bluuebunny/crossref_metadata_2025 huggingface dataset:
RARE-19. NETWORK AND DEEP LEARNING INFERENCE IN SINGLE CELL RNA SEQUENCING REVEAL DETAILED TRANSCRIPTIONAL SIGNATURES CONGRUENT WITH MOLECULAR UNDERSTANDING OF ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Prince Eric , Trudeau Tammy , Chatain Oscar , Chee Keanu , Vijmasi Trinka , Staulcup Susan , Donson Andrew , Foreman Nicholas , Hankinson Todd
Published: June 2021

Adamantinomatous Craniopharyngioma (ACP) is a highly morbid, cellularly heterogeneous pediatric tumor arising in the sellar/suprasellar region of the brain. This cellular heterogeneity makes ACP an ideal candidate for study using single-cell RNA-sequencing (scRNA-seq). We collected a 10,000 cell scRNA-seq dataset on the 10X v3 platform, from 6 unique patients. Using the industry standard Seurat software package, we identified 34 unique cell clusters. By crossing the results of two separate expert curated cellular reference atlases (Azimuth and scHCL), we determined that 33 of these cell types were immune-related (e.g., T cells, monocytes, etc.) or histologically related (e.g., glial cells). The remaining 2,048 cells were inferred to be ACP driver cells. Rigorous statistical testing of third-generation graph topology-based network enrichment methods utilizing the Reactome database supported this conclusion. In order to identify effective antitumor therapies, it is critical to understand the temporal evolution of tumor cell behavior. Computational solutions that describe the potential lifecycle of tumor cells have been derived using scRNA-seq datasets. Using a well-established method, Monocle3, we generated a potential model of temporal evolution of the ACP driver cell population. To identify a specific transcriptional “point-of-no-return” for ACP driver cells, which may help define a rational target for intervention, we created a custom probabilistic Deep Learning framework in the form of a Convolutional Variational Autoencoder (CVAE). By applying this CVAE to our data, we identified 31 anomalous transcripts, each of which was aberrantly active at all times or demonstrated a temporal pattern of anomalous activity. Strikingly, this small list – representing roughly 0.15% of the protein coding genome – aligns closely with extant data describing the molecular behavior of ACP. This work provides a novel transcriptome benchmark for comparison of in vitromodels, a deeper understanding of ACP heterogeneity, as well as a generalizable approach for scRNA-seq analysis.
EPCT-05. A PHASE 1/2 STUDY OF AVAPRITINIB FOR KIT- OR PDGFRA-MUTANT PEDIATRIC RELAPSED/REFRACTORY SOLID TUMORS
Authors: Chi Susan , Hsieh Antony , Foley Megan , Shi Hongliang , Swamy Preethi , Rodstrom Jill , Rudoltz Marc
Published: June 2021

Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; targeted therapies achieve response rates of only ~15%. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT mutations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) mutations. Two-year overall survival is <10% for pediatric patients with diffuse intrinsic pontine glioma, often driven by PDGFRA mutations. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid tumors. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 <2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM). CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for activity against CNS tumors. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA based on an overall response rate ³84% with 59% response durations >6 months, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. The objectives of this 2-part phase 1/2 multicenter, open-label study, anticipated to enroll 31 patients from Q3 2021, are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients with KIT/PDGFRA-mutant solid R/R tumors. Eligible patients are aged 2 to <18 years with no alternative treatment options. Part 1 will enroll ≥6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥25 patients at the recommended modeled avapritinib dose from Part 1; primary endpoint is overall response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.
EPCT-23 PRE-CLINICAL STUDY OF FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING AND PANOBINOSTAT FOR DIFFUSE INTRINSIC PONTINE GLIOMA TREATMENT
Authors: Wei Hong-Jian , Pouliopoulos Antonios , Yoh Nina , Tazhibi Masih , McQuillan Nicholas , Zhang Xu , Szalontay Luca , Gartrell Robyn , Pavisic Jovana , Zhang Zhiguo , Feldstein Neil , Becher Oren , Zacharoulis Stergios , Konofagou Elisa , Wu Cheng-Chia
Published: June 2021

Diffuse intrinsic pontine glioma (DIPG) is the lethal high-grade brain tumor in children with no effective treatment options to date. Despite excessive clinical trials, the prognosis remains poor, with a median overall survival (mOS) of less than 1 year. Genomic studies of DIPG tissue have identified highly recurrent mutations in genes encoding histone H3 resulting in the substitution of lysine to methionine at position 27 (K27M), which is found in approximately 80% of DIPG. Recent drug screening studies identified the histone deacetylase (HDAC) inhibitors panobinostat as a highly effective drug against DIPG in vitro. However, due to the poor Blood-Brain Barrier (BBB) penetration of systemic administration, to enhance the delivery of panobinostat to improve treatment efficacy is needed. Focused ultrasound (FUS) has been shown to be able to safely and non-invasively open BBB to enhance drug delivery. Hence, in this study, we hypothesize that FUS-mediated BBBO (BBBO) can enhance the delivery of panobinostat for a therapeutic benefit in DIPG. Herein we established the syngeneic DIPG model by intracranially injecting mouse DIPG cells (PDGFB+, H3.3K27M, p53−/−) and used FUS and microbubbles to open BBB and enhance the panobinostat delivery. Magnetic resonance (MR) imaging was utilized to evaluate BBBO and tumor progression. We first demonstrated that FUS-mediated BBB-opening is safe and feasible to mice with DIPG tumors by MR imaging and passive cavitation detection. Moreover, this DIPG cell line is very sensitive to panobinostat in in vitro cytotoxicity assay. The combined treatment of FUS-mediated BBBO and panobinostat showed benefits in both local control and overall survival. The current results demonstrated FUS could increase the treatment efficacy of panobinostat to DIPG animals may be due to the increase of targeted delivery of systemic panobinostat to DIPG tumors in brainstem.
Predictors of Enrollment of Older Smokers in Six Smoking Cessation Trials in the Lung Cancer Screening Setting: The Smoking Cessation at Lung Examination (SCALE) Collaboration
Authors: Eyestone Ellie , Williams Randi M , Luta George , Kim Emily , Toll Benjamin A , Rojewski Alana , Neil Jordan , Cinciripini Paul M , Cordon Marisa , Foley Kristie , Haas Jennifer S , Joseph Anne M , Minnix Jennifer A , Ostroff Jamie S , Park Elyse , Rigotti Nancy , Sorgen Lia , Taylor Kathryn L
Published: June 2021

