bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive genome-wide duplications in the eastern oyster (Crassostrea virginica)
Authors: Modak Tejashree H. , Literman Robert , Puritz Jonathan B. , Johnson Kevin M. , Roberts Erin M. , Proestou Dina , Guo Ximing , Gomez-Chiarri Marta , Schwartz Rachel S.
Published: April 2021

Genomic structural variation is an important source of genetic and phenotypic diversity, playing a critical role in evolution. The recent availability of a high-quality reference genome for the eastern oyster,Crassostrea virginica, and whole-genome sequence data of samples from across the species range in the USA, provides an opportunity to explore structural variation across the genome of this species. Our analysis shows significantly greater individual-level duplications of regions across the genome than that of most model vertebrate species. Duplications are widespread across all ten chromosomes with variation in frequency per chromosome. The eastern oyster shows a large interindividual variation in duplications as well as particular chromosomal regions with a higher density of duplications. A high percentage of duplications seen inC. virginicalie completely within genes and exons, suggesting the potential for impacts on gene function. These results support the hypothesis that structural changes may play a significant role in standing genetic variation inC. virginica, and potentially have a role in their adaptive and evolutionary success. Altogether, these results suggest that copy number variation plays an important role in the genomic variation ofC. virginica.

This article is part of the Theo Murphy meeting issue ‘Molluscan genomics: broad insights and future directions for a neglected phylum’.
Inference of DNA methylation patterns in molluscs
Authors: Männer Lisa , Schell Tilman , Provataris Panagiotis , Haase Martin , Greve Carola
Published: April 2021

Mollusca are the second largest and arguably most diverse phylum of the animal kingdom. This is in sharp contrast to our very limited knowledge concerning epigenetic mechanisms including DNA methylation in this invertebrate group. Here, we inferred DNA methylation patterns by analysing the normalized dinucleotide CG content in protein-coding sequences and identified DNA methyltransferases (DNMT1 and 3) in published transcriptomes and genomes of 140 species across all eight classes of molluscs. Given the evolutionary age and morphological diversity of molluscs, we expected to find evidence for diverse methylation patterns. Our inferences suggest that molluscs possess substantial levels of DNA methylation in gene bodies as a rule. Yet, we found deviations from this general picture with regard to (i) the CpG observed/expected distributions indicating a reduction in DNA methylation in certain groups and (ii) the completeness of the DNMT toolkit. Reductions were evident in Caudofoveata, Solenogastres, Polyplacophora, Monoplacophora, as well as Scaphopoda. Heterobranchia and Oegopsida were remarkable as they lacked DNMT3, usually responsible for de novo methylation, yet showed signs of DNA methylation. Our survey may serve as guidance for direct empirical analyses of DNA methylation in molluscs.

This article is part of the Theo Murphy meeting issue ‘Molluscan genomics: broad insights and future directions for a neglected phylum’.
Potential of genomic technologies to improve disease resistance in molluscan aquaculture
Authors: Potts Robert W. A. , Gutierrez Alejandro P. , Penaloza Carolina S. , Regan Tim , Bean Tim P. , Houston Ross D.
Published: April 2021

Molluscan aquaculture is a major contributor to global seafood production, but is hampered by infectious disease outbreaks that can cause serious economic losses. Selective breeding has been widely used to improve disease resistance in major agricultural and aquaculture species, and has clear potential in molluscs, albeit its commercial application remains at a formative stage. Advances in genomic technologies, especially the development of cost-efficient genomic selection, have the potential to accelerate genetic improvement. However, tailored approaches are required owing to the distinctive reproductive and life cycle characteristics of molluscan species. Transgenesis and genome editing, in particular CRISPR/Cas systems, have been successfully trialled in molluscs and may further understanding and improvement of genetic resistance to disease through targeted changes to the host genome. Whole-organism genome editing is achievable on a much greater scale compared to other farmed species, making genome-wide CRISPR screening approaches plausible. This review discusses the current state and future potential of selective breeding, genomic tools and genome editing approaches to understand and improve host resistance to infectious disease in molluscs.

This article is part of the Theo Murphy meeting issue ‘Molluscan genomics: broad insights and future directions for a neglected phylum’.
Estimated durations of asymptomatic, symptomatic, and care-seeking phases of tuberculosis disease
Authors: Ku Chu-Chang , MacPherson Peter , Khundi McEwen , Nzawa Rebecca , Feasey Helena RA. , Nliwasa Marriott , Horton Katherine C. , Corbett Elizabeth L. , Dodd Peter J.
Published: April 2021

Ratios of bacteriologically-positive tuberculosis prevalence to notification rates are used to characterise typical durations of tuberculosis disease, but have not accounted for asymptomatic periods prior to care-seeking. We developed novel statistical models to estimate progression from initial bacteriological-positivity including smear conversion, symptom onset and initial care-seeking and fitted them to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework. Asymptomatic tuberculosis duration was in the range 4 – 8 months for African countries; three countries in Asia showed longer durations of > 1 year. Care-seeking typically began half-way between symptom onset and notification. Our method also estimated smear progression rates and case-detection ratios. We found evidence for higher case-detection ratios and much shorter durations of tuberculosis for people living with HIV. To eradicate tuberculosis transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions.
Comprehensive assessment of humoral response after Pfizer BNT162b2 mRNA Covid-19 vaccination: a three-case series
Authors: Danese Elisa , Montagnana Martina , Salvagno Gian Luca , Gelati Matteo , Peserico Denise , Pighi Laura , De Nitto Simone , Henry Brandon M. , Porru Stefano , Lippi Giuseppe
Published: April 2021

Background

Since universal vaccination is a pillar against coronavirus disease 2019 (COVID-19), monitoring anti-SARS-CoV-2 neutralizing antibodies is essential for deciphering post-vaccination immune response.

