bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating diagnostic noise in panel-based genomic analysis
Authors: Beaumont Robin N. , Wright Caroline F. 
Published: March 2022

AbstractBackgroundGene panels with a series of strict variant filtering rules are often used for clinical analysis of exomes and genomes. Panels vary in size, which affects the sensitivity and specificity of the test. We sought to investigate the background rate of candidate diagnostic variants in a population setting using gene panels developed to diagnose a range of heterogeneous monogenic diseases.MethodsWe used the Genotype-2-Phenotype database with the Variant Effect Predictor plugin to identify rare non-synonymous variants in exome sequence data from 200,643 individuals in UK Biobank. We evaluated five clinically curated gene panels: developmental disorders (DD; 1708 genes), heritable eye disease (536 genes), skin disorders (293 genes), cancer syndromes (91 genes) and cardiac conditions (49 genes). We further tested the DD panel in 9,860 proband-parent trios from the Deciphering Developmental Disorders (DDD) study.ResultsAs expected, bigger gene panels resulted in more variants being prioritised, varying from an average of ∼0.3 per person in the smallest panels, to ∼3.5 variants per person using the largest panel. The number of individuals with prioritised variants varied linearly with coding sequence length for monoallelic disease genes (∼300 individuals per 1000 base pairs) and quadratically for biallelic disease genes, with some notable outliers. Based on cancer registry data from UK Biobank, there was no detectable difference between cases and controls in the number of individuals with prioritised variants using the cancer panel, presumably due to the predominance of sporadic disease. However, we observed a marked increase in the number of prioritised variants in the DD panel in the DDD study (∼5 variants per proband). Phasing of compound heterozygotes in biallelic genes resulted in a modest reduction in the number of prioritised variants.ConclusionsAlthough large gene panels may be the best strategy to maximize diagnostic yield in genetically heterogeneous diseases, they will frequently prioritise false positive candidate variants potentially requiring additional clinical follow-up. Most individuals will have at least one rare nonsynonymous variant in panels containing >500 monogenic disease genes. Extreme caution should therefore be applied when interpreting potentially pathogenic variants found in the absence of relevant phenotypes.
Exploring stroke survivors’ and physiotherapists’ perspectives of the potential for markerless motion capture technology in community rehabilitation
Authors: Faux-Nightingale Alice , Philp Fraser , Leone Enza , Helliwell Brinton Boreman , Pandyan Anand 
Published: March 2022

AbstractINTRODUCTIONMany stroke survivors do not receive optimal levels of personalised therapy to support their recovery. Use of technology stroke rehabilitation has increased in recent years to help minimise gaps in service provision. Markerless motion capture technology is currently being used for musculoskeletal and occupational health screening and could offer a means to provide personalised guidance to stroke survivors struggling to access rehabilitation.AIMSThis study considered context, stakeholders, and key uncertainties surrounding the use of markerless motion capture technology in community stroke rehabilitation from the perspectives of stroke survivors and physiotherapists with a view to adapting an existing intervention in a new context.METHODSThree focus groups were conducted with eight stroke survivors and five therapists. Data were analysed using reflexive thematic analysis.RESULTSFive themes were identified: limited access to community care; personal motivation; pandemic changed rehabilitation practice; perceptions of technology; and role of markerless technology for providing feedback.CONCLUSIONSParticipants identified problems associated with the access of community stroke rehabilitation, exacerbated by Covid-19 restrictions. Participants were positive about the potential for the use of markerless motion capture technology as a means to support personalised, effective stroke rehabilitation in the future, providing it is developed to meet stroke survivor specific needs.
Toward a preventive approach to prolonged grief disorder in palliative care: Insecure attachment moderates the impact of perceived support on the severity of symptoms
Authors: Lenzo Vittorio , Sardella Alberto , Faraone Cristina , Quattropani Maria C. 
Published: March 2022

