bluuebunny/crossref_metadata_2025 huggingface dataset:
The accuracy of saliva versus nasopharyngeal and/or oropharyngeal samples for the detection of SARS-CoV-2 in children – A rapid systematic review and meta-analysis
Authors: Dhillon Sharonjit K. , Schelstraete Petra , Cornelissen Laura , Lafort Yves , Bonde Jesper , Arbyn M.
Published: June 2021

Background

The comparative performance of saliva and nasopharyngeal samples for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by reverse transcriptase polymerase chain reaction (RT-PCR) in children remains unclear. As schools reopen around the world, there is an interest in the use of saliva samples for the detection of SARS-CoV-2 in children to circumvent barriers with nasopharyngeal sampling. We systematically reviewed the literature to understand the performance of saliva sampling using RT-PCR on naso- and/or oropharyngeal swabs as the reference standard.

Methods

Articles from PubMed/MEDLINE and Living Evidence were accessed until 28th April 2021. A search method without restriction to children population was applied and during the review phase, if a study included patients <18 years old, authors were contacted to provide additional information on the subset of children. Studies were eligible if they reported on matched saliva and naso- and/or oropharyngeal samples, taken from the same patient on the same day. Studies using other respiratory samples such as sputum samples were excluded. Each paired patient sample had to be tested on the same RT-PCR platform.

Results

Ten studies were included, comprising 1486 matched saliva and on naso- and/or oropharyngeal pairs from children aged 0 to 18 years old. The pooled absolute sensitivity and specificity of saliva sampling using RT-PCR on nasopharyngeal samples as the reference standard was 84.5% (95% CI; 78.0%-90.3%) and 99.5% (95% CI; 98.2%-100.0%). Comparable performance of saliva to nasopharyngeal samples was shown in both symptomatic and asymptomatic children. Stratified analyses of various covariates showed no significant differences.

Discussion

Our pooled accuracy estimates of RT-PCR SARS-CoV-2 testing on saliva in children did not seem to be different from meta-analyses of studies that enrolled mainly adults. Saliva could potentially be considered an alternative sampling method for screening in children and to pick up those with high viral load.
Altered cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy
Authors: Apostolidis Sokratis A. , Kakara Mihir , Painter Mark M. , Goel Rishi R. , Mathew Divij , Lenzi Kerry , Rezk Ayman , Patterson Kristina R. , Espinoza Diego A. , Kadri Jessy C. , Markowitz Daniel M. , Markowitz Clyde , Mexhitaj Ina , Jacobs Dina , Babb Allison , Betts Michael R. , Prak Eline T. Luning , Weiskopf Daniela , Grifoni Alba , Lundgreen Kendall A. , Gouma Sigrid , Sette Alessandro , Bates Paul , Hensley Scott E. , Greenplate Allison R. , Wherry E. John , Li Rui , Bar-Or Amit
Published: June 2021

SARS-CoV-2 mRNA vaccination in healthy individuals generates effective immune protection against COVID-19. Little is known, however, about the SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses in patients with multiple sclerosis on anti-CD20 (MS-aCD20) monotherapy following SARS-CoV-2 mRNA vaccination. Treatment with aCD20 significantly reduced Spike and RBD specific antibody and memory B cell responses in most patients, an effect that was ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. In contrast, all MS-aCD20 patients generated antigen-specific CD4 and CD8 T-cell responses following vaccination. However, treatment with aCD20 skewed these responses compromising circulating Tfh responses and augmenting CD8 T cell induction, while largely preserving Th1 priming. These data also revealed underlying features of coordinated immune responses following mRNA vaccination. Specifically, the MS-aCD20 patients who failed to generate anti-RBD IgG had the most severe defect in cTfh cell responses and more robust CD8 T cell responses compared to those who generated anti-RBD IgG, whose T cell responses were more similar to healthy controls. These data define the nature of SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients, and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making, patient education and public health policy for patients treated with aCD20 and other immunosuppressed patients.
On multifactorial drivers for malaria rebound in Brazil: a spatio-temporal analysis
Authors: Ayala Mario J.C. , Bastos Leonardo S , Villela Daniel A.M.
Published: June 2021

Background

Malaria incidence in Brazil reversed its decreasing trend when cases from recent years, as recent as 2015, exhibited an increase in the Brazilian Amazon basin, the area with highest transmission of Plasmodium vivax and Plasmodium falciparum. In fact, an increase of more than 20% in the years 2016 and 2017 revealed possible vulnerabilities in the national malaria-control program.

Methods

We studied factors that are potentially associated with this reversal, including migration, economical activities, and deforestation, and weakening of investment in control programs. We analyze past incidences of malaria cases due to Plasmodium vivax and Plasmodium falciparum with a spatio-temporal Bayesian model using more than 5 million individual records of malaria cases from January of 2003 to December of 2018 in the Brazilian Amazon to establish the municipalities with unexpected increases in cases.

Results

We observe an increase in imported cases from border countries in Roraima state and found small effects due to deforestation and change of occupations. Also, an overall funding reduction from 2013 to 2016 happened before an increase in malaria cases in five regions in Amazon basin, markedly for P. vivax incidence and especially, in Pará and Roraima States.