Methods

Three healthcare workers received 30 μg BNT162b2 mRNA Covid-19 Vaccine, followed by a second identical dose, 21 days afterwards. Venous blood was drawn at baseline and at serial intervals, up to 63 days afterwards, for assessing total immunoglobulins (Ig) anti-RBD (receptor binding domain), IgG anti-S1/S2, IgG anti-RBD, IgM anti-RBD, IgM anti-N/S1 and IgA anti-S1.

Results

All subjects were SARS-CoV-2 seronegative at baseline. Total Ig anti-RBD, IgG anti-S1/S2 and IgG anti-RBD levels increased between 91-368 folds until 21 days after the first vaccine dose, then reached a plateau. The levels raised further after the second dose (by ∼30-, ∼8- and ∼8-fold, respectively), peaking at day 35, but then slightly declining and stabilizing ∼50 days after the first dose. IgA anti-S1 levels increased between 7-11 days after the first dose, slightly declined before the second dose, after which levels augmented by ∼24-fold from baseline. The anti-RBD and anti-N/S1 IgM kinetics were similar to that of anti-S1 IgA, though displaying substantially weaker increases and modest peaks, only 4 to 7-fold higher than baseline. Highly significant inter-correlation was noted between total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG (all r=0.99), whilst other anti-SARS-CoV-2 antibodies displayed lower, though still significant, correlations. Serum spike protein concentration was undetectable at all time points.

Conclusions

BNT162b2 mRNA vaccination generates a robust humoral immune response, especially involving IgG and IgA, magnified by the second vaccine dose.
Subpopulation-specific Machine Learning Prognosis for Underrepresented Patients with Double Prioritized Bias Correction
Authors: Afrose Sharmin , Song Wenjia , Nemeroff Charles B. , Lu Chang , Yao Danfeng (Daphne)
Published: April 2021

Background

Many clinical datasets are intrinsically imbalanced, dominated by overwhelming majority groups. Off-the-shelf machine learning models that optimize the prognosis of majority patient types (e.g., healthy class) may cause substantial errors on the minority prediction class (e.g., disease class) and demographic subgroups (e.g., Black or young patients). In the typical one-machine-learning-model-fits-all paradigm, racial and age disparities are likely to exist, but unreported. In addition, some widely used whole-population metrics give misleading results.

Methods

We design a double prioritized (DP) bias correction technique to mitigate representational biases in machine learning-based prognosis. Our method trains customized machine learning models for specific ethnicity or age groups, a substantial departure from the one-model-predicts-all convention. We compare with other sampling and reweighting techniques in mortality and cancer survivability prediction tasks.

Results

We first provide empirical evidence showing various prediction deficiencies in a typical machine learning setting without bias correction. For example, missed death cases are 3.14 times higher than missed survival cases for mortality prediction. Then, we show DP consistently boosts the minority class recall for underrepresented groups, by up to 38.0%. DP also reduces relative disparities across race and age groups, e.g., up to 88.0% better than the 8 existing sampling solutions in terms of the relative disparity of minority class recall. Cross-race and cross-age-group evaluation also suggests the need for subpopulation-specific machine learning models.

Conclusions

Biases exist in the widely accepted one-machine-learning-model-fits-all-population approach. We invent a bias correction method that produces specialized machine learning prognostication models for underrepresented racial and age groups. This technique may reduce life-threatening prediction mistakes for minority populations.

Plain Language Summary

This work aims to improve the prediction accuracy of machine learning models in medical applications, e.g., estimating the likelihood of a patient dying in an emergency room visit or surviving cancer. Inaccurate prediction may produce life-threatening consequences. We first examine how biases in training data impact prediction outcomes, in particular how underrepresented patients (e.g., young patients or patients of color) are impacted. Then, we design a double prioritized (DP) bias correction technique. It allows one to train machine learning models for specific demographic groups, e.g., one machine learning model for Black patients and another model for Asian patients. Our results confirm the need for training subpopulation-specific machine learning models. Our work helps improve the medical care of minority patients in the age of digital health.
Retrospective feasibility study of Mycobacterium tuberculosis modified lipoprotein as a potential biomarker for TB detection in children
Authors: Yang Xinxin , Wipperman Matthew F. , Nachman Sharon , Sampson Nicole S.
Published: April 2021

Background

Current TB diagnostic methods available have been developed for adults and development efforts have neglected the differences in disease and sampling that occur between adults and children. Diagnostic challenges are even greater in HIV co-infected children and infants.

