Summix: A method for detecting and adjusting for population structure in genetic summary data.

Publicly available genetic summary data have high utility in research and the clinic, including prioritizing putative causal variants, polygenic scoring, and leveraging common controls. However, summarizing individual-level data can mask population structure, resulting in confounding, reduced power, and incorrect prioritization of putative causal variants. This limits the utility of publicly available data, especially for understudied or admixed populations where additional research and resources are most needed. Although several methods exist to estimate ancestry in individual-level data, methods to estimate ancestry proportions in summary data are lacking. Here, we present Summix, a method to efficiently deconvolute ancestry and provide ancestry-adjusted allele frequencies (AFs) from summary data. Using continental reference ancestry, African (AFR), non-Finnish European (EUR), East Asian (EAS), Indigenous American (IAM), South Asian (SAS), we obtain accurate and precise estimates (within 0.1%) for all simulation scenarios. We apply Summix to gnomAD v.2.1 exome and genome groups and subgroups, finding heterogeneous continental ancestry for several groups, including African/African American (∼84% AFR, ∼14% EUR) and American/Latinx (∼4% AFR, ∼5% EAS, ∼43% EUR, ∼46% IAM). Compared to the unadjusted gnomAD AFs, Summix's ancestry-adjusted AFs more closely match respective African and Latinx reference samples. Even on modern, dense panels of summary statistics, Summix yields results in seconds, allowing for estimation of confidence intervals via block bootstrap. Given an accompanying R package, Summix increases the utility and equity of public genetic resources, empowering novel research opportunities.

Screening of inhibitors on successful covalent tyrosinase coupling with help from SpyBank.

Microbial metabolites are an important source of tyrosinase (TYR) inhibitors because of their rich chemical diversity. However, because of the complex metabolic environment of microbial products, it is difficult to rapidly locate and identify natural TYR inhibitors. Affinity-based ligand screening is an important method for capturing active ingredients in complex samples, but ligand immobilization is an important factor affecting the screening process. In this paper, TYR was used as ligand, and the SpyTag/SpyCatcher coupling system was used to rapidly construct affinity chromatography vectors for screening TYR inhibitors and separating active components from complex samples. We successfully expressed SpyTag-TYR fusion protein and SpyCatcher protein, and incubated SpyCatcher protein with epoxy-activated agarose. The SpyTag-TYR protein was spontaneously coupled with SpyCatcher to obtain an affinity chromatography filler for immobilization of TYR, and the performance of the packaging material was characterized. Finally, compound 1 with enzyme inhibitory activity was successfully obtained from the fermentation product of marine microorganism C. Through HPLC, MS, 1H NMR and 13C NMR analyses, its structure was deduced as azelaic acid, and its activity was analyzed. The results showed that this is a feasible method for screening TYR inhibitors in complex systems.

Influence of Exosomes on Astrocytes in the Pre-Metastatic Niche of Lung Cancer Brain Metastases.

BACKGROUND: Lung cancer is the most common cause of cancer-related death globally. There are several reasons for this high mortality rate, including metastasis to multiple organs, especially the brain. Exosomes play a pivotal role in tumor metastasis by remodeling the microenvironment of remote target organs and promoting the pre-metastatic niche's formation. Since astrocytes are indispensable for maintaining the homeostasis of brain microenvironment, it's of great interest to explore the influence of lung cancer cell-derived exosomes on astrocytes to further understand the mechanism of lung cancer brain metastasis. RESULTS: Twenty four h after co-culture of H1299 cell-derived exosomes and SVG P12 cells, the viability of astrocytes decreased and the apoptosis increased. The levels of cytokines in the supernatant including GROα/CXCL1, IFN-γ, IL-3, IL-5, IL-15, LIF, M-CSF, NGF, PDGF, and VEGF were significantly enhanced, while IL-7 secretion was significantly reduced. Meanwhile, apoptosis-related proteins MAP2K1, TUBA1C, RELA, and CASP6 were up-regulated. And the differentially expressed proteins were involved in regulating metabolic pathways. CONCLUSION: Exosomes of H1299 could induce apoptosis of astrocytes as well as promote their secretion of cytokines that were conducive to the formation of the inflammatory microenvironment and immunosuppressive microenvironment, and affect their metabolic pathways, thus facilitating the formation of pre-metastatic niche in lung cancer brain metastases.

The Impact of Blade Technology on Paralympic Sprint Performance Between 1996 and 2016: Bilateral Amputees' Competitive Advantage.

