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The primary concern of this study is to examine how Information & Communication Technology (ICT) usage and dynamic capabilities impact the business resilience of Small and Medium Scale Enterprises (SMEs) to survive and continue during the COVID-19 pandemic. The data were collected from a sample of 129 ICT-used SMEs employing face-to-face and telephone interviews. Partial Least Square-Structural Equation Modelling (PLS-SEM) was used to analyse the data through SmartPLS software. The study findings reveal a significant positive relationship between ICT usage and business resilience during the pandemic. And ICT usage significantly affects the dynamic capabilities of the business. Results also claim that dynamic capabilities play a complementary mediating role in the relationship between ICT usage and business resilience. Consequently, the study concludes that the adoption of ICT and the ability to integrate, build and reconfigure the available resources of SMEs with ICT enablers enhanced their resilience and ensured survival during the pandemic. The research design, the methodology utilized, and the findings of this study will benefit researchers, policymakers, and entrepreneurs and contribute to future studies regarding the regrowth and resilience of SMEs during a crisis.

A hotel's economic feasibility and progress depend on the efficient use of all resources, along with human resources (HR). Absenteeism is a critical issue that almost all employers encounter daily. It imposes considerable financial burdens on organizations and has a negative impact on productivity and performance. The majority of research has revealed that absenteeism is a multifaceted construct impacted by numerous factors, both personal and organizational. Although researchers have attempted to identify the factors that contribute or are associated to absenteeism in order to devise suitable solutions. The research on the relationship between organizational and personal factors and absenteeism appears to be contradictory. A few studies found no correlation between these two variables, whereas some found a weak to moderate correlation between the two variables. Furthermore, there are few research studies on absenteeism in the Sri Lankan hotel industry. As a result, the current study sought to ascertain whether organizational and personal factors influence absenteeism in selected 3-5 star grade tourist hotels in the Galle District. The 14 three to five-star tourist hotels in Galle District were the study's target population. The sample size was determined using a non-probable random sampling method. As a result, a sample of five three to five star tourist hotels in the Galle District was preferred. A questionnaire was used to collect primary data from respondents for the study. The Statistical Package for Social Sciences (SPSS) was used for analysis, which allowed the researcher to express the data in the form of tables and figures. Previous research has discovered that there are several factors that can influence employee absenteeism. According to the literature review, factors such as promotion satisfaction, coworker support, pay satisfaction, age, gender, tenure, number of dependents, and marital status can all have an impact on absenteeism.

Following the aftermath of the civil war, the Sri Lankan tourism industry begins to surge and enters its golden era. However, due to the Easter Sunday attack in 2019 and the COVID-19 global pandemic, Sri Lankan tourism is struggling to perform as well as it did previously. When contemplating the hotel sector, particularly with this COVID-19 impact, the boutique hotel category has become one of the world's and Sri Lanka's fastest-growing segments of the hotel industry. They are comparatively small but exclusive properties designed to cater to privileged clients with an exemplary performance at premium prices. Tourists prefer boutique hotels because they want to spend their vacation in a more private secure setting. Even though guest satisfaction has an effect on hotel performance and previous studies show that service quality has a high impact on guest satisfaction, this study was conducted to investigate how service quality effects on guests' satisfaction in boutique hotels with special reference to the Central Province. The researchers chose four boutique hotels in Central Province and collected data from 100 guests who visited those four boutique hotels. The convenience sampling method was used and a structured questionnaire was used to collect data. The SERVQUAL model was used to evaluate service quality. With the help of SPSS 21.0, descriptive statistics, regression, and correlation were used to analyze the data. According to the findings, the tangibles, assurance, and reliability factors have the greatest impact on increasing guest satisfaction and the researchers recommend that service quality be enhanced by increasing the indicators that influence those dimensions.

Congenital disorders of glycosylation are genetic disorders that occur due to defects in protein and lipid glycosylation pathways. A deficiency of N-glycanase 1, encoded by the NGLY1 gene, results in a congenital disorder of deglycosylation. The NGLY1 enzyme is mainly involved in cleaving N-glycans from misfolded, retro-translocated glycoproteins in the cytosol from the endoplasmic reticulum before their proteasomal degradation or activation. Despite the essential role of NGLY1 in deglycosylation pathways, the exact consequences of NGLY1 deficiency on global cellular protein glycosylation have not yet been investigated. We undertook a multiplexed tandem mass tags-labeling-based quantitative glycoproteomics and proteomics analysis of fibroblasts from NGLY1-deficient individuals carrying different biallelic pathogenic variants in NGLY1. This quantitative mass spectrometric analysis detected 8041 proteins and defined a proteomic signature of differential expression across affected individuals and controls. Proteins that showed significant differential expression included phospholipid phosphatase 3, stromal cell-derived factor 1, collagen alpha-1 (IV) chain, hyaluronan and proteoglycan link protein 1, and thrombospondin-1. We further detected a total of 3255 N-glycopeptides derived from 550 glycosylation sites of 407 glycoproteins by multiplexed N-glycoproteomics. Several extracellular matrix glycoproteins and adhesion molecules showed altered abundance of N-glycopeptides. Overall, we observed distinct alterations in specific glycoproteins, but our data revealed no global accumulation of glycopeptides in the patient-derived fibroblasts, despite the genetic defect in NGLY1. Our findings highlight new molecular and system-level insights for understanding NGLY1-CDDG.