AbstractObjectiveThis study aimed to investigate the relationships between the perceived support at the time of assistance, insecure attachment (i.e., avoidance and anxious attachment factors), and the prolonged grief symptoms in family caregivers of palliative care patients deceased for at least one year. We also investigated the moderating role of insecure attachment in the relationship between perceived support and intensity of prolonged grief symptoms.MethodA sample of 157 participants completed the Prolonged Grief Scale (PG-13) and the Attachment Style Questionnaire (ASQ).ResultsCorrelational analysis indicated that prolonged grief symptoms were positively correlated with the Avoidance attachment factor but not with the Anxious one. The perceived support was negatively related to both the Avoidance and the Anxious attachment factors. Lastly, the two insecure attachment factors were moderately and positively correlated with each other. Results of moderation analysis showed that the high Avoidance attachment moderated the effect of the perceived family and social support on the intensity of prolonged grief symptoms among family caregivers of patients assisted in palliative home care. Results also showed that the Anxious attachment factor had a significant effect on prolonged grief symptoms, even though the interaction with the perceived support was not significant.ConclusionsOverall, these results underline that a high level of avoidance attachment may moderate the relationship between the perceived support and intensity of grief symptoms and thereby increasing the risk of developing a mental disorder. Intervention to prevent prolonged grief disorder among family caregivers should take into account these findings.
Projected impact on blood pressure, chronic kidney disease burden and healthcare costs of achieving the Australian sodium reduction targets: a modelling study
Authors: Aminde Leopold N. , Wanjau Mary , Cobiac Linda J. , Veerman J. Lennert 
Published: March 2022

AbstractBackgroundExcess sodium intake increases blood pressure and risk of vascular complications. Most studies have focused on heart disease and stroke, but the impact on chronic kidney disease (CKD) is less well-characterised. The aim of this study was to estimate the impact of sodium intake on CKD burden in Australia.MethodsA dynamic epidemiological model was developed to estimate the potential impact on CKD if the Australian Suggested Dietary Target (SDT) and the National Preventive Health Strategy 2021-2030 (NPHS) sodium target were achieved. Outcomes were estimated between 2019 (base year) and 2030, and lifetime.FindingsAchieving the SDT and NPHS target could lower overall mean systolic blood pressure by 2.1 mmHg and 1.7 mmHg respectively. Compared to current sodium intake levels, attaining the SDT could prevent 59,220 (95% UI, 53,140 – 65,500) incident CKD cases and 568 (95% UI, 479 – 652) CKD deaths by 2030. Over the lifetime, this is projected to generate 199,488 (95% UI, 180,910 – 218,340) HALYs and AU$ 644 million in CKD health expenditure savings. Similarly, if achieved, the NPHS is estimated to prevent 49,890 (95% UI, 44,377 – 55,569) incident CKD cases and 511 (95% UI, 426 – 590) CKD deaths by 2030. Over the lifetime, this could produce 170,425 (95% UI, 155,017 – 186,559) HALYs and AU$ 514 million in CKD health expenditure savings.ConclusionAchieving the national sodium reduction targets could deliver substantial health and economic benefits for people with CKD in Australia. Robust government action is required in order to achieve the projected outcomes of these policy targets.
Cannabinoids regulate an insula circuit controlling water intake
Authors: Zhao Zhe , Covelo Ana , Mitra Arojit , Varilh Marjorie , Wu Yifan , Jacky Débora , Cannich Astrid , Bellocchio Luigi , Marsicano Giovanni , Beyeler Anna 
Published: March 2022

ABSTRACTThe insular cortex, or insula, is a large brain region involved in the detection of thirst and the control of water intake. However our understanding of the topographical, circuit and molecular mechanisms the controlling water intake within the insula remains parcellated. We found that type-1 cannabinoid receptors (CB1) within the insular cortex participate to the regulation of water intake, and deconstructed circuit mechanisms of this control. Topographically, we revealed that the activity of excitatory neurons in both anterior (aIC) and posterior (pIC) insula increases in response to water intake, yet removal of CB1 receptors only in the pIC decreases water intake. Interestingly, we found that CB1 receptors are highly expressed in insula projections to the basolateral amygdala (BLA), while undetectable in the neighboring central part of the amygdala. Thus, we imaged the neurons of the anterior or posterior insula targeting the BLA (aIC-BLA and pIC-BLA), and found they oppositely respond to water intake, respectively decreasing and increasing their activity upon water drinking. Consistently, chemogenetic activation of pIC-BLA neurons decreased water intake. Finally, we uncovered CB1-dependent short term synaptic plasticity (depolarization-induced suppression of excitation, DSE) selectively in pIC-BLA, compared to aIC-BLA synapses. Altogether, our results support a model where CB1 signaling in the pIC-BLA pathway exerts a positive control on water intake.
Persistent Immune and Clotting Dysfunction Detected in Saliva and Blood Plasma after COVID-19
Authors: Jang Hyesun , Choudhury Saibyasachi , Yu Yanbao , Sievers Benjamin L. , Gelbart Terri , Singh Harinder , Rawlings Stephen A. , Proal Amy , Tan Gene S. , Smith Davey , Freire Marcelo 
Published: March 2022