Significance

Increased rates of smoking cessation will be essential to maximize the population benefit of low-dose CT screening for lung cancer. The NCI’s Smoking Cessation at Lung Examination (SCALE) Collaboration includes eight randomized trials, each assessing evidence-based interventions among smokers undergoing lung cancer screening (LCS). We examined predictors of trial enrollment to improve future outreach efforts for cessation interventions offered to older smokers in this and other clinical settings.

Methods

We included the six SCALE trials that randomized individual participants. We assessed demographics, intervention modalities, LCS site and trial administration characteristics, and reasons for declining.

Results

Of 6285 trial- and LCS-eligible individuals, 3897 (62%) declined and 2388 (38%) enrolled. In multivariable logistic regression analyses, Blacks had higher enrollment rates (OR 1.5, 95% CI 1.2,1.8) compared to Whites. Compared to “NRT Only” trials, those approached for “NRT + prescription medication” trials had higher odds of enrollment (OR 6.1, 95% CI 4.7,7.9). Regarding enrollment methods, trials using “Phone + In Person” methods had higher odds of enrollment (OR 1.6, 95% CI 1.2,1.9) compared to trials using “Phone Only” methods. Some of the reasons for declining enrollment included “too busy” (36.6%), “not ready to quit” (8.2%), “not interested in research” (7.7%), and “not interested in the intervention offered” (6.2%).

Conclusion

Enrolling smokers in cessation interventions in the LCS setting is a major priority that requires multiple enrollment and intervention modalities. Barriers to enrollment provide insights that can be addressed and applied to future cessation interventions to improve implementation in LCS and other clinical settings with older smokers.

Implications

We explored enrollment rates and reasons for declining across six smoking cessation trials in the lung cancer screening setting. Offering multiple accrual methods and pharmacotherapy options predicted increased enrollment across trials. Enrollment rates were also greater among Blacks compared to Whites. The findings offer practical information for the implementation of cessation trials and interventions in the lung cancer screening context and other clinical settings, regarding intervention modalities that may be most appealing to older, long-term smokers.
Clinical Features and Outcomes of Coronavirus Disease 2019 Among People With Human Immunodeficiency Virus in the United States: A Multicenter Study From a Large Global Health Research Network (TriNetX)
Authors: Yendewa George A , Perez Jaime Abraham , Schlick Kayla , Tribout Heather , McComsey Grace A
Published: June 2021

Background

Human immunodeficiency virus infection (HIV) is a presumed risk factor for severe coronavirus disease 2019 (COVID-19), yet little is known about COVID-19 outcomes in people with HIV (PWH).

Methods

We used the TriNetX database to compare COVID-19 outcomes of PWH and HIV-negative controls aged ≥18 years who sought care in 44 healthcare centers in the United States from January 1 to December 1, 2020. Outcomes of interest were rates of hospitalization (composite of inpatient non-intensive care [ICU] and ICU admissions), mechanical ventilation, severe disease (ICU admission or death), and 30-day mortality.

Results

Of 297 194 confirmed COVID-19 cases, 1638 (0.6%) were HIV-infected, with >83% on antiretroviral therapy (ART) and 48% virally suppressed. Overall, PWH were more commonly younger, male, African American or Hispanic, had more comorbidities, were more symptomatic, and had elevated procalcitonin and interleukin 6. Mortality at 30 days was comparable between the 2 groups (2.9% vs 2.3%, P = .123); however, PWH had higher rates hospitalization (16.5% vs 7.6%, P < .001), ICU admissions (4.2% vs 2.3%, P < .001), and mechanical ventilation (2.4% vs 1.6%, P < .005). Among PWH, hospitalization was independently associated with male gender, being African American, integrase inhibitor use, and low CD4 count; whereas severe disease was predicted by older age (adjusted odds ratio [aOR], 8.33; 95% confidence interval [CI], 1.06–50.00; P = .044) and CD4 <200 cells/mm3 (aOR, 8.33; 95% CI, 1.06–50.00; P = .044).