Methods and results

We established a sandwich ELISA assay to detect Mycobacterium tuberculosis modified lipoprotein (TLP) ex vivo in plasma. The study population contains plasma samples from 21 patients with active TB and 24 control samples with no TB, collected in the International Maternal Pediatric Adolescent AIDS Clinical Trails (IMPAACT) P1041 study. Retrospective analysis was performed and the result demonstrate that TLP level is associated with TB disease.

Conclusions

Plasma levels of TLP associate with active TB disease in HIV positive subjects and can be used as an indicator for TB detection in children.
Comparison of post-COVID depression and major depressive disorder
Authors: Perlis Roy H. , Santillana Mauricio , Ognyanova Katherine , Green Jon , Druckman James , Lazer David , Baum Matthew A.
Published: April 2021

Background

During the COVID-19 pandemic rates of depressive symptoms are markedly elevated, particularly among survivors of infection. Understanding whether such symptoms are distinct among those with prior SARS-CoV-2 infection, or simply a nonspecific reflection of elevated stress, could help target interventions.

Method

We analyzed data from multiple waves of a 50-state survey that included questions about COVID-19 infection as well as the Patient Health Questionnaire examining depressive and anxious symptoms. We utilized multiple logistic regression to examine whether sociodemographic features associated with depression liability differed for those with or without prior COVID-19, and then whether depressive symptoms differed among those with or without prior COVID-19.

Results

Among 91,791 respondents, in regression models, age, gender, race, education, and income all exhibited an interaction with prior COVID-19 in risk for moderate or greater depressive symptoms (p<0.0001 in all cases), indicating differential risk in the two subgroups. Among those with such symptoms, levels of motoric symptoms and suicidality were significantly greater among those with prior COVID-19 illness. Depression risk increased with greater interval following acute infection.

Discussion

Our results suggest that major depressive symptoms observed among individuals with prior COVID-19 illness may not reflect typical depressive episodes, and merit more focused neurobiological investigation.
Whole-Body Muscle MRI Characteristics of LAMA2 Gene Mutation Congenital Muscular Dystrophy Children
Authors: Sakr Hossam M. , Fahmy Nagia , Elsayed Nermine S. , Abdulhady Hala , El-Sobky Tamer A. , Saadawy Amr M. , Beroud Christophe , Udd Bjarne
Published: April 2021

Merosin-deficient or LAMA2-related congenital muscular dystrophy (CMD) belongs to a group of muscle diseases with an overlapping diagnostic spectrum. MRI plays an important role in the diagnosis and disease-tracking of muscle diseases. Whole-body MRI is ideal for describing patterns of muscle involvement. Our purpose is to analyze the pattern of muscle involvement in merosin-deficient CMD children employing whole-body muscle MRI. Ten children with merosin-deficient CMD underwent whole-body muscle MRI. We used a control group of other hereditary muscle diseases, which included 13 children. Overall, 37 muscles were graded for fatty infiltration using Mercuri scale modified by Fischer et al 2008. The results showed a fairly consistent pattern of muscle fatty infiltration in index group, which differed from that in control group. There was a highly statistically significant difference between the two groups in regard to the fatty infiltration of the neck, serratus anterior, rotator cuff, deltoid, forearm, gluteus maximus, gluteus medius, gastrocnemius and soleus muscles. Additionally, results showed relative sparing of the brachialis, biceps brachii, gracilis, sartorius, semitendinosus and extensor muscles of the ankle in index group. There is evidence to suggest that whole-body muscle MRI can become a useful contributor to the differential diagnosis of merosin deficient CMD.

Study Highlights

Whole-body muscle MRI is a useful contributor to the differential diagnosis of merosin-deficient (LAMA2-related) congenital muscular dystrophy.

The study demonstrated the presence of a fairly characteristic pattern of whole-body muscle MRI in children with merosin-deficient CMD in terms of sensitivity and specificity.

The study may be considered as a preliminary step of arriving at an MRI classification system for children with merosin-deficient CMD.
Real-time PCR assays for detection and quantification of early P. falciparum gametocyte stages
Authors: Gadalla Amal A.H. , Siciliano Giulia , Farid Ryan , Alano Pietro , Ranford-Cartwright Lisa , McCarthy James S , Thompson Joanne , Babiker Hamza
Published: April 2021

Introduction

The use of reverse transcription, quantitative qRT-PCR assays for detection and quantification of late gametocyte stages has revealed the high transmission capacity of the human malaria parasite, Plasmodium falciparum. A full understanding how the parasite adjusts its transmission in response to varying in-host environmental conditions during natural infections requires simultaneous quantification of early and late gametocytes. Here, we describe qRT-PCR assays that are specific for detection and quantification of early-stage gametocytes of P. falciparum.

Methods

The assays are based on expression of known early gametocyte genes (pfpeg4, pfg27, pfge1, pfge3 and pfgexp5). The specificity of the qRT-PCR assays was tested using purified stage II and stage V gametocytes. These validated assays were used with qRT-PCR assays targeting late stage (pfs25) and all-stage (pfs16) gametocyte-specific transcripts to quantify gametocytes in natural P. falciparum infections and in a controlled human clinical infection study.