Selection of tea [Camellia sinensis (L.) O. Kuntze] cultivars with wide adaptability over diverse environments is an important criteria to get prior information to recommend the cultivar for a particular region. A study was carried out to identify the most adaptable and stable tea genotypes for recommendation in the Up-country tea growing region in Sri Lanka by evaluating several potential tea genotypes for their wide adaptability and stability over diverse environments based on the analysis of GE interaction using within location non-replicated multi-environmental yield trials and GGE biplot methods. Six promising tea genotypes with desirable agronomic traits selected based on preliminary yield trials were evaluated along with a standard check in large scale within location non-replicated multi-locational yield trials at six locations (tea estates) in the Up-country tea growing region in Sri Lanka. The crop yields were recorded by harvesting green leaves in every seven days for three years covering six seasons (1st pruning cycle). Yield data were analyzed by within location non-replicated multi-locational yield trials and GGE biplot analysis. The genotype 272 was identified as the most adaptable and stable genotype followed by 582 and rest of the genotypes showed poor adaptability in the test region.

Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the association extends to statin users undergoing routine care. We sought to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Covariate-adjusted Cox regression models were used to compare the risk of cardiovascular outcomes between statin users and matched nonusers. Statin effectiveness on incident myocardial infarction showed no gradient with increasing 10-year Pooled Cohort Equations atherosclerotic cardiovascular disease (ASCVD) risk across low, borderline, intermediate, and high ASCVD risk score groups. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (hazard ratio (HR) 0.41, 95% confidence interval (CI), 0.31-0.53; P = 1.5E-11), intermediate in the intermediate polygenic risk score group (HR 0.56, 95% CI, 0.47-0.66; P = 8.4E-12), and smallest in the low polygenic risk score group (HR 0.67, 95% CI, 0.47-0.97; P = 0.03; P for high vs. low = 0.01). ASCVD risk and statin low-density lipoprotein cholesterol (LDL-C) lowering did not differ across polygenic risk score groups. In patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of LDL-C lowering. Our findings extend prior work by identifying a subset (i.e., self-identified White individuals with low CHD polygenic risk scores) with attenuated clinical benefit from statins.

Chronic T-cell receptor (TCR) signaling in the tumor microenvironment is known to promote T-cell dysfunction. However, we reasoned that poorly immunogenic tumors may also compromise T cells by impairing their metabolism. To address this, we assessed temporal changes in T-cell metabolism, fate, and function in models of B-cell lymphoma driven by Myc, a promoter of energetics and repressor of immunogenicity. Increases in lymphoma burden most significantly impaired CD4+ T-cell function and promoted regulatory T cell (Treg) and Th1-cell differentiation. Metabolomic analyses revealed early reprogramming of CD4+ T-cell metabolism, reduced glucose uptake, and impaired mitochondrial function, which preceded changes in T-cell fate. In contrast, B-cell lymphoma metabolism remained robust during tumor progression. Finally, mitochondrial functions were impaired in CD4+ and CD8+ T cells in lymphoma-transplanted OT-II and OT-I transgenic mice, respectively. These findings support a model, whereby early, TCR-independent, metabolic interactions with developing lymphomas limits T cell–mediated immune surveillance.

AimsAlthough highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS.Methods and resultsA genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS.ConclusionDyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Objective: The goal of this paper is to provide a consensus review on telehealth delivery prior to and during the COVID-19 pandemic to develop a set of recommendations for designing telehealth services and tools that contribute to system resilience and equitable health. Methods: The IMIA-Telehealth Working Group (WG) members conducted a two-step approach to understand the role of telehealth in enabling global health equity. We first conducted a consensus review on the topic followed by a modified Delphi process to respond to four questions related to the role telehealth can play in developing a resilient and equitable health system. Results: Fifteen WG members from eight countries participated in the Delphi process to share their views. The experts agreed that while telehealth services before and during COVID-19 pandemic have enhanced the delivery of and access to healthcare services, they were also concerned that global telehealth delivery has not been equal for everyone. The group came to a consensus that health system concepts including technology, financing, access to medical supplies and equipment, and governance capacity can all impact the delivery of telehealth services. Conclusion: Telehealth played a significant role in delivering healthcare services during the pandemic. However, telehealth delivery has also led to unintended consequences (UICs) including inequity issues and an increase in the digital divide. Telehealth practitioners, professionals and system designers therefore need to purposely design for equity as part of achieving broader health system goals.