Conclusion

Urban developments, discontinued funding for control programs, migration from border areas, deforestation activities, and different economic activities such as mining and agriculture appear linked to the rebound on malaria incidence. These multifactorial drivers show that malaria control programs require permanent attention towards elimination.
A proteomic survival predictor for COVID-19 patients in intensive care
Authors: Demichev Vadim , Tober-Lau Pinkus , Nazarenko Tatiana , Aulakh Simran Kaur , Whitwell Harry , Lemke Oliver , Röhl Annika , Freiwald Anja , Mittermaier Mirja , Szyrwiel Lukasz , Ludwig Daniela , Correia-Melo Clara , Lippert Lena J. , Helbig Elisa T. , Stubbemann Paula , Olk Nadine , Thibeault Charlotte , Grüning Nana-Maria , Blyuss Oleg , Vernardis Spyros , White Matthew , Messner Christoph B. , Joannidis Michael , Sonnweber Thomas , Klein Sebastian J. , Pizzini Alex , Wohlfarter Yvonne , Sahanic Sabina , Hilbe Richard , Schaefer Benedikt , Wagner Sonja , Machleidt Felix , Garcia Carmen , Ruwwe-Glösenkamp Christoph , Lingscheid Tilman , de Jarcy Laure Bosquillon , Stegemann Miriam S. , Pfeiffer Moritz , Jürgens Linda , Denker Sophy , Zickler Daniel , Spies Claudia , Edel Andreas , Müller Nils B. , Enghard Philipp , Zelezniak Aleksej , Bellmann-Weiler Rosa , Weiss Günter , Campbell Archie , Hayward Caroline , Porteous David J. , Marioni Riccardo E. , Uhrig Alexander , Zoller Heinz , Löffler-Ragg Judith , Keller Markus A. , Tancevski Ivan , Timms John F. , Zaikin Alexey , Hippenstiel Stefan , Ramharter Michael , Müller-Redetzky Holger , Witzenrath Martin , Suttorp Norbert , Lilley Kathryn , Mülleder Michael , Sander Leif Erik ,   PA-COVID-19 Study group, Kurth Florian , Ralser Markus
Published: June 2021

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Comprehensively capturing the host physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index and APACHE II score were poor predictors of survival. Plasma proteomics instead identified 14 proteins that showed concentration trajectories different between survivors and non-survivors. A proteomic predictor trained on single samples obtained at the first time point at maximum treatment level (i.e. WHO grade 7) and weeks before the outcome, achieved accurate classification of survivors in an exploratory (AUROC 0.81) as well as in the independent validation cohort (AUROC of 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that predictors derived from plasma protein levels have the potential to substantially outperform current prognostic markers in intensive care.

Trial registration

German Clinical Trials Register DRKS00021688
NeoScore integrates characteristics of the neoantigen:MHC class I interaction and expression to accurately prioritize immunogenic neoantigens
Authors: Borden Elizabeth S. , Buetow Kenneth H. , LaFleur Bonnie J. , Wilson Melissa A. , Hastings Karen Taraszka
Published: June 2021

Accurate prioritization of immunogenic neoantigens is key to developing personalized cancer vaccines and distinguishing those patients likely to respond to immune checkpoint inhibition. However, there is no consensus regarding which characteristics best predict neoantigen immunogenicity, and no model to date has both high sensitivity and specificity and a significant association with survival in response to immunotherapy. We address these challenges in the prioritization of immunogenic neoantigens by 1) identifying which neoantigen characteristics best predict immunogenicity, 2) integrating these characteristics into an immunogenicity score, NeoScore, and 3) demonstrating an improved association of the NeoScore with response to immune checkpoint inhibition compared to mutational burden. One thousand random and evenly split combinations of immunogenic and non-immunogenic neoantigens from a validated dataset were analyzed using a regularized regression model for characteristic selection. The selected characteristics, the dissociation constant and binding stability of the neoantigen:MHC class I complex and expression of the mutated gene in the tumor, were integrated into the NeoScore. A web application is provided for calculation of the NeoScore. The NeoScore results in improved, or equivalent, performance in four test datasets as measured by sensitivity, specificity, and area under the receiver operator characteristics curve compared to previous models. Among cutaneous melanoma patients treated with immune checkpoint inhibition, a high NeoScore had a greater association with improved survival compared to mutational burden. Overall, the NeoScore has the potential to improve neoantigen prioritization for the development of personalized vaccines and contribute to the determination of which patients are likely to respond to immunotherapy.
Molecular mapping of urinary complement peptides in kidney diseases
Authors: Wendt Ralph , Siwy Justyna , He Tianlin , Latosinska Agnieszka , Wiech Thorsten , Zipfel Peter F. , Tserga Aggeliki , Vlahou Antonia , Catanese Lorenzo , Rupprecht Harald , Mischak Harald , Beige Joachim
Published: June 2021