Results

The relative expression of pfpeg4, pfg27 and pfge3, but not of pfge1 and pfgexp5, was significantly higher in purified stage II compared to stage V gametocytes, indicating early gametocyte specificity. In natural infections, 71.2% of individuals had both early and late gametocyte transcripts (pfpeg4/pfg27 plus pfs25), 12.6% harboured only early gametocytes transcripts (pfpeg4/pfg27), and 15.2% had only late gametocytes transcripts (pfs25). In natural infections, the limit of detection was equivalent to 190 and 390 gametocytes/mL blood for pfpeg4 and pfg27, respectively. In infected volunteers, transcripts of pfpeg4 and pfg27 were detected shortly after the onset of blood stage infection, demonstrating the specificity of the assays.

Conclusion

The pfpeg4 and pfg27 qRT-PCR assays can be used specifically to quantify circulating immature gametocytes. Quantification of early gametocytes will improve understanding of epidemiological processes that modulate P. falciparum transmission and enhance the evaluation of transmission blocking interventions.
A Vaccination Simulator for COVID-19: Effective and Sterilizing Immunization Cases
Authors: Karabay Aknur , Kuzdeuov Askat , Ospanova Shyryn , Lewis Michael , Varol Huseyin Atakan
Published: April 2021

Accurate modeling provides a means by which a complex problem can be examined for informed decision-making. We present a particle-based SEIR epidemic simulator as a tool to assess the impact of vaccination strategies on viral propagation and to model both sterilizing and effective immunization outcomes. The simulator includes modules to support contact tracing of the interactions amongst individuals as well as epidemiological testing of the general population. The simulator particles are distinguished by age, thus enabling a more accurate representation of the rates of infection and mortality in accordance with differential demographic susceptibilities and medical outcomes. Moreover, thanks to the age differentiation of particles, the vaccination can be simulated based on the age group descending order or randomly across all age groups. The simulator can be calibrated by region of interest and variable vaccination strategies (i.e. random or prioritized by age) so as to enable locality-sensitive virus mitigation policy measures and resource allocation. The results described, based on the experience of the province of Lecco, Italy, indicate that the tool can be used to evaluate vaccination strategies in a way that incorporates local circumstances of viral propagation and demographic susceptibilities. Further, the simulator accounts for modeling the distinction between sterilizing immunization, in which immunized people are no longer contagious, and that of effective immunization, in which symptoms and mortality outcomes are diminished but individuals can still transmit the virus. The sterilizing-age-based vaccination scenario results in the least number of deaths compared to other scenarios. Furthermore, the results show that the vaccination of the most vulnerable portion of the population should be prioritized for the effective immunization case. As the vaccination rate increases, the mortality gap between the scenarios shrinks.
Evaluating the impact of Hazelwood mine fire event on students’ educational development with Bayesian interrupted time series hierarchical meta-regression
Authors: Gao Caroline X. , Broder Jonathan C. , Brilleman Sam , Campbell Tim C. H. , Berger Emily , Ikin Jillian , Smith Catherine L. , Wolfe Rory , Johnston Fay , Guo Yuming , Carroll Matthew
Published: April 2021

Background

Climate disasters such as wildfires, floods and droughts can introduce significant interruptions and trauma to impacted communities. Children and young people can be disproportionately affected with additional educational disruptions. However, evaluating the impact of disasters is challenging due to difficulties in establishing studies and recruitment post-disasters.

Objectives

With the increasing threat of climate change, we aimed to (1) establish a new analytical framework to evaluate the impact of climate disasters on academic achievement and (2) evaluate the impact of the 2014 Hazelwood mine fire (a six-week fire event in Australia).

Methods

Bayesian hierarchical meta-regression was developed to evaluate the impact of the mine fire using only aggregated school-level data from the standardised National Assessment Program-Literacy and Numeracy (NAPLAN) test. NAPLAN results and school characteristics (2008-2018) from 69 primary/secondary schools with different levels of mine fire-related smoke exposure were used to estimate the impact of the event. Using an interrupted time series design, the model estimated immediate effects and post-interruption trend differences with full Bayesian statistical inference.

Results

Major academic interruptions across NAPLAN domains were evident in high exposure schools in the year post-mine fire (greatest interruption in Writing: 11.09 [95%CI: 3.16-18.93], lowest interruption in Reading: 8.34 [95%CI: 1.07-15.51]). The interruption was comparable to a four to five-month delay in educational attainment and had not fully recovered after several years.

Discussion

Considerable academic delays were found as a result of a mine fire, highlighting the need to provide educational and community-based supports in response to future events. Importantly, this work provides a statistical method using readily available aggregated data to assess the educational impacts in response to other climate disasters.

Graphical abstract
Estimates and determinants of SARS-CoV-2 seroprevalence and infection fatality ratio using latent class analysis: the population-based Tirschenreuth study in the hardest-hit German county in spring 2020
Authors: Wagner Ralf , Peterhoff David , Beileke Stephanie , Guenther Felix , Berr Melanie , Einhauser Sebastian , Schütz Anja , Niller Hans Helmut , Steininger Philipp , Knöll Antje , Tenbusch Matthias , Maier Clara , Korn Klaus , Stark Klaus J. , Gessner Andre , Burkhardt Ralph , Kabesch Michael , Schedl Holger , Küchenhoff Helmut , Pfahlberg Annette B. , Heid Iris M. , Gefeller Olaf , Überla Klaus
Published: April 2021

SARS-CoV-2 infection fatality ratios (IFR) remain controversially discussed with implications for political measures, but the number of registered infections depends on testing strategies and deduced case fatality ratios (CFR) are poor proxies for IFR. The German county of Tirschenreuth suffered a severe SARS-CoV-2 outbreak in spring 2020 with particularly high CFR.