GWAS Summary Statistics for a Global Meta-Analysis of Aortic Stenosis in the TARGET Consortium 10.5281/zenodo.7630002 This dataset contains the genome-wide association summary statistics for a Global Meta-Analysis of Aortic Stenosis. For the analysis description and included cohorts, please see Chen et al., the European Heart Journal (2023). The data are provided on an "AS-IS" basis, without warranty of any type, expressed or implied, including but not limited to any warranty as to their performance, merchantability, or fitness for any particular purpose. If investigators use these data, any and all consequences are entirely their responsibility. By downloading and using these data, you agree that you will cite the appropriate publication in any communications or publications arising directly or indirectly from these data. When using this data, please cite the paper and this repository: Chenet al., GWAS Summary Statistics for a Global Meta-Analysis of Aortic Stenosis,the European Heart Journal (2023). Zenodo.10.5281/zenodo.7630002 Column headers: CHR: Chromosome code. Not present with 'no-map' modifier. BP: Base-pair coordinate. Not present with 'no-map' modifier. SNP: Variant identifier A1: Effect Allele A2: Other Allele N_cohort: Number of valid studies for variant P: Fixed-effects meta-analysis p-value P.R.: Random-effects meta-analysis p-value OR: Fixed-effects BETA/OR estimate OR.R.:  Random-effects BETA/OR estimate Q: p-value for Cochran's Q statistic I: I2 heterogeneity index (0-100 scale) N_ind: Number of individuals Fundings: Fundings for this study were obtained from the following (listed in alphabetical order): ALFEDIAM Ardix Medical Assistance Publique - Hôpitaux de Paris Association Diabète Risque Vasculaire Bayer Diagnostics Becton Dickinson British Heart Foundation British Heart Foundation Oxford Centre Canadian Institutes for Health Research Capital Regions Research Council Cardionics, Merck Santé, Novo Nordisk CNAMTS, Lilly, Novartis Pharma Cohortes Santé TGIR County Council of Västerbotten Crafoord Foundation Ellison Medical Foundation European Research Council Fédération Française de Cardiologie Fédération Française de Cardiologie, a Fondation Coeur et Recherche Fonds de Recherche du Québec - Santé. French Regional Council of Pays-de-la-Loire (VaCaRMe program) Heart and Stroke Foundation of Canada Heart Foundation of Northern Sweden. Kaiser Permanente Knut and Alice Wallenberg foundation to the Wallenberg Center La Fondation de France Medical Research Council and the University of Oxford National Center for Advancing Translational Sciences (CTSI) National Heart, Lung, and Blood Institute (NHLBI) National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) National Institutes of Health Novo Nordisk Foundation ONIVINS Robert Wood Johnson Foundation Sanofi-Aventis; by INSERM (Réseaux en Santé Publique, Interactions entre les déterminants de la santé) Skåne University Hospital Société francophone du diabète Swedish Foundation for Strategic Research Swedish Heart–Lung Foundation Swedish National Health Service Swedish Research Council The Innovation Fund Denmark Umeå University U.S. Department of Veteran Affairs Vanderbilt University Medical Center’s institutional funding Wayne and Gladys Valley Foundation &nbsp

Supplementary Table from TCR-Independent Metabolic Reprogramming Precedes Lymphoma-Driven Changes in T-cell Fate

Chronic T-cell receptor (TCR) signaling in the tumor microenvironment is known to promote T-cell dysfunction. However, we reasoned that poorly immunogenic tumors may also compromise T cells by impairing their metabolism. To address this, we assessed temporal changes in T-cell metabolism, fate, and function in models of B-cell lymphoma driven by Myc, a promoter of energetics and repressor of immunogenicity. Increases in lymphoma burden most significantly impaired CD4+ T-cell function and promoted regulatory T cell (Treg) and Th1-cell differentiation. Metabolomic analyses revealed early reprogramming of CD4+ T-cell metabolism, reduced glucose uptake, and impaired mitochondrial function, which preceded changes in T-cell fate. In contrast, B-cell lymphoma metabolism remained robust during tumor progression. Finally, mitochondrial functions were impaired in CD4+ and CD8+ T cells in lymphoma-transplanted OT-II and OT-I transgenic mice, respectively. These findings support a model, whereby early, TCR-independent, metabolic interactions with developing lymphomas limits T cell–mediated immune surveillance.