Defective complement activation has been associated with various types of kidney disease. This led to the hypothesis that specific urine complement fragments may be associated with kidney disease etiologies, and disease progression may be reflected by changes in these complement fragments. We investigated the occurrence of complement fragments in urine, their association with kidney function, proteinuria and disease etiology. Mass spectrometry based peptidomics data from the Human Urinary Proteome/Peptidome Database were extracted and the distribution of complement peptides in the different kidney disease etiologies and controls was investigated. All datasets with informations on disease/health status and detectable complement peptides were included (n=16027). Twenty-three different urinary peptides derived from complement proteins could be identified, originating from the complement proteins C3, C4 and complement factor B. For most C3-derived peptides an inverse association with eGFR was observed, while the majority of peptides derived from CFB demonstrated positive association with eGFR. Highest levels of significant C3 excretion relative to controls were seen in minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MGN), lupus nephritis (LN), diabetic kidney disease (DKD), IgAN, membranoproliferative glomerulonephritis (MPGN), and C3-glomerulonephritis. In conclusion, several peptides derived from the complement proteins C3, C4 and factor B are significantly associated with specific kidney disease etiologies. These peptides may depict disease-specific complement activation, as well as damage to the glomerular basement membrane. Further targeted investigation of these peptides may provide new insight into disease pathophysiology and could possibly guide therapeutic decisions, especially when targeting complement factors.
Opinion of Health Care Providers on Birth Companions in Obstetrics Department of a Tertiary Care Hospital in North India
Authors: Sarwal Tanvi , Sarwal Yamini , Tyagi Shakun , Sarwal Rakesh
Published: June 2021

Background

Despite impressive improvements in institutional births and a fall in maternal mortality, satisfaction of women with birthing experience in public health institutions is low (68%). Birth Companion is an important part of the Labour room Quality Improvement (LaQshya) programme introduced by the Government of India in 2017. Despite mandates, implementation of the concept has been unsatisfactory (9%), even though the importance of Birth Companion has increased due to enhanced risk posed by COVID-19. Little is known about awareness among health care providers on Birth Companions, perceived barriers or their suggestions.

Methods

We canvassed a 15-question instrument using ordinal scales on 151 health care providers comprising consultants, post graduates, residents, and nurses (response rate 69%) in the department of Obstetrics & Gynecology, Lok Nayak Hospital, Delhi, India to gauge their awareness and opinions about Birth Companions.

Results

Most health care providers across all categories were aware of the concept (93%), World Health Organization’s recommendation (83%) and Government’s instructions for its hospitals (68%) that every woman should be accompanied by a Birth Companion of her choice during labour. Birth Companions of choice suggested by them were the mother (70%), husband (69%). sister (46%) or nurse (43%). Most health care providers agreed that a Birth Companion should wear clean clothes (95%), be free from any communicable disease (91%), stay with the pregnant woman throughout the process of labour (74%) and should have herself gone though labour (42%). Almost all providers (95%) agreed that the presence of a Birth Companion during labour will be beneficial, as they would provide emotional support (99%), boost the woman’s confidence (98%), provide comfort measures like massage (95%), early initiation of breastfeeding (93%), reduce post-partum depression (91%), humanize labour (83%), reduce need for analgesia (70%) and increase spontaneous vaginal births (69%). Yet support for its introduction in their hospital was low (59%). Staff nurses had reservations (62%) with only 40% of those who believed Birth Companion to be beneficial approving of its introduction in their hospital. Over-crowding in labour room and privacy concerns for other women were identified as key barriers.

Conclusion

Even though most health care providers were aware of and convinced of multiple benefits of Birth Companion during labour, lack of adequate infrastructure in the labour room prevented them from supporting its introduction. Government should provide adequate funding to upgrade labour rooms in a way that provides privacy to the delivering women and frame guidelines and train Birth Companions to perform their role appropriately.
COVID-19 infection and subsequent psychiatric morbidity, sleep problems and fatigue: analysis of an English primary care cohort of 226,521 positive patients
Authors: Abel Kathryn M , Carr Matthew J. , Ashcroft Darren M. , Chalder Trudie , Chew-Graham Carolyn A. , Hope Holly , Kapur Navneet , McManus Sally , Steeg Sarah , Webb Roger T. , Pierce Matthias
Published: June 2021

Objectives

The primary hypothesis was that the risk of incident or repeat psychiatric illness, fatigue and sleep problems increased following COVID-19 infection. The analysis plan was pre-registered (https://osf.io/n2k34/).

Design

Matched cohorts were assembled using a UK primary care registry (the CPRD-Aurum database). Patients were followed-up for up to 10 months, from 1st February 2020 to 9th December 2020.

Setting

Primary care database of 11,923,499 adults (≥16 years).

Participants

From 232,780 adults with a positive COVID-19 test (after excluding those with <2 years historical data or <1 week follow-up), 86,922 without prior mental illness, 19,020 with anxiety or depression, 1,036 with psychosis, 4,152 with fatigue and 4,539 with sleep problems were matched to up to four controls based on gender, general practice and year of birth. A negative control used patients who tested negative for COVID-19 and patients negative for COVID with an influenza diagnosis.