Conclusions

People with HIV had higher rates of poor COVID-19 outcomes but were not more at risk of death than their non-HIV-infected counterparts. Older age and low CD4 count predicted adverse outcomes.
Climate change adaptation to extreme heat: a global systematic review of implemented action
Authors: Turek-Hankins Lynée L , Coughlan de Perez Erin , Scarpa Giulia , Ruiz-Diaz Raquel , Schwerdtle Patricia Nayna , Joe Elphin Tom , Galappaththi Eranga K , French Emma M , Austin Stephanie E , Singh Chandni , Siña Mariella , Siders A R , van Aalst Maarten K , Templeman Sienna , Nunbogu Abraham M , Berrang-Ford Lea , Agrawal Tanvi ,   the Global Adaptation Mapping Initiative team, Mach Katharine J
Published: June 2021

Extreme heat events impact people and ecosystems across the globe, and they are becoming more frequent and intense in a warming climate. Responses to heat span sectors and geographic boundaries. Prior research has documented technologies or options that can be deployed to manage extreme heat and examples of how individuals, communities, governments and other stakeholder groups are adapting to heat. However, a comprehensive understanding of the current state of implemented heat adaptations—where, why, how and to what extent they are occurring—has not been established. Here, we combine data from the Global Adaptation Mapping Initiative with a heat-specific systematic review to analyze the global extent and diversity of documented heat adaptation actions (n = 301 peer-reviewed articles). Data from 98 countries suggest that documented heat adaptations fundamentally differ by geographic region and national income. In high-income, developed countries, heat is overwhelmingly treated as a health issue, particularly in urban areas. However, in low- and middle-income, developing countries, heat adaptations focus on agricultural and livelihood-based impacts, primarily considering heat as a compound hazard with drought and other hydrological hazards. 63% of the heat-adaptation articles feature individuals or communities autonomously adapting, highlighting how responses to date have largely consisted of coping strategies. The current global status of responses to intensifying extreme heat, largely autonomous and incremental yet widespread, establishes a foundation for informed decision-making as heat impacts around the world continue to increase.
Effects of encapsulated cinnamaldehyde on growth performance, intestinal digestive and absorptive functions, meat quality and gut microbiota in broiler chickens
Authors: Yang Chongwu , Diarra Moussa S , Choi Janghan , Rodas-Gonzalez Argenis , Lepp Dion , Liu Shangxi , Lu Peng , Mogire Marion , Gong Joshua , Wang Qi , Yang Chengbo
Published: June 2021

Essential oils are potential antimicrobial alternatives and their applications in animal feeds are limited due to their fast absorption in the upper gastrointestinal tract. This study investigated the effects of encapsulated cinnamaldehyde (CIN) at 50 mg/kg or 100 mg/kg on the growth performance, organ weights, meat quality, intestinal morphology, jejunal gene expression, nutrient digestibility, and ileal and cecal microbiota. A total of 320 male day-old broiler Cobb-500 chicks were randomly allocated to four treatments with eight pens per treatment (10 birds per pen): 1) basal diet (negative control, NC); 2) basal diet supplemented with 30 mg/kg avilamycin premix (positive control, PC); 3) basal diet with 50 mg/kg encapsulated CIN (EOL); 4) basal diet with 100 mg/kg encapsulated CIN (EOH). Despite birds fed EOH tended to increase (P = 0.05) meat pH at 24 h, all pH values were normal. Similar to PC group, meats from birds fed EOL and EOH showed a reduced (P < 0.05) Warner–Bratzler force shear (WBFS) compared to the NC group. The highest villus to crypt ratios (VH/CD; P < 0.05) were observed in broilers fed either EOL or EOH, with an average of 14.67% and 15.13% in the duodenum and 15.13% and 13.58% in the jejunum, respectively. For jejunal gene expressions, only six out of the 11 studied genes showed statistically significant differences among the dietary treatments. Gene expressions of cationic amino acid transporter 1 (CAT-1) and neutral amino acid transporter 1 (B0AT-1) were upregulated in EOH-fed birds compared to PC and NC-fed birds (P < 0.05), respectively; while the expression of proliferating cell nuclear antigen (PCNA) was downregulated in EOL-fed birds when compared to NC birds (P < 0.05). Nonetheless, the expressions of cadherin 1 (CDH-1), zonula occludens 1 (ZO-1), and maltase-glucoamylase (MG) were all upregulated (P < 0.05) in EOH-fed birds compared to PC-fed birds. The apparent ileal digestibility (AID) of dry matter, crude protein, crude fat and of all 18 tested amino acids increased in EOL-fed birds (P < 0.01). Additionally, relative abundances (%) of ileal Proteobacteria decreased, while ileal and cecal Lactobacillus increased in EOH-fed birds (P < 0.05). In conclusion, dietary encapsulated CIN improved meat quality and gut health by reducing meat WBFS, increasing VH/CD in intestines, jejunal gene expressions, AID of nutrients and beneficial ileal and cecal microbiota composition.
Experimental Evidence Pointing to Rain as a Reservoir of Tomato Phyllosphere Microbiota
Authors: Mechan Llontop Marco E. , Tian Long , Sharma Parul , Heflin Logan , Bernal-Galeano Vivian , Haak David C. , Clarke Christopher R. , Vinatzer Boris A.
Published: June 2021