It is known that high-performance sprinters with unilateral and bilateral prosthetic lower limbs run at different speeds using different spatiotemporal strategies. Historically, these athletes still competed together in the same races, but 2018 classification rule revisions saw the separation of these two groups. This study sought to compare Paralympic sprint performance between all-comer (i.e., transfemoral and transtibial) unilateral and bilateral amputee sprinters using a large athlete sample. A retrospective analysis of race speed among Paralympic sprinters between 1996 and 2016 was conducted. In total, 584 published race results from 161 sprinters revealed that unilateral and bilateral lower-extremity amputee sprinters had significantly different race speeds in all three race finals (100 m, p value <.001; 200 m, <.001; 400 m, <.001). All-comer bilateral amputee runners ran faster than their unilateral counterparts; performance differences increased with race distance. These data support current classification criteria in amputee sprinting, which may create more equal competitive fields in the future.

Statin Pretreatment Might Be Associated with Decreased Myocardial Injury After Ischemic Stroke.

BACKGROUND: Myocardial injury is a complication of stroke associated with unfavorable outcome, with the elevation of cardiac troponin as the most sensitive marker. In this study, we aimed at investigating the association between statin pretreatment and poststroke myocardial injury. METHODS: Six hundred seventy-one patients diagnosed as acute ischemic stroke were enrolled. According to the histories of statin pretreatment before stroke, patients were categorized into nonstatin (n = 474) and statin groups (n = 197), with the latter further divided into low-dosage, standard-dosage, and high-dosage subgroups according the dosages of statins. The level of troponin-T was tested and troponin-T level ≥14 ng/l was identified to indicate the presence of myocardial injury. The level of troponin-T and the prevalence of myocardial injury was compared between groups. Logistic regression was used to identify the effect of statin pretreatment for the presence of post-stroke myocardial injury. RESULTS: Statin users had lower levels of troponin-T after stroke, with the level of troponin-T being the lowest in the high-dosage subgroup. The results of logistic regression showed that statin pretreatment and high-dosage statin were independent protective factors for the elevation of troponin-T levels. CONCLUSIONS: Statin pretreatment might be associated with the decreased myocardial injury after ischemic stroke.

Leukoaraiosis correlates with the neurologic deterioration after small subcortical infarction.

BACKGROUND: Patients of small subcortical infarction sometimes have neurologic deterioration (ND), with the risk factors and specific pathogenesis unclear. Small subcortical infarction is often accompanied by other phenotypes of small vessel disease such as leukoaraiosis, which indicates the white matter hyperintensities in the deep or periventricular areas on the fluid-attenuated inversion recovery series of magnetic resonance images and was proved to be associated with stroke in various aspects. In this study, we intended to investigate whether leukoaraiosis was associated with ND after small subcortical infarction, and explore other possible risk factors of ND. METHODS: Patients with single acute subcortical infarction (<1.5 cm in diameter) were recruited consecutively and evaluated everyday. ND was defined as worsening by 2 points or more in the National Institutes Health Stroke Scale (NIHSS) score, or by 1 point or more in the NIHSS score for motor function within 1 week after stroke onset. Leukoaraiosis was rated according to the age-related white matter changes scale. Univariate and multivariate analyses were performed to identify the risk factors for ND. RESULTS: Eighty-four of 435 patients (19.31%) had ND. Univariate analysis showed that age, severity of leukoaraiosis, baseline NIHSS score, presence of diabetes, hemoglobin A1c, and total cholesterol levels were all associated with ND. Multivariate analysis further identified that the severity of leukoaraiosis especially leukoaraiosis adjacent to the index infarction, baseline NIHSS score, and diabetes were independently associated with ND. CONCLUSIONS: Severity of leukoaraiosis and baseline neurologic deficits, and the presence of diabetes were all independently associated with ND after small subcortical infarction.

DFO and DMOG up-regulate the expression of CXCR4 in bone marrow mesenchymal stromal cells.

