revaccination or prophylactic monoclonal antibody therapy to prevent COVID-19 in this patient population
Phase 1 Safety and Pharmacokinetics Studies of BRII-196 and BRII-198, SARS-CoV-2 Spike-Targeting Monoclonal Antibodies
Authors: Zhang Yao , Hao Xiaohua , Ma Ji , Wang Mingming , Li Yanyan , Liu Yang , Zhao Dong , Zhang Wen , Li Chunming , Yan Li , Zhu Qing , Zhang Fujie
Published: July 2021

Background

BRII-196 and BRII-198 are two anti-SARS-CoV-2 monoclonal neutralizing antibodies with modified Fc region that extends half-life and are being developed as cocktail therapy for the treatment of COVID-19. Safety, tolerability, pharmacokinetics, and immunogenicity of BRII-196 and BRII-198 were investigated in healthy adults.

Methods

Single ascending doses of BRII-196 and BRII-198 were evaluated in parallel in the first-in-human, placebo-controlled phase 1 studies. A total of 32 healthy adults were randomized and received a single intravenous infusion of 750, 1500, and 3000 mg of BRII-196 (n=12), BRII-198 (n=12), or placebo (n=8) and were followed for 180 days.

Results

All infusions were well tolerated at infusion rates between 0.5 mL/min to 4 mL/min with no dose-limiting adverse events, deaths, serious adverse events, or any systemic or local infusion reactions. Most treatment-emergent adverse events were isolated asymptomatic laboratory abnormalities of Grade 1-2 in severity. Each mAb displayed pharmacokinetics expected of Fc-engineered human IgG1 with mean terminal half-lives of approximately 46 days and 76 days, respectively, with no evidence of significant anti-drug antibody development.

Conclusions

BRII-196 and BRII-198 were well-tolerated. Clinical results support further development as therapeutic or prophylactic options for SARS-CoV-2 infection.
Trait Mindful Nonreactivity and Nonjudgment Prospectively Predict of COVID-19 Health Protective Behaviors Across a Two-Month Interval in a USA Sample
Authors: O’Brien William H. , Wang Shan , Varga Aniko Viktoria , Lim Chung Xiann , Xu Huanzhen , Jarukasemthawee Somboon , Pisitsungkagarn Kullaya , Suvanbenjakule Piraorn , Braden Abby
Published: July 2021

The COVID-19 pandemic has prompted a growing recommendation for social distancing and using personal protective equipment (PPE) to help mitigate the virus transmission. Previous studies have shown promising relationships between perceived susceptibility to COVID-19, mindfulness-related variables, and COVID-19 health protective behaviors (social distancing and PPE use). In this longitudinal study, the variables were measured across a two-month interval during the earlier phase of the pandemic in June (Time 1) and August (Time 2), 2020. The results from 151 matched USA MTurk participants indicated that the perceived susceptibility to COVID-19 did not significantly predict the health protective behaviors. For mindfulness, nonreactivity was positively related to PPE use while nonjudgement was negatively related to PPE use. Accordingly, mindfulness promotion messages could be a way to increase the likelihood of people performing health protective behaviors to better constrain the COVID-19 outbreak.
Kinome state is predictive of cell viability in pancreatic cancer tumor and stroma cell lines
Authors: Berginski Matthew E. , Jenner Madison R. , Joisa Chinmaya U. , Herrera Loeza Silvia G. , Golitz Brian T. , Lipner Matthew B. , Leary John R. , Rashid Naim U. , Johnson Gary L. , Yeh Jen Jen , Gomez Shawn M.
Published: July 2021

Numerous aspects of cellular signaling are regulated by the kinome – the network of over 500 protein kinases that guides and modulates information transfer throughout the cell. The key role played by both individual kinases and assemblies of kinases organized into functional subnetworks leads to kinome dysregulation being a key driver of many diseases, particularly cancer. In the case of pancreatic ductal adenocarcinoma (PDAC), a variety of kinases and associated signaling pathways have been identified for their key role in the establishment of disease as well as its progression. However, the identification of additional relevant therapeutic targets has been slow and is further confounded by interactions between the tumor and the surrounding tumor microenvironment. Fundamentally, it is an open question as to the degree to which knowledge of the state of the kinome at the protein level is able to provide insight into the downstream phenotype of the cell.