To estimate seroprevalence, dark figure, and IFR for the Tirschenreuth population aged ≥14 years in June/July 2020 with misclassification error control, we conducted a population-based study, including home visits for elderly, and analyzed 4203 participants for SARS-CoV-2 antibodies via three antibody tests (64% of our random sample). Latent class analysis yielded 8.6% standardized county-wide seroprevalence, dark figure factor 5.0, and 2.5% overall IFR. Seroprevalence was two-fold higher among medical workers and one third among current smokers with similar proportions of registered infections. While seroprevalence did not show an age-trend, the dark figure was 12.2 in the young versus 1.7 for ≥85-year-old. Age-specific IFRs were <0.5% below 60 years of age, 1.0% for age 60-69, 13.2% for age 70+, confirming a previously reported age-model for IFR. Senior care homes accounted for 45% of COVID-19-related deaths, reflected by an IFR of 7.5% among individuals aged 70+ and an overall IFR of 1.4% when excluding senior care home residents from our computation.

Our data underscore senior care home infections as key determinant of IFR additionally to age, insufficient targeted testing in the young, and the need for further investigations on behavioral or molecular causes of the fewer infections among current smokers.
Situation of COVID-19 in Brazil: An analysis via growth models as implemented in the ModInterv system for monitoring the pandemic
Authors: Vasconcelos Giovani L. , Duarte-Filho Gerson C. , Brum Arthur A. , Ospina Raydonal , Almeida Francisco A. G. , Macêdo Antônio M. S.
Published: April 2021

In this work we analyze the cumulative curves of deaths attributed to COVID-19 in the 26 Brazilian States and the Federal District up until August 21, 2020. Mathematical growth models implemented by the application ModInterv COVID-19, which can be accessed via internet browser or via a mobile app, were used to investigate at which stage the epidemic is in each of the Brazilian federal units. The analysis revealed that almost all states in the Northern and Northeastern regions were already in the saturation phase, meaning that the epidemic was relatively under control, whereas in all Southern states and in most states in the Midwest the epidemic was still accelerating or showed only a slight deceleration. The Southeastern region presented a great diversity of epidemic stages, with each state being found at a different stage, ranging from acceleration to saturation. It is argued that understanding this heterogeneous geographical distribution of the epidemic is relevant for public health authorities, as it may help in devising more effective strategies against the COVID-19 pandemic in a continental country like Brazil.
Visuospatial neglect: Recovery & Functional outcome after 6 months
Authors: Moore Margaret Jane , Vancleef Kathleen , Riddoch M. Jane , Gillebert Celine R , Demeyere Nele
Published: April 2021

Background/Objective

This study aims to investigate how complex visuospatial neglect behavioural phenotypes predict long-term outcomes, both in terms of neglect recovery and broader functional outcomes.

Methods

This study presents a secondary cohort study of acute and 6 month follow up data from 400 stroke survivors who completed the Oxford Cognitive Screen’s Cancellation Task. At follow-up, patients also completed the Stroke Impact Scale questionnaire. These data were analysed to identify whether any specific combination of neglect symptoms is more likely to result in long-lasting neglect or higher levels of functional impairment, therefore warranting more targeted rehabilitation.

Results

Overall, 98/142(69%) neglect cases recovered by follow-up and there was no significant difference in the persistence of egocentric/allocentric (X2(1)=0.66, p=0.418) or left/right neglect (X2(2)=0.781, p= 0.677). Egocentric neglect was found to follow a proportional recovery pattern with all patients demonstrating a similar level of improvement over time. Conversely, allocentric neglect followed a non-proportional recovery pattern with chronic neglect patients exhibiting a slower rate of improvement than those who recovered. A multiple regression analysis revealed that the initial severity of acute allocentric, but not egocentric, neglect impairment acted as a significant predictor of poor long-term functional outcomes (F(9,383)=3.96, p<0.001, R2=0.066).

Conclusions

Our findings call for systematic neuropsychological assessment of both egocentric and allocentric neglect following stroke, as the occurrence and severity of these conditions may help predict recovery outcomes.
Using PARIHS framework to design a community-based COVID-19 intervention in rural Ghana
Authors: Frimpong Shadrack , Seidu Moro , Hilton Sam Kris
Published: April 2021