Main Outcomes and Measures

Cox proportional hazard models estimated the association between a COVID-19 positive test and subsequent psychiatric morbidity (depression, anxiety, psychosis, or self-harm), sleep problems, fatigue or psychotropic prescribing. Models adjusted for comorbidities, ethnicity, smoking and BMI.

Results

After adjusting for observed confounders, there was an association between testing positive for COVID-19 and almost all markers of psychiatric morbidity, fatigue and sleep problems. The adjusted hazard ratio (aHR) for incident psychiatric morbidity was 1.75 (95% CI 1.56-1.96). However, there was a similar risk of incident psychiatric morbidity for those with a negative COVID-19 test (aHR 1.57, 95% CI 1.51-1.63) and a larger increase associated with influenza (aHR 2.97, 95% CI 1.36-6.48).

Conclusions

There is consistent evidence that COVID-19 infection elevates risk of fatigue and sleep problems, however the results from the negative control analysis suggests that residual confounding may be responsible for at least some of the association between COVID-19 and psychiatric morbidity.
Monitoring SARS-CoV-2 Populations in Wastewater by Amplicon Sequencing and Using the Novel Program SAM Refiner
Authors: Gregory Devon A. , Wieberg Chris G. , Wenzel Jeff , Lin Chung-Ho , Johnson Marc C.
Published: June 2021

Sequencing SARS-CoV-2 from wastewater has become a useful tool in monitoring the spread of variants. We use a novel computation workflow with SARS-CoV-2 amplicon sequencing in order to track wastewater populations of the virus. As part of this workflow, we developed a program for both variant reporting and removal of PCR generated chimeric sequences. With these methods, we are able to track viral population dynamics over time. We observe the emergence of the variants of concern B.1.1.7 and P.1, and their displacement of the D614G B.1 variant.
A Web-based Tool for Automatically linking Clinical Trials to their Publications
Authors: Smalheiser Neil R. , Holt Arthur W.
Published: June 2021

Objective

Evidence synthesis teams, physicians, policy makers, and patients and their families all have an interest in following the outcomes of clinical trials and would benefit from being able to evaluate both the results posted in trial registries and in the publications that arise from them. Manual searching for publications arising from a given trial is a laborious and uncertain process. We sought to create a statistical model to automatically identify PubMed articles likely to report clinical outcome results from each registered trial in ClinicalTrials.gov.

Materials and Methods

A machine learning-based model was trained on pairs (publications linked to specific registered trials). Multiple features were constructed based on the degree of matching between the PubMed article metadata and specific fields of the trial registry, as well as matching with the set of publications already known to be linked to that trial.

Results

Evaluation of the model using NCT-linked articles as gold standard showed that they tend to be top ranked (median best rank = 1.0), and 91% of them are ranked in the top ten.

Discussion

Based on this model, we have created a free, public web based tool at http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/TrialPubLinking/trial_pub_link_start.cgithat, given any registered trial in ClinicalTrials.gov, presents a ranked list of the PubMed articles in order of estimated probability that they report clinical outcome data from that trial. The tool should greatly facilitate studies of trial outcome results and their relation to the original trial designs.
Enteric viruses nucleic acids distribution along the digestive tract of rhesus macaques with idiopathic chronic diarrhea
Authors: Delwart Eric , Merriam David , Ardeshir Amir , Altan Eda , Li Yanpeng , Deng Xutao , Hartigan-O’Connor J. Dennis
Published: June 2021

Idiopathic chronic diarrhea (ICD) is a common clinical condition in captive rhesus macaques, claiming 33% of medical culls (i.e. deaths unrelated to research). Using viral metagenomics we characterized the eukaryotic virome in digestive tract tissues collected at necropsy from nine animals with ICD. We show the presence of multiple viruses in the Parvoviridae and Picornaviridae family. We then compared the distribution of viral reads in the stomach, duodenum, jejunum, ileum, and the proximal, transverse, and distal colons. Tissues and mucosal scraping from the same locations showed closely related results while different gut tissues from the same animal varied widely. Picornavirus reads were generally more abundant in the lower digestive tract, particularly in the descending (distal) colon. Parvoviruses were more abundant in the upper reach particularly in the stomach. In situ hydridization (ISH) of fixed tissues showed punctuated staining for both these RNA and DNA viruses in the distal colon. Parvovirus ISH staining was also detected in the stomach/duodenum/jejunum in distinct oval-shaped structures. Therefore, the location of enteric viral nucleic acid differed widely between different viral families and along the length of the digestive tract.
Genomic Analyses of the Metastasis-derived LNCaP, VCaP, and PC3-AR Prostate Cancer Cell Lines
Authors: Sienkiewicz Karolina , Yang Chunsong , Paschal Bryce M. , Ratan Aakrosh
Published: June 2021