In this work, we attempt to link the state of the kinome, or kinotype, with cell viability in representative PDAC tumor and stroma cell lines. Through the application of both regression and classification models to independent kinome perturbation and kinase inhibitor cell screen data, we find that the inferred kinotype of a cell has a significant and predictive relationship with cell viability. While regression models perform poorly, we find that classification approaches are able to predict drug viability effects. We further find that models are able to identify a set of kinases whose behavior in response to perturbation drive the majority of viability responses in these cell lines. Using the models to predict new compounds with cell viability effects and not in the initial data set, we conducted a validation screen that confirmed the accuracy of the models. These results suggest that characterizing the state of the protein kinome provides significant opportunity for better understanding signaling behavior and downstream cell phenotypes, as well as providing insight into the broader design of potential therapy design for PDAC.
Prediction of fluorophore brightness in designed mini fluorescence activating proteins
Authors: Hostetter Emma R. , Keyes Jeffrey R. , Poon Ivy , Nguyen Justin P. , Nite Jacob ,   Molecular Modeling and Design Class, Jimenez Hoyos Carlos A. , Smith Colin A.
Published: July 2021

The de novo computational design of proteins with predefined three-dimensional structure is becoming much more routine due to advancements both in force fields and algorithms. However, creating designs with functions beyond folding is more challenging. In that regard, the recent design of small beta barrel proteins that activate the fluorescence of an exogenous small molecule chromophore (DFHBI) is noteworthy. These proteins, termed mini Fluorescence Activating Proteins (mFAPs), have been shown increase the brightness of the chromophore more than 100-fold upon binding to the designed ligand pocket. The design process created a large library of variants with different brightness levels but gave no rational explanation for why one variant was brighter than another. Here we use quantum mechanics and molecular dynamics simulations to investigate how molecular flexibility in the ground and excited states influences brightness. We show that the ability of the protein to resist dihedral angle rotation of the chromophore is critical for predicting brightness. Our simulations suggest that the mFAP/DFHBI complex has a rough energy landscape, requiring extensive ground-state sampling to achieve converged predictions of excited-state kinetics. While computationally demanding, this roughness suggests that mFAP protein function can be enhanced by reshaping the energy landscape towards states that better resist DFHBI bond rotation.
CoverageMaster: comprehensive CNV detection and visualization from NGS short reads for genetic medicine applications
Authors: Rapti Melivoia , Meylan Jenny , Ranza Emmanuele , Antonarakis Stylianos E. , Santoni Federico A.
Published: July 2021

CoverageMaster (CoM) is a Copy Number Variation (CNV) calling algorithm based on depth-of-coverage maps designed to detect CNVs of any size in exome (WES) and genome (WGS) data. The core of the algorithm is the compression of sequencing coverage data in a multiscale Wavelet space and the analysis through an iterative Hidden Markov Model (HMM). CoM processes WES and WGS data at nucleotide scale resolution and accurately detect and visualize full size range CNVs, including single or partial exon deletions and duplications. The results obtained with this approach support the possibility for coverage-based CNV callers to replace probe-based methods such array CGH and MLPA in the near future.
Integrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer
Authors: Crispin-Ortuzar Mireia , Woitek Ramona , Moore Elizabeth , Reinius Marika , Beer Lucian , Bura Vlad , Rundo Leonardo , McCague Cathal , Ursprung Stephan , Sanchez Lorena Escudero , Martin-Gonzalez Paula , Mouliere Florent , Chandrananda Dineika , Morris James , Goranova Teodora , Piskorz Anna M. , Singh Naveena , Sahdev Anju , Pintican Roxana , Zerunian Marta , Addley Helen , Jimenez-Linan Mercedes , Markowetz Florian , Sala Evis , Brenton James D.
Published: July 2021