AbstractA growing number of studies indicate that coronavirus disease 2019 (COVID-19) is associated with inflammatory sequelae, but molecular signatures governing the normal vs. pathologic convalescence process have not been well-delineated. We characterized global immune and proteome responses in matched plasma and saliva samples obtained from COVID-19 patients collected between 4-6 weeks after initial clinical symptoms resolved. Convalescent subjects showed robust IgA and IgG responses and positive antibody correlations between matched saliva and plasma samples. However, global shotgun proteomics revealed persistent inflammatory patterns in convalescent samples including dysfunction of salivary innate immune cells and clotting factors in plasma (e.g., fibrinogen and antithrombin), with positive correlations to acute COVID-19 disease severity. Saliva samples were characterized by higher concentrations of IgA, and proteomics showed altered pathways that correlated positively with IgA levels. Our study positions saliva as a viable fluid to monitor immunity beyond plasma to document COVID-19 immune, inflammatory, and coagulation-related sequelae.
Ultrasound Neuromodulation and Correlation Change in the Rat Somatosensory Cortex
Authors: Ramachandran Sandhya , Niu Xiaodan , Yu Kai , He Bin 
Published: March 2022

AbstractTranscranial focused ultrasound (tFUS) is a neuromodulation technique which has been the focus of increasing interest for noninvasive brain stimulation with high spatial specificity. Its ability to excite and inhibit neural circuits as well as to modulate perception and behavior has been demonstrated, however, we currently lack understanding of how tFUS modulates the ways neurons interact with each other. This understanding would help explain tFUS’s mechanism of high-level neuromodulation and allow future development of therapies for neurological disorders. In this study we investigate how tFUS modulates neural interaction and response to peripheral electrical limb stimulation through intracranial multi-electrode recordings in the rat somatosensory cortex. We deliver ultrasound in a pulsed pattern to attempt to induce frequency dependent plasticity in a manner similar to that found following electrical stimulation. We show that neural firing in response to peripheral electrical stimulation is increased after ultrasound stimulation at all frequencies, showing tFUS induced excitation in individual neurons in vivo. We demonstrate tFUS frequency dependent pairwise correlation changes between neurons, with both potentiation and depression observed at different frequencies. These results extend previous research showing tFUS to be capable of inducing synaptic depression and demonstrate its ability to modulate network dynamics as a whole.
Human Galectin-9 Potently Enhances SARS-CoV-2 Replication and Inflammation in Airway Epithelial Cells
Authors: Du Li , Bouzidi Mohamed S. , Gala Akshay , Deiter Fred , Billaud Jean-Noël , Yeung Stephen T. , Dabral Prerna , Jin Jing , Simmons Graham , Dossani Zain , Niki Toshiro , Ndhlovu Lishomwa C. , Greenland John R. , Pillai Satish K. 
Published: March 2022