The lymph node metastasis-derived LNCaP, the bone metastasis-derived PC3 (skull), and VCaP (vertebral) cell lines are widely used preclinical models of human prostate cancer (CaP) and have been described in >19,000 publications. Here, we report on short-read whole-genome sequencing and genomic analyses of LNCaP, VCaP, and PC3 cells stably transduced with WT AR (PC3-AR). LNCaP cells are composed of multiple subpopulations, which results in non-integral copy number states and a high mutational load when the data is analyzed in bulk. All three cell lines contain pathogenic mutations and homozygous deletions in genes involved in DNA mismatch repair, along with deleterious mutations in cellcycle, Wnt signaling, and other cellular processes. Furthermore, LNCaP cells contain a missense mutation in a well-known CaP hotspot of TP53, whereas both PC3-AR and VCaP have truncating mutations in TP53 and do not express p53 protein. In addition, we detect the signatures of chromothripsis of the q arms of chromosome 5 in both PC3-AR and VCaP cells, strengthening the association of TP53 inactivation with chromothripsis reported in other systems. Our work provides a resource for genetic, genomic, and biological studies employing these commonly-used prostate cancer cell lines.
A lineage tree-based hidden Markov model to quantify cellular heterogeneity and plasticity
Authors: Mohammadi Farnaz , Visagan Shakthi , Gross Sean M. , Karginov Luka , Lagarde JC , Heiser Laura M. , Meyer Aaron S.
Published: June 2021

Cell plasticity operates alongside other sources of cell-to-cell heterogeneity, such as genetic mutations and variation in signaling, together preventing most cancer therapies from being curative. The predominant methods of quantifying tumor-drug response operate on snapshot, population-level measurements and therefore lack evolutionary dynamics, which are particularly critical for dynamic processes such as plasticity. Here we apply a lineage tree-based adaptation of a hidden Markov model that employs single cell lineages as input to learn the characteristic patterns of single cell phenotypic heterogeneity and state transitions in an unsupervised fashion. To benchmark our model, we paired cell fate with either cell lifetimes or individual cell cycle phase lengths on synthetic data and demonstrated that the model successfully classifies cells within experimentally tractable dataset sizes. As an application, we analyzed experimental measurements of same measurements in cancer and non-cancer cell populations under various treatments. We find that in each case multiple phenotypically distinct states exist, with significant heterogeneity and unique drug responses. In total, this framework allows for the flexible classification of single cell heterogeneity across lineages.
Host-specific epibiomes of distinctAcropora cervicornisgenotypes persist after field transplantation
Authors: Aguirre Emily G. , Million Wyatt C. , Bartels Erich , Krediet Cory J. , Kenkel Carly D.
Published: June 2021

Microbiome studies across taxa have established the influence of host genotype on microbial recruitment and maintenance. However, research exploring host-specific epibionts in scleractinian corals is scant and the influence of intraspecific differences across environments remains unclear. Here, we studied the epibiome of tenAcropora cervicornisgenotypes to investigate the relative roles of host genotype and environment in structuring the epibiome. Coral mucus was sampled in a common garden nursery from replicate ramets of distinct genotypes (T0). Coral fragment replicates (n=3) of each genotype were then transplanted to nine different field sites in the Lower Florida Keys and mucus was again sampled one year later from surviving ramets (T12). 16S rRNA amplicon sequencing was used to assess microbial composition, richness, and beta-diversity. The most abundant and consistent amplicon sequencing variants (ASVs) in all samples belonged to Fokiniaceae (MD3-55 genus) and Cyanobacteria (Synechococccus). The abundances of these bacterial taxa varied consistently between genotypes whereas neither the composition nor taxonomic abundance were significantly different among field sites. Interestingly, several high MD3-55 hosting genotypes showed rapid diversification and an increase in MD3-55 following transplantation. Overall, our results indicate healthyA. cervicornisgenotypes retain distinct epibiome signatures through time, suggesting a strong host component. Lastly, our results show that differences in MD3-55 abundances can be consistently detected in the epibiome of distinct host-genotypes ofA. cervicornis. As this organism (sensuAquarickettsia rohweri) has been implicated as a marker of disease resistance, this finding reinforces the potential use of microbial indicators in reef restoration efforts via non-invasive surface/mucus sampling.
The Mixed Blessing of AMPK Signaling in Cancer Treatments
Authors: Sadria Mehrshad , Seo Deokhwa , Layton Anita T.
Published: June 2021

Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. Given its conflicting roles, the effects of AMPK activation in cancer can be counter-intuitive. Prior to the establishment of cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, AMPK has been shown to either suppress or promote cancer, depending on cell type or state. To unravel the controversial roles of AMPK in cancer, we developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with specific focus on AMPK, mTORC, and their modulators. Model simulations clarify the competing effects and the roles of key metabolic signalling pathways in tumorigenesis, which may yield insights on innovative therapeutic strategies.
Dynamic rewiring of biological activity across genotype and lineage revealed by context-dependent functional interactions
Authors: Kim Eiru , Novak Lance C. , Gheorghe Veronica , Bristow Christopher A. , Hart Traver
Published: June 2021