High grade serous ovarian cancer (HGSOC) is a highly heterogeneous disease that often presents at an advanced, metastatic state. The multi-scale complexity of HGSOC is a major obstacle to measuring response to neoadjuvant chemotherapy (NACT) and understanding its determinants. Here we propose a radiogenomic framework integrating clinical, radiomic, and blood-based biomarkers to measure and predict the response of HGSOC patients to NACT, showing how quantitative imaging data can serve as the backbone of multi-scale data integration. We developed and validated our approach in two independent highly-annotated multi-omic multi-lesion data sets. In a discovery cohort (n=72) we found that different tumour sites present distinct response patterns, and identified volumetric response assessment as a better predictor of overall survival (OS) than RECIST 1.1 status. We trained an ensemble machine learning approach to predict tumour volume response to NACT from data obtained prior to treatment, and validated the model in an internal hold-out cohort (n=20) and an independent external patient cohort (n=42). Benchmarking integrated models against models built on single data types highlighted the importance of comprehensive patient characterisation. Our study sets the foundation for developing new clinical trials of NACT in HGSOC.
Change in Plasma Alpha-Tocopherol Associations with Attenuated Pulmonary Function Decline and with CYP4F2 Missense Variation
Authors: Xu Jiayi , Guertin Kristin A. , Gaddis Nathan C. , Agler Anne H. , Parker Robert S. , Feldman Jared M. , Kristal Alan R. , Arnold Kathryn B. , Goodman Phyllis J. , Tangen Catherine M. , Hancock Dana B. , Cassano Patricia A.
Published: July 2021

Background

Given its antioxidant activity, vitamin E is hypothesized to attenuate the age-related decline in pulmonary function.

Objective

We investigated the association between change in plasma vitamin E (ΔvitE) and pulmonary function decline and examined genetic and non-genetic factors associated with ΔvitE.

Design

We studied 1,144 men randomized to vitE in the Selenium and Vitamin E Cancer Prevention Trial. ΔvitE was calculated as the difference between baseline and year 3 vitE concentrations measured with gas chromatography-mass spectrometry. Pulmonary function (forced expiratory volume in the first second [FEV1]) was measured longitudinally with spirometry. We genotyped 555 participants (vitE-only arm) using the Illumina MEGAex array. We examined the association of ΔvitE with annual change in FEV1 using mixed-effects linear regression. We also examined the association of previously reported genetic and non-genetic factors with ΔvitE.

Results

Greater ΔvitE was associated with attenuated FEV1 decline, with stronger effects in adherent supplement responders: a 1 SD higher ΔvitE (+4 µmol/mmol free-cholesterol-adjusted α-tocopherol) attenuated FEV1 decline by ∼8.9 mL/year (P=0.014). This effect size is ∼1/4 of the effect of one year of aging, but in the opposite direction. The ΔvitE-FEV1 association was positive in never and current smokers (9.7 and 11.0 mL/year attenuated FEV1 decline, respectively), but there was little to no association in former smokers. Greater ΔvitE was associated with lower baseline α-tocopherol, higher baseline γ-tocopherol, higher baseline free cholesterol, European ancestry (vs. African ancestry) (all P<0.0001), and the minor allele of a missense variant in CYP4F2 (rs2108622-T) (2.4 µmol/L greater ΔvitE; P=0.0032).

Conclusions

Greater response to vitE supplementation was associated with attenuated FEV1 decline, and this response was differed by rs2108622 such that individuals with the C allele may need a higher vitE intake dose to reach the same plasma level, compared to the T allele.
Systematic Review and Meta-analysis of Eculizumab, Inebilizumab, Tocilizumab, and Satralizumab for Neuromyelitis Optica
Authors: Chamlagain Rajan , Shah Sangam , Gaire Suman , Paudel Anuj Krishna , Dahal Krishna , kandel Bipin , Dhital Roman , Paudel Basanta Sharma , Dhakal Sandesh , Basnet Madan
Published: July 2021

Neuromyelitis optica is rare, autoimmune-mediated inflammation and demyelination of the central nervous system with a prevalence of 1-2 persons per 100,000 populations. We aim to generate a head-to-head comparison of these drugs with appropriate evidence to guide future trials and treatment guidelines in a patient with recurrent attacks of NMO. We searched the databases like PubMed, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase for studies published prior to April 2021 using the keywords. Over all 929 patients from 11 different publications were included in the study. Five studies were included for quantitative synthesis. Pooling of studies showed significant mean reduction of ARR in the monoclonal antibody group (-0.26 [-0.35, -0.17], P <0.00001, I2=0%) and the mean difference in EDSS score from baseline in monoclonal antibodies was - 0.23(95% CI [-0.43, -0.03], P=0.02, I2=0%). There was no significant difference in frequency of total reported adverse events between monoclonal antibody and the comparator arm (RR: 1.01 [0.95, 1.07], P=0.74, I2=14%). Our findings, particularly seen from the context of a few RCTs, support the pursuit of larger, multi-center RCTs that evaluate the effectiveness of each of the currently available monoclonal antibodies and better describe their adverse risk profile.
Assessing target engagement using proteome-wide solvent shift assays
Authors: Van Vranken Jonathan G. , Li Jiaming , Navarrete-Perea José , Gygi Steven P.
Published: July 2021