Plant microbiota play essential roles in plant health and crop productivity. Comparisons of community composition have suggested seed, soil, and the atmosphere as reservoirs of phyllosphere microbiota. After finding that leaves of tomato (Solanum lycopersicum) plants exposed to rain carried a higher microbial population size than leaves of tomato plants not exposed to rain, we experimentally tested the hypothesis that rain is a thus-far-neglected reservoir of phyllosphere microbiota. Therefore, rain microbiota were compared with phyllosphere microbiota of tomato plants either treated with concentrated rain microbiota, filter-sterilized rain, or sterile water. Based on 16S ribosomal RNA amplicon sequencing, 104 operational taxonomic units (OTUs) significantly increased in relative abundance after inoculation with concentrated rain microbiota but no OTU significantly increased after treatment with either sterile water or filter-sterilized rain. Some of the genera to which these 104 OTUs belonged were also found at higher relative abundance on tomato plants exposed to rain outdoors than on tomato plants grown protected from rain in a commercial greenhouse. Taken together, these results point to precipitation as a reservoir of phyllosphere microbiota and show the potential of controlled experiments to investigate the role of different reservoirs in the assembly of phyllosphere microbiota.
Where is my hand in space? The internal model of gravity influences proprioception
Authors: Gallagher Maria , Kearney Breanne , Ferrè Elisa Raffaella
Published: June 2021

Knowing where our limbs are in space is crucial for a successful interaction with the external world. Joint position sense (JPS) relies on both cues from muscle spindles and joint mechanoreceptors, as well as the effort required to move. However, JPS may also rely on the perceived external force on the limb, such as the gravitational field. It is well known that the internal model of gravity plays a large role in perception and behaviour. Thus, we have explored whether direct vestibular-gravitational cues could influence JPS. Participants passively estimated the position of their hand while they were upright and therefore aligned with terrestrial gravity, or pitch-tilted 45° backwards from gravity. Overall participants overestimated the position of their hand in both upright and tilted postures; however, the proprioceptive bias was significantly reduced when participants were tilted. Our findings therefore suggest that the internal model of gravity may influence and update JPS in order to allow the organism to interact with the environment.
Differential effects of COVID-19 lockdowns on well-being: interaction between age, gender and chronotype
Authors: Oved Shay , Mofaz Merav , Lan Anat , Einat Haim , Kronfeld-Schor Noga , Yamin Dan , Shmueli Erez
Published: June 2021

The unprecedented restrictions imposed due to the COVID-19 pandemic altered our daily habits and severely affected our well-being and physiology. The effect of these changes is yet to be fully understood. Here, we analysed highly detailed data on 169 participants for two to six months, before and during the second COVID-19 lockdown in Israel. We extracted 12 well-being indicators from sensory data of smartwatches and from self-reported questionnaires, filled daily using a designated mobile application. We found that, in general, lockdowns resulted in significant changes in mood, sleep duration, sport duration, social encounters, resting heart rate and number of steps. Examining subpopulations, we found that younger participants (aged 20–40 years) suffered from a greater decline in mood and number of steps than older participants (aged 60–80 years). Likewise, women suffered from a higher increase in stress and reduction in social encounters than men. Younger early chronotypes did not increase their sleep duration and exhibited the highest drop in mood. Our findings underscore that while lockdowns severely impacted our well-being and physiology in general, greater damage has been identified in certain subpopulations. Accordingly, special attention should be given to younger people, who are usually not in the focus of social support, and to women.
Model building and assessment of the impact of covariates for disease prevalence mapping in low-resource settings: to explain and to predict
Authors: Giorgi Emanuele , Fronterrè Claudio , Macharia Peter M. , Alegana Victor A. , Snow Robert W. , Diggle Peter J.
Published: June 2021

This paper provides statistical guidance on the development and application of model-based geostatistical methods for disease prevalence mapping. We illustrate the different stages of the analysis, from exploratory analysis to spatial prediction of prevalence, through a case study on malaria mapping in Tanzania. Throughout the paper, we distinguish between predictive modelling, whose main focus is on maximizing the predictive accuracy of the model, and explanatory modelling, where greater emphasis is placed on understanding the relationships between the health outcome and risk factors. We demonstrate that these two paradigms can result in different modelling choices. We also propose a simple approach for detecting over-fitting based on inspection of the correlation matrix of the estimators of the regression coefficients. To enhance the interpretability of geostatistical models, we introduce the concept of domain effects in order to assist variable selection and model validation. The statistical ideas and principles illustrated here in the specific context of disease prevalence mapping are more widely applicable to any regression model for the analysis of epidemiological outcomes but are particularly relevant to geostatistical models, for which the separation between fixed and random effects can be ambiguous.
A massively multi-scale approach to characterizing tissue architecture by synchrotron micro-CT applied to the human placenta
Authors: Tun W. M. , Poologasundarampillai G. , Bischof H. , Nye G. , King O. N. F. , Basham M. , Tokudome Y. , Lewis R. M. , Johnstone E. D. , Brownbill P. , Darrow M. , Chernyavsky I. L.
Published: June 2021