Coessentiality networks derived from CRISPR screens in cell lines provide a powerful framework for identifying functional modules in the cell and for inferring the role of uncharacterized genes. However, these networks integrate signal across all underlying data, and can mask strong interactions that occur in only a subset of the cell lines analyzed. Here we decipher dynamic functional interactions by identifying significant cellular contexts, primarily by oncogenic mutation, lineage, and tumor type, and discovering coessentiality relationships that depend on these contexts. We recapitulate well-known gene-context interactions such as oncogene-mutation, paralog buffering, and tissue-specific essential genes, show how mutation rewires known signal transduction pathways, including RAS/RAF and IGF1R-PIK3CA, and illustrate the implications for drug targeting. We further demonstrate how context-dependent functional interactions can elucidate lineage-specific gene function, as illustrated by the maturation of proreceptors IGF1R and MET by proteases FURIN and CPD. This approach advances our understanding of context-dependent interactions and how they can be gleaned from these data. We provide an online resource to explore these context-dependent interactions at diffnet.hart-lab.org.
Assessing physical fitness during pregnancy: validity and reliability of fitness tests, and relationship with maternal and neonatal health-related outcomes. A systematic review
Authors: ROMERO-GALLARDO LIDIA , ROLDAN-REOYO OLGA , CASTRO-PINERO JOSE , APARICIO VIRGINIA ARIADNA , MAY LINDA , OCON-HERNANDEZ OLGA , Soriano-Maldonado Alberto
Published: June 2021

Background: Physical fitness (PF) is a powerful marker of health throughout the lifespan. In pregnant women, higher PF is associated with better maternal and fetal health, better delivery outcomes and earlier postpartum recovery. The assessment of PF during pregnancy requires special considerations to preserve fetal and maternal health; thus, providing a compilation of the most frequently used fitness tests, and assessing their validity, reliability, and association with maternal and neonatal health-related outcomes is of scientific and clinical interest. Objectives: To systematically review studies evaluating one or more components of PF in pregnant women, to answer two research questions: 1) What fitness tests have been previously employed in pregnant women? and 2) What is the validity and reliability of these tests and their relationship with health-related outcomes? Data Sources: PubMed and Web of Science. Methods: Two independent reviewers systematically examined the articles in each database. The information from the included articles was summarized by a single researcher. Results: A total of 149 articles containing a sum of 191 fitness tests were included. Among the 191 fitness tests, 99 (i.e.,52%) assessed cardiorespiratory fitness through 75 different protocols, 28 (15%) assessed muscular fitness through 16 different protocols, 14 (7%) assessed flexibility through 13 different protocols, 45 (24%) assessed balance through 40 different protocols, 2 assessed speed with the same protocol and 3 were multidimensional tests using one protocol. A total of 19 articles with 23 tests (13%) assessed either validity (n=4), reliability (n=6), or the relationship of PF with health-related outcomes (n=16). Conclusion: PF during pregnancy has been assessed through a wide variety of protocols, mostly lacking validity and reliability data.
New intranasal and injectable gene therapy for healthy life extension
Authors: Jaijyan Dabbu Kumar , Selariu Anca , Cruz-Cosme Ruth , Tong Mingming , Yang Shaomin , Church George , Kekich David , Fallah Ali , Sadoshima Junichi , Tang Qiyi , Parrish Elizabeth , Zhu Hua
Published: June 2021

As the global elderly population grows, it is socioeconomically and medically critical to have diverse and effective means of mitigating the impact of aging on human health. Previous studies showed that adenovirus-associated virus (AAV) vector induced overexpression of certain proteins can suppress or reverse the effects of aging in animal models. Here, we sought to determine whether the high-capacity cytomegalovirus vector can be an effective and safe gene delivery method for two such-protective factors: telomerase reverse transcriptase (TERT) and follistatin (FST). We found that the mouse cytomegalovirus (MCMV) carrying exogenous TERT or FST (MCMVTERT or MCMVFST) extended median lifespan by 41.4% and 32.5%, respectively. This is the first report of CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity. Treatment significantly improved glucose tolerance, physical performance, and prevented loss of body mass and alopecia. Telomere shortening seen with aging was ameliorated by TERT, and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects. Translating this research to humans could have significant benefits associated with increased health span.
A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity
Authors: Klein Luisa , Van Steenwinckel Juliette , Fleiss Bobbi , Scheuer Till , Bührer Christoph , Faivre Valerie , Bokobza Cindy , Lemoine Sophie , Blugeon Corinne , Schwendimann Leslie , Csaba Zsolt , Vousden Dulcie A. , Lerch Jason P. , Vernon Anthony C. , Gressens Pierre , Schmitz Thomas
Published: June 2021