This study utilized the Promoting Action on Research Implementation in Health Services (PARIHS) framework to guide the design of the evidence-based practice – COVID Preparedness & Outbreak Prevention Plan (CoCoPOPP) for rural communities in Ghana. Through a participatory academic-community team discussion, interactive dissemination, review of evidence about community-based interventions during Ebola, HIV/AIDS, and Influenza outbreaks via snowball sampling, continuous discourse within the design team, feedback from other local stakeholders and national experts, the evidence-based intervention was developed consistent with the PARIHS framework. By applying the three core elements of the PARIHS framework (that is, evidence, context and facilitation), the study developed orientation, logistic needs and planning as well as social mobilization. The components also included participants recruitment and training, communication, research and M&E plan, execution and technical assistance and facilitation with three overall aims: (1) meet a pressing health need during the COVID-19 pandemic in local underserved settings, (2) ensure that the strategy is informed by high-quality evidence from similar interventions in past outbreaks and (3) evaluate and learn from research on interventions to garner data for organizational use and to share insights on pandemic management and control with the Ghanaian government, wider global health and education community. Hence, CoCoPOPP can be implemented across other rural communities in Ghana and beyond, particularly in other Sub-Saharan African countries with similar cultural settings.
Dynamics of amygdala connectivity in bipolar disorders: A longitudinal study across mood states
Authors: Rey Gwladys , Bolton Thomas A.W. , Gaviria Julian , Piguet Camille , Preti Maria Giulia , Favre Sophie , Aubry Jean-Michel , Van De Ville Dimitri , Vuilleumier Patrik
Published: April 2021

Alterations in activity and connectivity of brain circuits implicated in emotion processing and emotion regulation have been observed during resting-state for different clinical phases of bipolar disorders (BD), but longitudinal investigations across different mood states in the same patients are still rare. Furthermore, measuring dynamics of functional connectivity patterns offers a powerful method to explore changes in the brain’s intrinsic functional organization across mood states. We used a novel co-activation pattern (CAP) analysis to explore the dynamics of amygdala connectivity at rest in a cohort of 20 BD patients prospectively followed-up and scanned across distinct mood states: euthymia (20 patients; 39 sessions), depression (12 patients; 18 sessions), or mania/hypomania (14 patients; 18 sessions). We compared them to 41 healthy controls scanned once or twice (55 sessions). We characterized temporal aspects of dynamic fluctuations in amygdala connectivity over the whole brain as a function of current mood. We identified 6 distinct networks describing amygdala connectivity, among which an interoceptive-sensorimotor CAP exhibited more frequent occurrences during hypomania compared to other mood states, and predicted more severe symptoms of irritability and motor agitation. In contrast, a limbic CAP comprising the hippocampus and ventral tegmental area exhibited fewer occurrences during both depression and hypomania compared to euthymia. Our results reveal distinctive interactions between amygdala and distributed brain networks in different mood states, and foster research on interoception systems especially during the manic phase. Our study also demonstrates the benefits of assessing brain dynamics in BD.
Multilevel and Quasi Monte Carlo methods for the calculation of the Expected Value of Partial Perfect Information
Authors: Fang Wei , Wang Zhenru , Giles Michael B. , Jackson Chris H. , Welton Nicky J. , Andrieu Christophe , Thom Howard
Published: April 2021

The expected value of partial perfect information (EVPPI) provides an upper bound on the value of collecting further evidence on a set of inputs to a cost-effectiveness decision model. Standard Monte Carlo (MC) estimation of EVPPI is computationally expensive as it requires nested simulation. Alternatives based on regression approximations to the model have been developed, but are not practicable when the number of uncertain parameters of interest is large and when parameter estimates are highly correlated. The error associated with the regression approximation is difficult to determine, while MC allows the bias and precision to be controlled. In this paper, we explore the potential of Quasi Monte-Carlo (QMC) and Multilevel Monte-Carlo (MLMC) estimation to reduce computational cost of estimating EVPPI by reducing the variance compared with MC, while preserving accuracy. In this paper, we develop methods to apply QMC and MLMC to EVPPI, addressing particular challenges that arise where Markov Chain Monte Carlo (MCMC) has been used to estimate input parameter distributions. We illustrate the methods using a two examples: a simplified decision tree model for treatments for depression, and a complex Markov model for treatments to prevent stroke in atrial fibrillation, both of which use MCMC inputs. We compare the performance of QMC and MLMC with MC and the approximation techniques of Generalised Additive Model regression (GAM), Gaussian process regression (GP), and Integrated Nested Laplace Approximations (INLA-GP). We found QMC and MLMC to offer substantial computational savings when parameter sets are large and correlated, and when the EVPPI is large. We also find GP and INLA-GP to be biased in those situations, while GAM cannot estimate EVPPI for large parameter sets.
A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis
Authors: Franke Megan K. , MacLean Adam L.
Published: April 2021

Cells do not function in isolation. Arguably, every cell fate decision occurs in response to environmental signals. In many cases cell-cell communication alters the dynamics of a cell’s internal gene regulatory network to initiate cell fate transitions, yet models rarely take this into account. Here we develop a multiscale perspective to study the granulocyte-monocyte vs. megakaryocyte-erythrocyte fate decisions. This transition is dictated by the GATA1-PU.1 network, a classical example of a bistable cell fate system. We show that, for a wide range of cell communication topologies, even subtle changes in signaling can have pronounced effects on cell fate decisions. We go on to show how cell-cell coupling through signaling can spontaneously break the symmetry of a homogenous cell population. Noise, both intrinsic and extrinsic, shapes the decision landscape profoundly, and affects the transcriptional dynamics underlying this important hematopoietic cell fate decision-making system.
Effect of telomerization on the growth patterns of adult cutaneous diploid fibroblasts
Authors: Zgurskiy Alexander A. , Prokhorov Leonid Yu.
Published: April 2021