UNLABELLED: The C-X-C chemokine receptor 4 (CXCR4) is a receptor of the chemokine stromal cell-derived factor 1. CXCR4/stromal cell-derived factor 1 is essential to the migration of cells. Up-regulated expression of chemokines or their receptors is crucial to enhancing the migration capability of bone marrow mesenchymal stromal cells (BM-MSCs) so that their application in treatment can be optimized. The objective of this study was to determine whether desferrioxamine (1,8-diazafluoren-9-one; DFO) and dimethyloxaloylglycine (DMOG) upregulate the expression of CXCR4 in BM-MSCs. Western blot analysis was used to study the expression of CXCR4 in three groups: DFO group, DMOG group, and control group. Immunofluorescence was also used to determine whether CXCR4 exists in the membrane of BM-MSCs. RESULTS: Compared with that in the control group, the expression of CXCR4 was upregulated in the DFO group. Meanwhile, 500 and 1000 microM DMOG exhibited similar effects on CXCR4. Western blot analysis revealed that the two reagents are correlated with the upregulation of CXCR4 in a dose-dependent manner, whereas immunofluorescence demonstrated that CXCR4 exists in the membrane. In conclusion, DFO and DMOG upregulate the expression of CXCR4, their effects are dose dependent, and CXCR4 is distributed in the membrane of BM-MSCs.

The Accessibility of YouTube Fitness Videos for Individuals Who Are Disabled Before and During the COVID-19 Pandemic: Preliminary Application of a Text Analytics Approach.

BACKGROUND: People with disabilities face barriers to in-person physical activity (PA), including a lack of adaptive equipment and knowledgeable instructors. Given this and the increased need for digital resources due to widespread COVID-19 lockdowns, it is necessary to assess the accessibility of digital fitness resources for people with disabilities. To investigate whether YouTube fitness content creators have made videos accessible to people with disabilities would be informative about access to PA during COVID-19 and could also provide insight into the feasibility of individuals who are disabled relying on YouTube for PA in a post-COVID-19 world. OBJECTIVE: This study aims to ascertain if disability-friendly PA videos on YouTube are accessible through searching general fitness terms and whether a change in the availability of accessible fitness resources for people with disabilities occurred on YouTube between before and during the COVID-19 pandemic on "Hospital/Medical Institutions," "Individual(s)," and "Other(s)" channels. Secondary aims are to investigate if different categories of YouTube channels produce more accessible fitness content and highlight any disparities in disability-friendly PA content on YouTube. METHODS: A cross-sectional text analysis of exercise-related YouTube videos was conducted. The authors used Python (version 3.0) to access the YouTube database via its data application programming interface. Terms pertaining to PA that were searched on YouTube were at-home exercise, exercise at home, exercise no equipment, home exercise, home-based exercise, no equipment workout, and workout no equipment. Various elements (eg, view count and content generation) of the videos published between January 1 and June 30, 2019 (n=700), were compared to the elements of videos published between January 1 and June 30, 2020 (n=700). To capture a broad idea of disability-friendly videos on YouTube, videos were labeled "accessible" if they were found in the first 100 video results and if their title, description, or tags contained the following terms: para, paralympic, adaptive, adapted, disabled, disability, differently abled, disability-friendly, wheelchair accessible, and inclusive. Each video and channel were categorized as "Hospitals/Medical Institutions," "Individuals," or "Other(s)." RESULTS: The analysis revealed a statistically significant increase in viewership of fitness content on YouTube (P=.001) and in fitness content generated by Hospitals/Medical Institutions (P=.004). Accessible terms applicable to people with disabilities had minimal appearances in 2019 (21 videos) and 2020 (19 videos). None of the top viewed fitness videos that populated on YouTube from 2019 or 2020 were accessible. CONCLUSIONS: The proportion of accessible disability-friendly videos remains diminutive relative to the prevalence of disability in the general population, revealing that disability-friendly videos are seldom findable on YouTube. Thus, the need for disability-friendly fitness content to be easily searched and found remains urgent if access to digital fitness resources is to improve.

The clinical outcome and risk factors analysis of immune checkpoint inhibitor-based treatment in lung adenocarcinoma patients with brain metastases.