Preterm infants often show pathologies of the cerebellum, which are associated with impaired motor performance, lower IQ and poor language skills at school ages. Because 1 in 10 babies is born preterm cerebellar injury is a significant clinical problem. The causes of cerebellar damage are yet to be fully explained. Herein, we tested the hypothesis that perinatal inflammatory stimuli may play a key role in cerebellar injury of preterm infants. We undertook our studies in an established mouse model of inflammation-induced encephalopathy of prematurity driven by systemic administration of the prototypic pro-inflammatory cytokine interleukin-1β (IL-1β). Inflammation is induced between postnatal day (P) 1 to day 5, timing equivalent to the last trimester for brain development in humans the period of vulnerability to preterm birth related brain injury. We investigated acute and long-term consequences for the cerebellum on brain volume expansion, oligodendroglial maturation, myelin levels and the microglial transcriptome. Perinatal inflammation induced global mouse brain volume reductions, including specific grey and white matter volume reductions in cerebellar lobules I and II (5% FDR) in IL-1β versus control treated mice from P15 onwards. Oligodendroglia damage preceded the MRI-detectable volume changes, as evidenced by a reduced proliferation of OLIG2+ cells at P10 and reduced levels of the myelin proteins MOG, MBP and MAG at P10 and P15. Increased density of Iba1+ cerebellar microglia was observed at P5 and P45, with evidence for increased microglial proliferation at P5 and P10. Comparison of the transcriptome of microglia isolated from P5 cerebelli and cerebrum revealed significant enrichment of pro-inflammatory markers in microglia from both regions, but in the cerebellum microglia displayed a unique type I interferon signalling dysregulation. Collectively, these data suggest that in our model that systemic inflammation causes chronic activation of microglia and maldevelopment of cerebellum that includes myelin deficits which is driven in the cerebellum by type I interferon signalling. Future protective strategies for preterm infants should consider sustained type I interferon signalling driven cerebellar inflammation as an important target.
Age-related declines in neural distinctiveness correlate across brain areas and result from both decreased reliability and increased confusability
Authors: Simmonite M. , Polk T. A.
Published: June 2021

According to the neural dedifferentiation hypothesis, age-related reductions in the distinctiveness of neural representations contribute to sensory, cognitive, and motor declines associated with aging: neural activity associated with different stimulus categories becomes more confusable with age and behavioural performance suffers as a result. Initial studies investigated age-related dedifferentiation in the visual cortex, but subsequent research has revealed declines in other brain regions, suggesting that dedifferentiation may be a general feature of the aging brain. In the present study, we used functional magnetic resonance imaging to investigate age-related dedifferentiation in the visual, auditory, and motor cortices. Participants were 58 young adults and 79 older adults. The similarity of activation patterns across different blocks of the same condition was calculated (within-condition correlation, a measure of reliability) as was the similarity of activation patterns elicited by different conditions (between-category correlations, a measure of confusability). Neural distinctiveness was defined as the difference between the mean within- and between-condition similarity. We found age-related reductions in neural distinctiveness in the visual, auditory, and motor cortices, which were driven by both decreases in within-category similarity and increases in between-category similarity. There were significant positive cross-region correlations between neural distinctiveness in different regions. These correlations were driven by within-category similarities, a finding that indicates that declines in the reliability of neural activity appear to occur in tandem across the brain. These findings suggest that the changes in neural distinctiveness that occur in healthy aging result from changes in both the reliability and confusability of patterns of neural activity
Heat stress reveals the existence of a specialized variant of the pachytene checkpoint in meiosis of Arabidopsis thaliana
Authors: De Jaeger-Braet Joke , Krause Linda , Buchholz Anika , Schnittger Arp
Published: June 2021

Plant growth and fertility strongly depend on environmental conditions such as temperature. Remarkably, temperature also influences meiotic recombination and thus, the current climate change will affect the genetic make-up of plants. To further understand temperature effects on meiosis, we have followed male meiocytes of Arabidopsis thaliana by live cell imaging under three different temperature regimes, at 21°C and at heat shock conditions of 30°C and 34°C as well as after an acclimatization phase of one week at 30°C. This work led to a cytological framework of meiotic progression at elevated temperature. We found that an increase to 30°C, sped up meiotic progression with specific phases being more amenable to heat than others. An acclimatization phase often moderated this effect. A sudden increase to 34°C promoted a faster progression of meiosis in early prophase compared to 21°C. However, the phase in which cross-overs maturate was found to be prolonged at 34°C. Interestingly, mutants involved in the recombination pathway did not show the extension of this phase at 34°C demonstrating that the delay is recombination dependent. Further analysis revealed the involvement of the ATM kinase in this prolongation indicating the existence of a specialized variant of the pachytene checkpoint in plants.
Improving long-read consensus sequencing accuracy with deep learning
Authors: Lal Avantika , Brown Michael , Mohan Rahul , Daw Joyjit , Drake James , Israeli Johnny
Published: June 2021

The PacBio HiFi sequencing technology combines less accurate, multi-read passes from the same molecule (subreads) to yield consensus sequencing reads that are both long (averaging 10-25 kb) and highly accurate. However, these reads can retain residual sequencing error, predominantly insertions or deletions at homopolymeric regions. Here, we train deep learning models to polish HiFi reads by recognizing and correcting sequencing errors. We show that our models are effective at reducing these errors by 25-40% in HiFi reads from human as well as E. coli genomes.
Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging
Authors: Wang Chaoyue , Martins-Bach Aurea B. , Alfaro-Almagro Fidel , Douaud Gwenaëlle , Klein Johannes C. , Llera Alberto , Fiscone Cristiana , Bowtell Richard , Elliott Lloyd T. , Smith Stephen M. , Tendler Benjamin C. , Miller Karla L.
Published: June 2021