Multi-scale structural assessment of biological soft tissue is challenging but essential to gain insight into structure–function relationships of tissue/organ. Using the human placenta as an example, this study brings together sophisticated sample preparation protocols, advanced imaging and robust, validated machine-learning segmentation techniques to provide the first massively multi-scale and multi-domain information that enables detailed morphological and functional analyses of both maternal and fetal placental domains. Finally, we quantify the scale-dependent error in morphological metrics of heterogeneous placental tissue, estimating the minimal tissue scale needed in extracting meaningful biological data. The developed protocol is beneficial for high-throughput investigation of structure–function relationships in both normal and diseased placentas, allowing us to optimize therapeutic approaches for pathological pregnancies. In addition, the methodology presented is applicable in the characterization of tissue architecture and physiological behaviours of other complex organs with similarity to the placenta, where an exchange barrier possesses circulating vascular and avascular fluid spaces.
Anticipating response function in gene regulatory networks
Authors: Gautam Pankaj , Kumar Sinha Sudipta
Published: June 2021

The origin of an ordered genetic response of a complex and noisy biological cell is intimately related to the detailed mechanism of protein–DNA interactions present in a wide variety of gene regulatory (GR) systems. However, the quantitative prediction of genetic response and the correlation between the mechanism and the response curve is poorly understood. Here, we report
in silico
binding studies of GR systems to show that the transcription factor (TF) binds to multiple DNA sites with high cooperativity spreads from specific binding sites into adjacent non-specific DNA and bends the DNA. Our analysis is not limited only to the isolated model system but also can be applied to a system containing multiple interacting genes. The controlling role of TF oligomerization, TF–ligand interactions, and DNA looping for gene expression has been also characterized. The predictions are validated against detailed grand canonical Monte Carlo simulations and published data for the
lac
operon system. Overall, our study reveals that the expression of target genes can be quantitatively controlled by modulating TF–ligand interactions and the bending energy of DNA.
Antigenic minimalism of SARS-CoV-2 is linked to surges in COVID-19 community transmission and vaccine breakthrough infections
Authors: Venkatakrishnan A.J. , Anand Praveen , Lenehan Patrick , Ghosh Pritha , Suratekar Rohit , Siroha Abhishek , Chowdhury Dibyendu Roy , O’Horo John C. , Yao Joseph D. , Pritt Bobbi S. , Norgan Andrew , Hurt Ryan T. , Badley Andrew D. , Halamka John D. , Soundararajan Venky
Published: June 2021

The raging COVID-19 pandemic in India and reports of “vaccine breakthrough infections” globally have raised alarm mandating the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed 1.57 million SARS-CoV-2 genomes from 187 countries/territories and performed whole-genome viral sequencing from 53 COVID-19 patients, including 20 vaccine breakthrough infections. We identified 89 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a three-month window. Deletions in the Spike protein N-terminal domain (NTD) are highly enriched for these ‘surge-associated mutations’ (Odds Ratio = 41.8, 95% CI: 6.36-1758, p-value = 7.7e-05). In the recent COVID-19 surge in India, an NTD deletion (ΔF157/R158) increased over 10-fold in prevalence from February 2021 (1.1%) to April 2021 (15%). During the recent surge in Chile, an NTD deletion (Δ246-253) increased rapidly over 30-fold in prevalence from January 2021 (0.86%) to April 2021 (33%). Strikingly, these simultaneously emerging deletions associated with surges in different parts of the world both occur at an antigenic supersite that is targeted by neutralizing antibodies. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences and identified deletions within this NTD antigenic supersite in a patient with vaccine breakthrough infection (Δ156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of Spike protein deletions throughout the pandemic and their association with case surges and vaccine breakthrough infections point to antigenic minimalism as an emerging evolutionary strategy for SARS-CoV-2 to evade immune responses. This study highlights the urgent need to sequence SARS-CoV-2 genomes at a larger scale globally and to mandate a public health policy for transparent reporting of relevant clinical annotations (e.g. vaccination status) in order to aid the development of comprehensive therapeutic strategies.
Parental plans to vaccinate children for COVID-19 in New York City
Authors: Teasdale Chloe A. , Borrell Luisa N. , Shen Yanhan , Kimball Spencer , Rinke Michael L. , Fleary Sasha A. , Nash Denis
Published: June 2021

Once COVID-19 vaccines are approved for children <12 years of age, high pediatric vaccination coverage will be needed to help minimize the public health threat from the SARS-CoV-2 epidemic. We conducted an online survey of 1,119 parents and caregivers of children ≤12 years in New York City from March 9 to April 11, 2021. Among parents surveyed, 61.9% reported plans to vaccinate their youngest child for COVID-19, 14.8% said they do not plan to vaccinate their child and 23.3% were unsure. Female and non-Hispanic Black parents were least likely to report plans to vaccinate their children. Safety, effectiveness and perceptions that children do not need vaccination were the primary reasons for vaccine hesitancy/resistance. Parents who have or will vaccinate themselves were significantly more likely to report they would vaccinate their children. Efforts to increase awareness about vaccine safety and education about the importance of vaccinating children are needed.
A Transcriptomic Severity Metric that Predicts Clinical Outcomes in Critically Ill Surgical Sepsis Patients
Authors: Brakenridge Scott C. , Starostik Petr , Ghita Gabriella , Midic Uros , Darden Dijoia , Fenner Brittany , Wacker James , Efron Philip A. , Liesenfeld Oliver , Sweeney Timothy E , Moldawer Lyle L.
Published: June 2021

Purpose

Prognostic metrics for the rapid and accurate prediction of sepsis severity that could elicit a meaningful change in clinical practice are currently lacking. Here, we evaluated a whole blood, multiplex host mRNA expression metric, Inflammatix-Severity-2 (IMX-SEV-2), for identifying septic, hospitalized patients for 30-day mortality, development of chronic critical illness (CCI), discharge disposition, and/or secondary infections.