Background: The data about efficacy of immunotherapy for non-small cell lung cancer with brain metastases (BMs) from real-word settings are controversial. This real-word study is aimed to evaluate the clinical outcome of immune checkpoint inhibitor (ICI)-based treatment in lung adenocarcinoma patients with brain metastases (BMs) and explore potential risk factors, with a focus on the spatial distribution of BMs as previous studies suggested spatial heterogeneity on the brain immune microenvironment. Methods: Advanced lung adenocarcinoma patients with non-oncogene-addicted, who received ICI monotherapy or plus chemotherapy, were enrolled. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Intergroup comparisons were performed using Pearson's χ2 or Fisher's exact tests for categorical variables. The progression-free survival (PFS) was estimated using Kaplan-Meier method and compared using log-rank test. Cox proportional hazards model was used for multivariate analyses. Peripheral blood was collected from 15 patients with BMs. Tumor-derived exosomes in plasma were isolated by size exclusion chromatography and the cDNA library preparations for miRNA were sequenced on an Illumina Hiseq platform. Differentially expressed genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed. Results: A total of 198 patients were enrolled and brain metastasis occurred in 20.7% patients (N=41). Compared with patients without BMs, those with BMs had a comparable objective response rate (ORR; 29.3% vs. 43.9%; P=0.089), a lower disease control rate (DCR; 58.5% vs. 78.3%; P=0.01), and a shorter PFS (3.6 vs. 8.6 months; P=0.069). For patients with BMs, factors, including the presence of neurological symptoms, the treatment of intracranial radiotherapy, and the combination of ICI with chemotherapy, had no impact on PFS, whereas cerebellum metastasis was significantly associated with shorter PFS (2.8 vs. 13.8 months, P=0.007). Six upregulated miRNAs were identified in patients with cerebellum metastases (N=8) compared with those without (N=7). The enrichment of differentially expression genes in the KEGG pathways indicated upregulated sulfur metabolism pathway in patients with cerebellum metastases. Conclusions: For lung adenocarcinoma patients, those with BMs have inferior response to ICI-based treatment, but not significantly, and cerebellum metastasis is an independent risk factor with poor outcome for such patients, might attributing to the upregulated sulfur metabolism.

'Knowing we have these rights does not always mean we feel free to use them': athletes' perceptions of their human rights in sport.

Objectives: Modern sport safeguarding strategies include published global rights declarations that enshrine athletes' entitlements at the policy level. It is unclear how these documents translate to athletes' lived experiences. The study aimed to determine athletes' knowledge, attitudes and beliefs about their human rights in sports settings. Setting: Web-based survey. Participants: 1159 athletes from 70 countries completed a validated web-based survey. Over half of participants (60.1%) were between 18 and 29 years, currently competing (67.1%), not members of players' unions (54.6%), elite (60.0%) and participating in individual (55.8%) non-contact (75.6%) Olympic (77.9%) sports. Gender distribution was equal. Primary and secondary outcome measures: Participant demographics (eg, gender, age) and athletes' knowledge, attitudes and beliefs about their human rights in sports settings. Results: Most (78.5%) were unaware of any athletes' rights declarations. Gender influenced participants' confidence in acting on their rights in sport significantly. Males were more likely to accept pressure from coaches and teammates than females, but age affected how likely males were to accept this pressure. Paralympic athletes were less likely to agree that violence is acceptable in sports, compared with Olympic. Player union membership increased confidence in freely expressing one's opinion in sports settings. Athletes' rights-related awareness, knowledge and beliefs were disconnected. Conclusions: Awareness raising is not enough to prevent human rights violations in sports. The cultural climate of the entire ecosystem must be targeted, using systems-level strategies to shift stakeholders' biases, beliefs and behaviours. This approach takes the onus of addressing abuse off athletes' shoulders and places accountability on sports organisations.

Complete Genome Sequence of Salmonella enterica Serovar Pullorum Multidrug Resistance Strain S06004 from China.

As Salmonella enterica serovar Pullorum remains a major economic problem for the poultry industries of countries with no efficient control measures, we presented a multidrug resistance strain S06004 (isolated from a clinically sick chicken in China in 2006) for genome sequencing. The genome comparison showed that the strain contained two prophages, the ST104 and prophage-4 (Fels2) of E. coli LF82, which were not detected in the only published genomes of S. Pullorum RKS5078 and CDC1983-67. In addition, the GyrA Ser83 point mutation, drugresistant genes, and many antibiotic pump systems that are present in S06004 may be contributing to the multidrug resistance of this strain.

[Purification of anti-HBcAg monoclonal antibodies using immobilized metal ion affinity chromatography].

Anti-HBcAg monoclonal antibodies from mouse ascites were purified by using immobilized metal ion affinity chromatography. We optimized the conditions of sample loading and elution. The results showed that when the pH stepwise elution was used, the best solution for sample loading was 20 mmol/L phosphate buffer containing 0.5 mol/L sodium chloride at pH 8.0 and the mAb was eluted at pH 5.0. The purity of obtained mAb was more than 85% and recovery reached 80%. When the adsorbed proteins were eluted by using gradient elution of an imidazole, the best solution for loading condition was 20 mmolL phosphate buffer containing 5 mmol/L imidazole at pH 8.0. The purity and recovery of antibody were up to 95%.