The article describes effects of telomerization on proliferative activity in cultured cutaneous diploid fibroblasts obtained from an adult men aged 57 years. It is shown that the cells in the control culture initially divide quite actively, but starting from the 27th to the 40th passages, the rate of their division decreases and the time to reach the monolayer increases by about 2 times, and starting from the 42nd passage, the time to reach the monolayer increases by 4-10 times (up to 16-40 days). In a single case, an increase in the doubling time of control non-thelomerized cells was recorded up to 30 times (136 days). The introduction of the telomerase gene allowed cells maintain a high rate of cell division to about 45-47 passages. At the same time, the culture with the telomerase gene exceeds the control culture by 10 passages. Rate of growth the cells with telomerase gene after 48 and up to 57 passages slowed down by 10-18 times (up to 40-73 days). At the 47th passage in the control culture and at the 57th passage in the experimental culture, the cells practically stopped dividing and their number did not increase. The results show that the inclusion of the telomerase gene in adult fibroblasts does not always cancel the limit of cell divisions.
Single extracellular vesicle analysis performed by imaging flow cytometry in contrast to NTA rigorously assesses the accuracy of urinary extracellular vesicle preparation techniques
Authors: Droste Marvin , Tertel Tobias , Jeruschke Stefanie , Dittrich Robin , Kontopoulou Evangelia , Walkenfort Bernd , Börger Verena , Hoyer Peter F. , Büscher Anja K. , Thakur Basant K. , Giebel Bernd
Published: April 2021

Extracellular vesicles (EVs) from several body fluids, including urine, appear as promising biomarkers. Within the last decade, numerous groups have compared the efficacy of EV preparation protocols. Frequently, the efficacy of EV preparation methods is judged by the recovery of particles as estimated by conventional nanoparticle tracking analysis (NTA) or other particle quantification devices. Here, at the example of different urinary EV (uEV) preparation methods, we determined the particle yield in obtained samples with conventional NTA, analyzed their EV content by imaging flow cytometry (IFCM) and quantified the intensity of TSG101 and the contaminant protein uromodulin (UMOD) in Western blots. Our results demonstrate a correlation among CD9-positive objects detected by IFCM and TSG101 Western blot intensities, while particle numbers as determined by NTA correlated with the amount of UMOD.

Consequently, our results question the reliability of conventional NTA analyses for identifying the optimal EV preparation method. Here, in our method comparison, a combination of size exclusion chromatography followed by ultra-filtration showed the highest CD9-positive object and TSG101 protein recovery, and in relation to the number of CD9-positive objects, the lowest amount of UMOD contamination.
Privacy Preserving RNA-Model Validation Across Laboratories
Authors: Ahmed Talal , Carty Mark A , Wenric Stephane , Dry Jonathan R , Salahudeen Ameen Abdulla , Khan Aly A. , Lefkofsky Eric , Stumpe Martin C , Pelossof Raphael
Published: April 2021

Reproducibility of results obtained using RNA data across labs remains a major hurdle in cancer research. Often, molecular predictors trained on one dataset cannot be applied to another due to differences in RNA library preparation and quantification. While current RNA correction algorithms may overcome these differences, they require access to all patient-level data, which necessitates the sharing of training data for predictors when sharing predictors. Here, we describe SpinAdapt, an unsupervised RNA correction algorithm that enables the transfer of molecular models without requiring access to patient-level data. It computes data corrections only via aggregate statistics of each dataset, thereby maintaining patient data privacy. Furthermore, SpinAdapt can correct new samples, thereby enabling evaluation of validation cohorts. Despite an inherent tradeoff between privacy and performance, SpinAdapt outperforms current correction methods that require patient-level data access. We expect this novel correction paradigm to enhance research reproducibility and patient privacy. Finally, SpinAdapt lays a mathematical framework that can be extended to other -omics modalities.
Temporal dynamics of base excision / single-strand break repair protein complex assembly and disassembly are modulated by the PARP1/NAD+/SIRT6 axis
Authors: Koczor Christopher A. , Saville Kate M. , Andrews Joel F. , Clark Jennifer , Fang Qingming , Li Jianfeng , Makarov Mikhail V. , Migaud Marie , Sobol Robert W.
Published: April 2021

Assembly and disassembly of DNA repair protein complexes at sites of DNA damage is essential to maintain genomic integrity. We investigated factors coordinating assembly of the base excision repair (BER) proteins, DNA polymerase β (Polβ) and XRCC1, to DNA lesion sites, identifying a new role for Polβ in regulating XRCC1 disassembly from DNA repair complexes and conversely, demonstrating Polβ’s dependence on XRCC1 for complex assembly. RealPAR, a genetically-encoded probe for live cell imaging of poly(ADP-ribose) (PAR), reveals that Polβ and XRCC1 require PAR for repair complex assembly and PAR degradation for disassembly. We find that BER complex assembly is further modulated by attenuation / augmentation of NAD+biosynthesis. Finally, SIRT6 does not regulate PARP1 activation but impairs XRCC1 recruitment, leading to diminished Polβ abundance at sites of DNA damage. These findings highlight coordinated yet independent roles for both PARP1 and SIRT6 and their regulation by NAD+bioavailability to facilitate BER.
Efficient reprogramming of the heavy-chain CDR3 regions of a human antibody repertoire
Authors: Ou Tianling , He Wenhui , Quinlan Brian D. , Guo Yan , Karunadharma Pabalu , Park Hajeung , Davis-Gardner Meredith E. , Tran Mai H. , Yin Yiming , Zhang Xia , Wang Haimin , Zhong Guocai , Farzan Michael
Published: April 2021