Recent advances in mass spectrometry (MS) have enabled quantitative proteomics to become a powerful tool in the field of drug discovery, especially when applied toward proteome-wide target engagement studies. Similar to temperature gradients, increasing concentrations of organic solvents stimulate unfolding and precipitation of the cellular proteome. This property can be influenced by physical association with ligands and other molecules, making individual proteins more or less susceptible to solvent-induced denaturation. Herein, we report the development of proteome-wide solvent shift assays by combining the principles of solvent-induced precipitation (Zhang et al., 2020) with modern quantitative proteomics. Using this approach, we developed solvent proteome profiling (SPP), which is capable of establishing target engagement through analysis of SPP denaturation curves. We readily identified the specific targets of compounds with known mechanisms of action. As a further efficiency boost, we applied the concept of area-under-the-curve analysis to develop solvent proteome integral solubility alteration (solvent-PISA) and demonstrate that this approach can serve as a reliable surrogate for SPP. We propose that by combining SPP with alternative methods, like thermal proteome profiling, it will be possible to increase the absolute number of high-quality melting curves that are attainable by either approach individually thereby increasing the fraction of the proteome that can be screened for evidence of ligand binding.
Conformation and membrane interaction studies of the potent antimicrobial and anticancer peptide palustrin-Ca
Authors: Timmons Patrick B. , Hewage Chandralal M.
Published: July 2021

Palustrin-Ca (GFLDIIKDTGKEFAVKILNNLKCKLAGGCPP) is a host defense peptide with potent antimicrobial and anticancer activities, first isolated from the skin of the American bullfrogLithobates catesbeianus. The peptide is 31 amino acid residues long, cationic and amphipathic. Two-dimensional NMR spectroscopy was employed to characterise its three-dimensional structure in a 50/50% water/2,2,2-trifluoroethanol-d3mixture. The structure is defined by anα-helix that spans between Ile6-Ala26, and a cyclic disulphide bridged domain at the C-terminal end of the peptide sequence, between residues 23 and 29.

A molecular dynamics simulation was employed to model the peptide’s interactions with sodium dodecyl sulphate micelles, a widely used bacterial membrane-mimicking environment. Throughout the simulation, the peptide was found to maintain itsα-helical conformation between residues Ile6-Ala26, while adopting a position parallel to the surface to micelle, which is energetically-favourable due to many hydrophobic and electrostatic contacts with the micelle.
Quantification of archaea-driven freshwater nitrification: from single cell to ecosystem level
Authors: Klotz Franziska , Kitzinger Katharina , Ngugi David Kamanda , Büsing Petra , Littmann Sten , Kuypers Marcel M. M. , Schink Bernhard , Pester Michael
Published: July 2021

Deep oligotrophic lakes sustain large archaeal populations of the class Nitrososphaeria in their hypolimnion. They are thought to be the key ammonia oxidizers in these freshwater systems and as such responsible for the rate-limiting step in nitrification. However, the impact that planktonic Nitrososphaeria have on N cycling in lakes is severely understudied and yet to be quantified. Here, we followed this archaeal population in one of Central Europe’s largest lakes, Lake Constance, over two consecutive years using metagenomics and metatranscriptomics combined with stable isotope-based activity measurements. A single, highly abundant and transcriptionally active freshwater ecotype of Nitrososphaeria dominated the nitrifying community. Phylogenomic analysis of its metagenome-assembled genome showed that this ecotype represents a new lacustrine Nitrosopumilus species. Stable isotope probing revealed that Nitrososphaeria incorporated significantly more 15N-labeled ammonium than most other microorganisms at near-natural conditions and oxidized ammonia at an average rate of 0.22 ± 0.11 fmol cell−1 d−1. This translates to 1.9 gigagram of ammonia oxidized per year, corresponding to 12% of the N-biomass produced annually by photosynthetic organisms in Lake Constance. Here, we show that ammonia-oxidizing archaea play an equally important role in the nitrogen cycle of deep oligotrophic lakes as their counterparts in marine ecosystems.
GM1 mediates the formation and maintenance of cytotoxic Aβ oligomers
Authors: Zhang Dong Yan , Wang Jian , Fleeman Rebecca M. , Kuhn Madison K. , Swulius Matthew T. , Proctor Elizabeth A. , Dokholyan Nikolay V.
Published: July 2021