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral immunopathogenesis, were reported to be elevated in the setting of severe COVID-19 disease. However, the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated. Here, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including primary AECs in air-liquid interface (ALI) culture. Gal-9-glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an ACE2-dependent manner, enhancing the binding affinity of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induce the expression of key pro-inflammatory programs in AECs including the IL-6, IL-8, IL-17, EIF2, and TNFα signaling pathways. Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection.ImportanceCOVID-19 continues to have a major global health and economic impact. Identifying host molecular determinants that modulate SARS-CoV-2 infectivity and pathology is a key step in discovering novel therapeutic approaches for COVID-19. Several recent studies have revealed that plasma concentrations of the human β-galactoside-binding protein galectin-9 (Gal-9) are highly elevated in COVID-19 patients. In this study, we investigated the impact of Gal-9 on SARS-CoV-2 pathogenesis ex vivo in airway epithelial cells (AECs), the critical initial targets of SARS-CoV-2 infection. Our findings reveal that Gal-9 potently enhances SARS-CoV-2 replication in AECs, interacting with glycans to enhance the binding between viral particles and entry receptors on the target cell surface. Moreover, we determined that Gal-9 accelerates and exacerbates several virus-induced pro-inflammatory programs in AECs that are established signature characteristics of COVID-19 disease and SARS-CoV-2-induced acute respiratory distress syndrome (ARDS). Our findings suggest that Gal-9 is a promising pharmacological target for COVID-19 therapies.
Transposon activities drive the selection and diversification of sweet orange (Citrus × sinensis) cultivars in the last 500 years
Authors: Wu Bo , Cui Yiping , Duan Yongping , Gmitter Frederick G. , Luo Feng 
Published: March 2022

AbstractSweet orange (SWO) has one of the largest numbers of cultivar groups inCitruswith diverse horticultural traits just through asexual breeding. However, the molecular mechanism driving its fast selection and diversification is unclear. In this study, we completely surveyed the transposon activities in SWO genomes and unraveled six transposon families with up to 8,974.2-fold activity increase in modern SWO cultivars. Based on the transposon insertion phylogenetic tree, we inferred that modern SWOs date back to a common ancestor ∼500 years ago and reconstructed three major spread events in SWO cultivation history. Activation, acceleration, and silencing of the six families have recurred in distinct lineages. Their insertions are presented as tag mutations for all SWO cultivar groups and can distinguish over 99% of all analyzed SWO accessions. The insertions are enriched in impacting plant development and hormone signaling. This study demonstrated the importance of transposon activities in asexual breeding.
STING controls T cell memory fitness during infection through T cell intrinsic and IDO dependent mechanisms
Authors: Quaney Michael J. , Newth Rebecca J. , Karin Knudson M. , Saxena Vikas , Pritzl Curtis J. , Rae Chris S. , Lauer Peter , Daniels Mark A. , Teixeiro Emma 
Published: March 2022

AbstractStimulator of interferon genes (STING) signaling has been extensively studied in inflammatory diseases and cancer while its role in T cell responses to infection is unclear. UsingListeria monocytogenesstrains engineered to induce different levels of c-di-AMP, we found that strong STING signals impaired T cell memory upon infection via increased Bim levels and apoptosis. Unexpectedly, reduction of TCR signal strength or T cell-STING expression decreased Bim expression, T cell apoptosis and recovered T cell memory. We found that TCR signal intensity coupled STING signal strength to the Unfolded Protein Response (UPR) and T cell survival. Under strong STING signaling, IDO inhibition also reduced apoptosis and led to a recovery of T cell memory in STING sufficient CD8 T cells. Thus, STING signaling regulates CD8 T cell memory fitness through both cell-intrinsic and extrinsic mechanisms. These studies provide insight into how IDO and STING therapies could improve long-term T cell protective immunity.Significance StatementSTING signaling is an innate pathway that triggers host immunity against pathogens and cancer in response to cytosolic DNA. Additionally, STING signaling overactivation has been linked to autoimmunity. Yet, the interaction between antigenic and STING signaling and its impact in the development of protective immunity has remained unexplored. We found that strong levels of STING signaling impair CD8 T cell memory but only in response to high affinity TCR-pMHC interactions. Here, we provide evidence of how TCR signal strength controls STING signaling and IDO metabolism to regulate T cells’ survival as they mature to memory. These data have important implications for the design of STING and IDO combination immunotherapies
Cloning of Nine Glucocorticoid Receptor Isoforms from the Slender African lungfish (Protopterus dolloi)
Authors: Katsu Yoshinao , Oana Shin , Lin Xiaozhi , Hyodo Susumu , Bianchetti Laurent , Baker Michael E. 
Published: March 2022