B cells have been engineeredex vivoto express an HIV-1 broadly neutralizing antibody (bNAb). B-cell reprograming may be scientifically and therapeutically useful, but current approaches limit B-cell repertoire diversity and disrupt the organization of the heavy-chain locus. A more diverse and physiologic B-cell repertoire targeting a key HIV-1 epitope could facilitate evaluation of vaccines designed to elicit bNAbs, help identity more potent and bioavailable bNAb variants, or directly enhance viral controlin vivo. Here we address the challenges of generating such a repertoire by replacing the heavy-chain CDR3 (HCDR3) regions of primary human B cells. To do so, we identified and utilized an uncharacterized Cas12a ortholog that recognizes PAM motifs present in human JH genes. We also optimized the design of 200 nucleotide homology-directed repair templates (HDRT) by minimizing the required 3’-5’ deletion of the HDRT-complementary strand. Using these techniques, we edited primary human B cells to express a hemagglutinin epitope tag and the HCDR3 regions of the bNAbs PG9 and CH01. Those edited with bNAb HCDR3 efficiently bound trimeric HIV-1 antigens, implying they could affinity mature in vivo in response to the same antigens. This approach generates diverse B-cell repertoires recognizing a key HIV-1 neutralizing epitope.
IQCELL: A platform for predicting the effect of gene perturbations on developmental trajectories using single-cell RNA-seq data
Authors: Heydari Tiam , Langley Matthew A. , Fisher Cynthia , Aguilar-Hidalgo Daniel , Shukla Shreya , Yachie-Kinoshita Ayako , Hughes Michael , McNagny Kelly M. , Zandstra Peter W.
Published: April 2021

The increasing availability of single-cell RNA-sequencing (scRNA-seq) data from various developmental systems provides the opportunity to infer gene regulatory networks (GRNs) directly from data. Herein we describe IQCELL, a platform to infer, simulate, and study executable logical GRNs directly from scRNA-seq data. Such executable GRNs provide an opportunity to inform fundamental hypotheses in developmental programs and help accelerate the design of stem cell-based technologies. We first describe the architecture of IQCELL. Next, we apply IQCELL to a scRNA-seq dataset of early mouse T-cell development and show that it can infera prioriover 75% of causal gene interactions previously reported via decades of research. We will also show that dynamic simulations of the derived GRN qualitatively recapitulate the effects of the known gene perturbations on the T-cell developmental trajectory. IQCELL is applicable to many developmental systems and offers a versatile tool to infer, simulate, and study GRNs in biological systems. (https://gitlab.com/stemcellbioengineering/iqcell)
Barrier effects on the spatial distribution ofXylella fastidiosain Alicante, Spain
Authors: Cendoya Martina , Hubel Ana , Conesa David , Vicent Antonio
Published: April 2021

Spatial models often assume isotropy and stationarity, implying that spatial dependence is direction invariant and uniform throughout the study area. However, these assumptions are violated when dispersal barriers are present in the form of geographical features or disease control interventions. Despite this, the issue of non-stationarity has been little explored in the context of plant health. The objective of this study was to evaluate the influence of different barriers in the distribution of the quarantine plant pathogenic bacteriumXylella fastidiosain the demarcated area in Alicante, Spain. Occurrence data from the official surveys in 2018 were analyzed with four spatial Bayesian hierarchical models: i) a stationary model representing a scenario without any control interventions or geographical features; ii) a model with mountains as physical barriers; iii) a model with a continuous or iv) discontinuous perimeter barrier as control interventions surrounding the infested area. Barriers were assumed to be totally impermeable, so they should be interpreted as areas without host plants and in which it is not possible for infected vectors or propagating plant material to pass through. Inference and prediction were performed through the integrated nested Laplace approximation methodology and the stochastic partial differential equation approach. In the stationary model the posterior mean of the spatial range was 4,030.17 m 95% CI (2,907.41, 5,563.88), meaning that host plants that are closer to an infected plant than this distance would be at risk forX. fastidiosa. This distance can be used to define the buffer zone around the infested area in Alicante. In the non-stationary models, the posterior mean of the spatial range varied from 3,860.88 m 95% CI (2,918.61, 5,212.18) in the mountain barrier model to 6,141.08 m 95% CI (4,296.32, 9,042.99) in the continuous barrier model. Compared with the stationary model, the perimeter barrier models decreased the probability ofX. fastidiosapresence in the area outside the barrier. Differences between the discontinuous and continuous barrier models showed that breaks in areas with low sampling intensity resulted in a higher probability ofX. fastidiosapresence. These results may help authorities prioritize the areas for surveillance and implementation of control measures.