The aggregation of amyloid beta (Aβ) peptide is associated with Alzheimer’s disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of Aβ fibrils, yet little is known about the roles of GM1 in the early steps of Aβ oligomer formation. Here, by using GM1-contained liposomes as a mimic of neuronal cell membrane, we demonstrate that GM1 is a critical trigger of Aβ oligomerization and aggregation. We find that GM1 not only promotes the formation of Aβ fibrils, but also facilitates the maintenance of Aβ oligomers on liposome membranes. We structurally characterize the Aβ oligomers formed on the membrane and find that GM1 captures Aβ by binding to its arginine-5 residue. To interrogate the mechanism of Aβ oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the Aβ ion channel hypothesis. Finally, we conduct cell viability assay to determine the toxicity of Aβ oligomers formed on membranes. Overall, by uncovering the roles of GM1 in mediating early Aβ oligomer formation and maintenance, our work provides a novel direction for pharmaceutical research for AD.
Temperature dependence of spontaneous mutation rates
Authors: Waldvogel Ann-Marie , Pfenninger Markus
Published: July 2021

Mutation is the source of genetic variation and the fundament of evolution. Temperature has long been suggested to have a direct impact on realized spontaneous mutation rates. If mutation rates vary in response to environmental conditions, such as the variation of the ambient temperature through space and time, they should no longer be described as species-specific constants. By combining mutation accumulation with whole-genome sequencing in a multicellular organism, we provide empirical support to reject the null hypothesis of a constant, temperature-independent mutation rate. Instead, mutation rates depended on temperature in a U-shaped manner with increasing rates toward both temperature extremes. This relation has important implications for mutation-dependent processes in molecular evolution, processes shaping the evolution of mutation rates, and even the evolution of biodiversity as such.
Impact of socioeconomic development on inflation in South Asia: evidence from panel cointegration analysis
Authors: Islam Md. Saiful
Published: July 2021

Purpose

This study aims to examine the influence of socioeconomic development on inflation in South Asia using the foreign exchange rate and money supply as control variables.

Design/methodology/approach

The study uses annual panel data for five South Asian economies, namely, Bangladesh, India, Nepal, Pakistan and Sri Lanka over the period 1990–2018, applies cointegrating regression techniques, namely, the panel dynamic ordinary least square (OLS) and fully modified OLS estimators to examine the long-run relations and conducts the Toda-Yamamoto Granger causality test to detect the direction of causality among variables.

Findings

The cointegrating regression estimations have documented that the socioeconomic development proxied by the human development index (HDI) has no significant impact on inflation. Although economic development represented by gross domestic product (GDP) growth causes inflation, socioeconomic development represented by HDI has no impact on inflation and has demonstrated as a better macroeconomic indicator, and thus creates no inflationary pressure in the economy. The foreign exchange rate has a positive impact on inflation. The broad money supply has the usual positive effect on domestic inflation that endorses the monetarist view about prices. The Toda-Yamamoto Granger causality test has confirmed several unidirectional causalities: inflation causes HDI, money supply causes both inflation and HDI and the foreign exchange rate causes HDI.

Practical implications

The study has practical implications for policymakers in South Asia, to improve HDI, particularly GDP per capita, education and health-care facilities to realize continuous socioeconomic development, which will take care of inflation. Moreover, these counties may follow a conservative monetary policy to control inflationary pressure in their economies.

Originality/value

The study is original and claims to be the first to examine the impact of socioeconomic development on inflation. The findings have socioeconomic values regarding controlling inflation in South Asia.