Methods

This is a retrospective, validation cohort analysis of a prospectively enrolled 335 patient study with surgical sepsis treated in the surgical intensive care unit. Whole blood collected in PAXgene®Blood RNA collection tubes at 24 hours post sepsis diagnosis was analyzed using a custom 29-mRNA classifier (IMX-SEV-2) in a CLIA-CAP-accredited diagnostic laboratory using the NanoString FLEX®profiler.

Results

Among patients meeting Sepsis-3 criteria, the IMX-SEV-2 severity score was significantly better (p<0.05) at predicting secondary infections (AUROC 0.71) and adverse clinical outcomes (AUROC 0.75) than C-reactive protein (CRP), absolute lymphocyte counts (ALC), total white blood cell (WBC) count, age and Charlson comorbidity index (and better, albeit nonsignificantly, than IL-6 and APACHE II). Using multivariate logistic regression analysis, only combining the Charlson comorbidity index (AUROC 0.80) or APACHE II (AUROC 0.81) with the IMX-SEV-2 significantly improved prediction of adverse clinical outcomes, and combining with the Charlson comorbidity index for predicting 30-day mortality (AUROC 0.79).

Conclusions

The IMX-SEV-2 severity score was superior at predicting secondary infections and overall adverse clinical outcomes versus other common metrics. Importantly, combining a rapidly measured transcriptomic metric with clinical or physiologic indices has sufficient precision to optimize resource utilization and allow adjustments to patient management that may improve outcomes in surgical sepsis. Hospitalized patients who are septic and present with an elevated IMX-SEV2 severity score and pre-existing comorbidities would be strong candidates for clinical interventions aimed at reducing the risk of secondary infections and adverse clinical outcomes.
Social support, social strain and declines in verbal memory: 16-year follow-up of the English Longitudinal Study of Ageing cohort
Authors: Scholes Shaun , Liao Jing
Published: June 2021

Objective

Estimate differences in the rate of decline in verbal memory by levels of perceived relationship quality among community-dwelling adults.

Participants

In the English Longitudinal Study of Ageing (ELSA), n = 10,109 participants aged 50-89 years were assessed at wave 1 (baseline: 2002-03) and followed-up over 16 years to wave 9 (2017-18).

Methods

Verbal memory was assessed biennially by tests of immediate and delayed word-recall. Positive and negative aspects of perceived relationship quality (social support and strain, respectively) were measured by relationship type (spouse; children; extended family members; friends). Random effects within-between (REWB) modelling was used to separate between- and within-person effects. Associations were estimated between levels of social support/strain and (i) baseline levels of memory (main effects), and (ii) the 2-year decline in memory (interaction with time).

Results

Longitudinal associations were most prominent for men, specific to relationship type, and showed between-rather than within-person effects. Among men, higher spousal strain was associated with faster decline in memory (βbetween-effect×time= -0.043; 95% CI: -0.084, -0.002; p = 0.039), whilst greater support from children was associated with slower decline (βbetween-effect×time= 0.020; 95% CI: 0.002, 0.039; p = 0.033). Men with higher levels of strain from friends had lower baseline memory (βbetween-effect= -0.382; 95% CI: -0.627, -0.137; p = 0.002) and showed faster decline (βbetween-effect×time= -0.047; 95% CI: -0.095, 0.000; p = 0.051).

Conclusions

Differences between persons in levels of social support and social strain were modestly associated with the rate of memory decline, especially among men. Our findings can inform future research studies and intervention strategies designed to maximise the potential of social relations to promote healthy cognitive ageing.
A Randomised Crossover Trial: Exploring the Dose-Response effect Of Carbohydrate restriction on glycaemia in people with type 2 diabetes (D-ROC2)
Authors: Ozairi Ebaa Al , Abdul-Ghani Muhammad , Oliver Nick , Whitcher Brandon , Awadi Reem Al , Samad Abeer El , Taghadom Etab , Al-Kandari Jumana , Guess Nicola
Published: June 2021

Aims

The role of carbohydrate restriction in the management of glycaemia in type 2 diabetes (T2D) has been a subject of immense debate and controversy partly due to low-carbohydrate trials being confounded by multiple factors including degree of calorie restriction, dietary protein content, and by no clear definition of a low-carbohydrate diet. The current study sought to provide insight into the relationship between carbohydrate restriction and glycaemia by testing the effect of varying doses of carbohydrate on continuous glucose concentrations within a range of intakes defined as low-carbohydrate while controlling for confounding factors.

Methods

This was a randomised crossover trial in participants with T2D testing 5 different 6-day eucaloric, isocaloric dietary treatments with varying carbohydrate contents (10%, 15%, 20%, 25%, and 30% kcal). Diets were kept isocaloric by exchanging %kcal from carbohydrate with predominantly unsaturated fat, keeping protein constant at 15% kcal. Daily self-weighing was employed to ensure participants maintained their weight throughout each treatment arm. Between dietary treatments, participants underwent a washout period of at least 7 days and were advised to maintain their habitual diet. Glycemic control was assessed using a continuous glucose monitoring device that was placed while the participant was on their normal diet, and was worn for the 6 days of each treatment.