A key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging MRI technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We developed a QSM processing pipeline to estimate magnetic susceptibility of multiple brain structures in 35,885 subjects from the UK Biobank prospective epidemiological study. We identified phenotypic associations of magnetic susceptibility that include body iron, disease, diet, and alcohol consumption. Genome-wide associations related magnetic susceptibility to genetic variants with biological functions involving iron, calcium, myelin, and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers world-wide, creating potential to discover novel, non-invasive markers of brain health.
Population genetics of polymorphism and divergence in rapidly evolving populations
Authors: Melissa Matthew J. , Good Benjamin H. , Fisher Daniel S. , Desai Michael M.
Published: June 2021

In rapidly evolving populations, numerous beneficial and deleterious mutations can arise and segregate within a population at the same time. In this regime, evolutionary dynamics cannot be analyzed using traditional population genetic approaches that assume that sites evolve independently. Instead, the dynamics of many loci must be analyzed simultaneously. Recent work has made progress by first analyzing the fitness variation within a population, and then studying how individual lineages interact with this traveling fitness wave. However, these “traveling wave” models have previously been restricted to extreme cases where selection on individual mutations is either much faster or much slower than the typical coalescent timescaleTc. In this work, we show how the traveling wave framework can be extended to intermediate regimes in which the scaled fitness effects of mutations (Tcs) are neither large nor small compared to one. This enables us to describe the dynamics of populations subject to a wide range of fitness effects, and in particular, in cases where it is not immediately clear which mutations are most important in shaping the dynamics and statistics of genetic diversity. We use this approach to derive new expressions for the fixation probabilities and site frequency spectra of mutations as a function of their scaled fitness effects, along with related results for the coalescent timescaleTcand the rate of adaptation or Muller’s ratchet. We find that competition between linked mutations can have a dramatic impact on the proportions of neutral and selected polymorphisms, which is not simply summarized by the scaled selection coefficientTcs. We conclude by discussing the implications of these results for population genetic inferences.
De novo brain-computer interfacing deforms manifold of populational neural activity patterns in human cerebral cortex
Authors: Iwama Seitaro , Yichi Zhang , Ushiba Junichi
Published: June 2021

Human brains are capable of modulating innate activities to adapt to novel environmental stimuli; for sensorimotor cortices (SM1) this means acquisition of a rich repertoire of motor behaviors. We investigated the adaptability of human SM1 motor control by analyzing net neural population activity during the learning of brain-computer interface (BCI) operations. We found systematic interactions between the neural manifold of cortical population activities and BCI classifiers; the neural manifold was stretched by rescaling motor-related features of electroencephalograms with model-based fixed classifiers, but not with adaptive classifiers that were constantly recalibrated to user activity. Moreover, operation of a BCI based on a de novo classifier with a fixed decision boundary based on biologically unnatural features, deformed the neural manifold to be orthogonal to the boundary. These principles of neural adaptation at a macroscopic level may underlie the ability of humans to learn wide-ranging behavioral repertoires and adapt to novel environments.

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Voxelated Bioprinting of Mechanically Robust Multiscale Porous Scaffolds for Pancreatic Islets
Authors: Zhu Jinchang , He Yi , Kong Linlin , He Zhijian , Kang Kaylen Y. , Grady Shannon P. , Nguyen Leander Q. , Chen Dong , Wang Yong , Oberholzer Jose , Cai Li-Heng
Published: June 2021

Three-dimensional (3D) bioprinting additively assembles bio-inks to manufacture tissue-mimicking biological constructs, but with the typical building blocks limited to one-dimensional filaments. Here, we develop a technique for the digital assembly of spherical particles (DASP), which are effectively zero-dimensional voxels – the basic unit of 3D structures. We show that DASP enables on-demand generation, deposition, and assembly of viscoelastic bio-ink droplets. We establish a phase diagram that outlines the viscoelasticity of bio-inks required for printing spherical particles of good fidelity. Moreover, we develop a strategy for engineering bio-inks with independently controllable viscoelasticity and mesh size. Using DASP, we create mechanically robust, multiscale porous scaffolds composed of interconnected yet distinguishable hydrogel particles. Finally, we demonstrate the application of the scaffolds in encapsulating human pancreatic islets for responsive insulin release. Together with the knowledge of bio-ink design, DASP might be used to engineer highly heterogeneous yet tightly organized tissue constructs for therapeutic applications.

Table of Contents

A three-dimensional bioprinting technology is developed to enable on-demand generation, deposition, and assembly of viscoelastic bio-ink droplets in a biofriendly environment. A strategy is developed to independently control elasticity, viscosity, and mesh size of bio-inks. The technique allows for easy manufacturing mechanically robust multiscale porous scaffolds, which can be used to encapsulate human pancreatic islets for sustained responsive insulin release.