ABSTRACTWe wanted to clone the glucocorticoid receptor (GR) from slender African lungfish (Protopterus dolloi) for comparison to P. dolloi MR, which we had cloned and were characterizing, as well as for comparison to the GRs from humans, elephant shark and zebrafish. However, although sequencing of the genome of the Australian lungfish (Neoceratodus forsteri), as well as, that of the West African lungfish (Protopterus annectens) were reported in the first three months of 2021, we could not retrieve a GR sequence with a BLAST search of GenBank, when we submitted our research for publication in July 2021. Moreover, we were unsuccessful in cloning the GR from slender African lungfish using a cDNA from the ovary of P. dolloi and PCR primers that had successfully cloned a GR from elephant shark, Xenopus and gar GRs. On October 21, 2021 the nucleotide sequence of West African lungfish (P. annectens) GR was deposited in GenBank. We used this GR sequence to construct PCR primers that successfully cloned the GR from the slender spotted lungfish. Here, we report the sequences of nine P. dolloi GR isoforms and explain the basis for the previous failure to clone a GR from slender African lungfish using PCR primers that cloned the GR from elephant shark, Xenopus and gar. Studies are underway to determine corticosteroid activation of these slender African lungfish GRs.
Correlations between human mating partners: a comprehensive meta-analysis of 22 traits and raw data analysis of 133 traits in the UK Biobank
Authors: Horwitz Tanya B. , Balbona Jared V. , Paulich Katie N. , Keller Matthew C. 
Published: March 2022

AbstractPositive correlations between human mating partners are consistently observed across traits. Such correlations can increase phenotypic variation and, to the extent that they reflect genetic similarity in co-parents, can also increase prevalence for rare phenotypes and bias estimates in genetic designs. We conducted the largest set of meta-analyses on human partner correlations to date, incorporating 480 partner correlations across 22 traits. We also calculated 133 trait correlations between up to 79,074 male-female couples in the UK Biobank (UKB). Estimates of the mean meta-analyzed correlations ranged fromrmeta=.08 for extraversion tormeta=.58 for political values. UKB correlations ranged fromrUKB=-.18 for chronotype torUKB=.87 for birth year. Overall, attitudes, education, and substance use traits mostly showed the highest correlations, while psychological and biological traits generally yielded lower but still positive correlations. We observed high between-study heterogeneity for most meta-analyzed traits, likely because of both systematic differences between samples and true differences in partner correlations across populations.
The Outcome of Gynecologic Cancer Patients With Covid-19 Infection: A Systematic Review And Meta-Analysis
Authors: Sastra Winata I Gde , Simatupang Januar , Polim Arie A , Togar Yakob , Tondang Advenny Elisabeth 
Published: March 2022

AbstractObjectiveCancer is a comorbidity that leads to progressive worsening of Covid-19 with increased mortality. This is a systematic review and meta-analysis to yield evidence of adverse outcomes of Covid-19 in gynecologic cancer.MethodsSearches through PubMed, Google Scholar, ScienceDirect, and medRxiv to find articles on the outcome of gynecologic cancer with Covid-19 (24 July 2021-19 February 2022). Newcastle-Ottawa Scale tool is used to evaluate the quality of included studies. Pooled odds ratio (OR), 95% confidence interval (CI), random-effects model were presented. This study was registered to PROSPERO (CRD42021256557).ResultsWe accepted 51 studies (1991 gynecologic cancer with Covid-19). Covid-19 infection was lower in gynecologic cancer vs hematologic cancer (OR 0.71, CI 0.56-0.90, p 0.005). Severe Covid and death were lower in gynecologic cancer vs lung and hematologic cancer (OR 0.36, CI 0.16-0.80, p 0.01), (OR 0.52, CI 0.44-0.62, p <0.0001), (OR 0.26, CI 0.10-0.67 p 0.005), (OR 0.63, CI 0.47-0.83, p 0.001) respectively. Increased Covid death is seen in gynecologic cancer vs breast, non-covid cancer, and non-cancer covid (OR 1.50, CI 1.20-1.88, p 0.0004), (OR 11.83, CI 8.20-17.07, p <0.0001), (OR 2.98, CI 2.23-3.98, p <0.0001) respectively.ConclusionGynecologic cancer has higher Covid-19 adverse outcomes compared to non-cancer, breast cancer, non-metastatic, and Covid-19 negative population. Gynecologic cancer has fewer Covid-19 adverse outcomes compared to other cancer types, lung cancer, and hematologic cancer. These findings may aid health policies and services during the ongoing global pandemic.