Results

12 participants completed the study. There were no differences in 24-hour and postprandial sensor glucose concentrations between the 30%kcal and 10%kcal doses (7.4 ± 1.1mmol/L vs 7.6 ± 1.4mmol/L (P=0.28) and 8.0 ± 1.4mmol/L vs 8.3 ± 1.3mmol/L (P=0.28) respectively). In our exploratory analyses we did not find any dose-response relationship between carbohydrate intake and glycaemia. A small amount of weight loss occurred in each treatment arm (range: 0.4 to 1.1kg over the 6 days) but adjusting for these differences did not influence the primary or secondary outcomes.

Conclusions

Modest changes in dietary carbohydrate content in the absence of weight loss while keeping dietary protein intake constant do not appear to influence glucose concentrations in people with T2D.

Trial Registration

ISRCTN 11067343.
Association between discrimination stress and suicidality in preadolescent children
Authors: Argabright Stirling T. , Visoki Elina , Moore Tyler M. , Ryan Dallas T. , DiDomenico Grace E. , Njoroge Wanjiku F.M. , Taylor Jerome H. , Guloksuz Sinan , Gur Ruben C. , Gur Raquel E. , Benton Tami D. , Barzilay Ran
Published: June 2021

Objective

US youth suicide rates are increasing in recent years, especially in Black Americans, the reasons for which are unclear. Environmental adversity is key in youth suicidality, hence there is a need to study stressors that disproportionately impact Black youths. We aimed to disentangle the unique contribution of racial/ethnic discrimination from other adversities associated with childhood suicidal ideation and attempts (suicidality) across races.

Method

We analyzed data from the Adolescent Brain Cognitive Development (ABCD) Study® that included a large, diverse sample of US children (N=11,235, mean age 10.9 years, 20.2% Black) phenotyped for environmental adversities including discrimination. Multivariate regression models tested the association of self-reported racial/ethnic discrimination with suicidality, covarying for multiple confounders including other discrimination types (towards non-US born individuals; sexual orientation-based; weight-based). Matched analyses contrasted effects of racial/ethnic discrimination and racial identity on suicidality.

Results

Black youths reported more discrimination and higher suicidality rates than non-Black youths. High racial/ethnic discrimination was positively associated with suicidality, adjusting for other discrimination types (odds ratio [OR]=2.6, 95%CI=2.1-3.2). Findings remained significant after adjusting for multiple suicidality risk factors. Once experienced, racial/ethnic discrimination was similarly associated with suicidality in White, Black, and Hispanic youths. Matched analyses revealed that racial/ethnic discrimination was associated with suicidality (relative risk [RR]=2.7, 95%CI=2-3.5), while Black race was not (RR=0.9, 95%CI=0.7-1.2).

Conclusion

Racial/ethnic discrimination is disproportionately experienced by Black children, and is associated with preadolescent suicidality, over and above other adversities. Findings highlight the need to address discrimination as part of suicide prevention strategies. Cross-sectional design hampers causal inferences.
Evolutionary transition of doublesex regulation in termites and cockroaches: from sex-specific splicing to male-specific transcription
Authors: Miyazaki Satoshi , Fujiwara Kokuto , Kai Keima , Masuoka Yudai , Gotoh Hiroki , Niimi Teruyuki , Hayashi Yoshinobu , Shigenobu Shuji , Maekawa Kiyoto
Published: June 2021

The sex determination gene doublesex (dsx), which encodes a transcription factor with two domains: oligomerisation domain 1 (OD1) and OD2, is conserved among insects. The sex-specific Dsx splicing isoforms regulate the transcription of target genes and trigger sex differentiation in all holometabolous insects examined to date. However, in some hemimetabolous insects, dsx is less conserved and not spliced sexually. Here, to elucidate evolutionary changes in dsx in the gene structure and its regulatory manner in termites, we searched genome and/or transcriptome databases for the OD1 and OD2 of dsx in six termite species and their sister group (woodroach). Molecular phylogenetic analysis identified OD1 sequences of termites and a woodroach clustered with dsx of holometabolous insects and regarded them as dsx orthologues. In the woodroach, a dsx orthologue containing OD2 was spliced sexually, as previously shown in other insects. However, OD2 were not found in all termite dsx orthologues. These orthologues were encoded by only a single exon in three termites with genome information; they were not alternatively spliced, but transcribed in a male-specific manner in two species examined. Evolution of dsx regulation from sex-specific splicing to male-specific transcription might be occurred at the early stage of social evolution in termites.
Spike mutation T403R allows bat coronavirus RaTG13 to use human ACE2
Authors: Zech Fabian , Schniertshauer Daniel , Jung Christoph , Herrmann Alexandra , Xie Qinya , Nchioua Rayhane , Bozzo Caterina Prelli , Volcic Meta , Koepke Lennart , Krüger Jana , Heller Sandra , Kleger Alexander , Jacob Timo , Conzelmann Karl-Klaus , Ensser Armin , Sparrer Konstantin M.J. , Kirchhoff Frank
Published: June 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the COVID-19 pandemic, most likely emerged from bats1. A prerequisite for this devastating zoonosis was the ability of the SARS-CoV-2 Spike (S) glycoprotein to use human angiotensin-converting enzyme 2 (ACE2) for viral entry. Although the S protein of the closest related bat virus, RaTG13, shows high similarity to the SARS-CoV-2 S protein it does not efficiently interact with the human ACE2 receptor2. Here, we show that a single T403R mutation allows the RaTG13 S to utilize the human ACE2 receptor for infection of human cells and intestinal organoids. Conversely, mutation of R403T in the SARS-CoV-2 S significantly reduced ACE2-mediated virus infection. The S protein of SARS-CoV-1 that also uses human ACE2 also contains a positive residue (K) at this position, while the S proteins of CoVs utilizing other receptors vary at this location. Our results indicate that the presence of a positively charged amino acid at position 403 in the S protein is critical for efficient utilization of human ACE2. This finding could help to predict the zoonotic potential of animal coronaviruses.
Integrated Multi-Omics Data Reveals the Molecular Subtypes of Prostate Cancer
Authors: Meng Jialin , Lu Xiaofan , Jin Chen , Zhou Yujie , Ge Qintao , Zhang Meng , Zhou Jun , Hao Zongyao , Yan Fangrong , Liang Chaozhao
Published: June 2021

Prostate cancer (PCa), the second most common male malignancy, is the fifth leading cause of cancer-related death and places notable burdens on medical resources. Most of the previous subtypes only focused on one or fewer types of data or ignored the genomic heterogeneity among PCa patients with diverse genetic backgrounds. Therefore, it is essential to precisely identify the specific molecular features and judge potential clinical outcomes based on multi-omics data. In the current study, we first identified the PCa multi-omics classification (PMOC) system based on the multi-omics, including mRNA, miRNA, lncRNA, DNA methylation, and gene mutation, using a total of ten state-of-the-art clustering algorithms. The PMOC1 subtype, also called the inflammatory subtype, contains the highest expression levels of immune checkpoint proteins, moderate activated immune-associated pathways. The PMOC2 tumor-activated subtype demonstrated the worst prognosis, which might be impacted by the activated cell cycle and DNA repair pathways, and also characterized by the most genetic alterations of mutant TP53, mutant APC and copy number alteration of 8q24.21 region. The PMOC3 subtype is likely to be a balance subtype, with the activated oncogenic signaling pathways, including hypoxia, angiogenesis, epithelial mesenchymal transition, and PI3K/AKT pathways. As well as with the activated proinflammatory pathways, including IL6/JAK/STAT3, IL2/STAT5, Notch and TNF-α signaling. Additionally, PMOC3 subtype also linked with the activation of the androgen response and the high response rate of ARSI treatment. Taken together, we defined the PMOC system for PCa patients via multi-omics data and consensus results of ten algorithms, this multi-omics consensus PCa molecular classification can further assist in the precise clinical treatment and development of targeted therapy.
Skeletal Muscle Histidine Containing Dipeptide Contents are Increased in Freshwater Turtles (Chrysemys picta bellii) with Cold-Acclimation
Authors: Dolan Eimear , Warren Daniel E. , Harris Roger C. , Sale Craig , Gualano Bruno , Saunders Bryan
Published: June 2021

Freshwater turtles found in higher latitudes can experience extreme challenges to acid-base homeostasis while overwintering, due to a combination of cold temperatures along with the potential for environmental hypoxia. Histidine containing dipeptides (HCDs; carnosine, anserine and balenine) may facilitate pH regulation in response to these challenges, through their role as pH buffers. We measured the HCDs content of three tissues (liver, cardiac muscle and skeletal muscle) from the anoxia-tolerant painted turtle (Chrysemys picta bellii) acclimated to either 3 or 20°C. HCDs were detected in all tissues, with the highest content shown in the skeletal muscle. Turtles acclimated to 3°C had more HCD in their skeletal muscle than those acclimated to 20°C (carnosine = 20.8±4.5 vs 12.5±5.9 mmol·kg DM-1; ES = 1.59 (95%CI: 0.16 – 3.00), P = 0.013). The higher HCD content observed in the skeletal muscle of the cold-acclimated turtles suggests a role in acid-base regulation in response to physiological challenges associated with living in the cold, with the increase possibly related to the temperature sensitivity of carnosine’s dissociation constant and buffering power of the skeletal muscle during anoxic submergence.

Highlights

pH regulation is a major challenge for overwintering freshwater turtles.

Histidine containing dipeptides are important intracellular buffers.

Turtles acclimated to 3°C had higher HCD content than those at 20°C.

HCDs may be important pH regulators in cold-acclimated turtles.
An olfactory pattern generator for on-demand combinatorial control of receptor activities
Authors: Si Guangwei , Baron Jacob , Feng Yu , Samuel Aravinthan D.T.
Published: June 2021

Olfactory systems employ combinatorial receptor codes for odors. Systematically generating stimuli that address the combinatorial possibilities of an olfactory code poses unique challenges. Here, we present a stimulus method to probe the combinatorial code, demonstrated using the Drosophila larva. This method leverages a set of primary odorants, each of which targets the activity of one olfactory receptor neuron (ORN) type at an optimal concentration. Our setup uses microfluidics to mix any combination of primary odorants on demand to activate any desired combination of ORNs. We use this olfactory pattern generator to demonstrate a spatially distributed olfactory representation in the dendrites of a single interneuron in the antennal lobe, the first olfactory neuropil of the larva. In the larval mushroom body, the next processing layer, we characterize diverse receptive fields of a population of Kenyon cells. The precision and flexibility of the olfactory pattern generator will facilitate systematic studies of processing and transformation of the olfactory code.