Supplementary Figure from TCR-Independent Metabolic Reprogramming Precedes Lymphoma-Driven Changes in T-cell Fate

Supplementary Table S1. Descriptive factors for KP study population, broken down by study. Supplementary Table S2. Genome-wide significant SNPs found in our cohort. Supplementary Table S3. Cis-eQTL expression of rs4646284. Supplementary Table S4. Results at the 105 loci previously found to be associated with prostate cancer. Supplementary Table S5. Risk score of and variance explained by the 105 previously reported hits. Supplementary Figure S1. Manhattan and Q-Q plots of each race/ethnicity and meta-analysis. Supplementary Figure S2. Local plots of novel replicated rs4646284 and suggestive rs2659124. Supplementary Figure S3. Cis-eQTL of SLC22A1 and SLC22A3. Supplementary Figure S4. Comparison of ORs of KP to previous reports by race/ethnicity. Supplementary Figure S5. KP AUC estimates.

Supplemental Figure 1: Biodistribution data reflecting the accumulation of 68Ga-citrate over time in the tissues of male nu/nu mice bearing PC3 xenografts. Peak radiotracer uptake was observed at 4 hours post injection. Supplemental Figure 2: Biodistribution data reflecting the accumulation of 68Ga-citrate at 4 hours post injection in the tissues of male nu/nu mice bearing 22Rv1 xenografts. Supplemental Figure 3: Biodistribution data collected 4 hours post injection of 68Ga-citrate in male nu/nu mice bearing subcutaneous PC3 xenografts, and 48 hours post injection of 89Zr-Tf in male nu/nu mice with subcutaneous PC3 xenografts. Supplemental Figure 4. BET inhibitors suppress MYC and transferrin uptake in MYC positive prostate cancer cell lines. Supplemental Figure 5: Biodistribution data collected 4 hours post injection of 68Ga-Tf in male nu/nu mice bearing subcutaneous PC3 or 22Rv1 xenografts. Mice were treated with vehicle, (+)-JQ1 (25 mg/kg, BID), or iBET (50 mg/kg, daily oral gavage) for 5 days prior to radiotracer injection. Supplemental Figure 6: Representative PET data collected 4 hours post injection of 68Ga-citrate or 48 hours post injection of 89Zr-Tf in male nu/nu mice bearing subcutaneous 22Rv1 xenografts. Supplemental Figure 7: Paired PET imaging plus CT-guided biopsy of tracer-avid liver metastasis in patient-003 with mCRPC. Supplemental Figure 8: H&E staining of the PDX tissue isolated from the liver metastasis of patient-003 shows morphological features consistent with the liver biopsy. Supplemental Figure 9. Biodistribution data acquired 4 hours post injection of 68Ga-citrate shows the accumulation of the radiotracer in the PDX tissue and selected normal mouse tissues. Supplemental Table 1. A summary of the tumor:blood and tumor: muscle ratios for 68Ga-citrate Supplemental Table 2. A summary of the patient characteristics in this study. Supplemental Table 3. A summary of the test/re-test data for 68Ga-citrate in normal tissues. Data are presented as SUVmax. Supplementary Table 4. A summary of the histological subclassifications for the prostate cancer biopsies acquired during this study.

Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with 68Ga-citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that 68Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68Ga-citrate for tumors with hyperactive MYC.Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221–9. ©2017 AACR.

Figure S1-S6, Table S1-S10

STING co-immunoprecipitates with IRE-1 (S1); Chemical structures of STING agonists (S2); Analysis of 3'3'-cGAMP by RP-HPLC and NMR (S3); STING does not undergo N-linked glycosylation before and after stimulations by 3'3'-cGAMP (S4); Deletion of mouse STING gene by ZFN (S5); STING-null A20 cells are resistant to 3'3'-cGAMP-induced apoptosis (S6); Tandem MS spectra of phosphorylated S357 and S365 peptides of mouse STING (S7); The affinity-purified anti-STING antibody specifically immunostains mouse STING in 5TGM1 myeloma cells (S8); An IRE-1/XBP-1 pathway inhibitor, B-I09, enhances the cytotoxicity of 3'3'-cGAMP in normal and malignant B cells (S9); STING agonists do not induce apoptosis, but elicit phosphorylation of IRF3 and STAT1 in melanoma, hepatoma, and Lewis lung cancer cells (S10); STING agonists do not induce apoptosis in normal T cells (S11); STING-deficient 5TGM1 and A20 cells respond normally to ER stress inducers, and exhibit normal intracellular transport of class I MHC molecules (S12); 5TGM1 myeloma cells grafted subcutaneously in immunodeficient NSG mice do not migrate to bone marrow, peripheral blood and spleens (S13).

Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3′3′-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3′3′-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells. Cancer Res; 76(8); 2137–52. ©2016 AACR.

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th–60th percentile OR = 2.62, P = 2.55 × 10−191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits.Significance:This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637

Legends for Supplementary Figures S1-S13.

TRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.Exome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients' blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics.All 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites.We identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:108 issue:11 pages:2130-2144 ispartof: location:United States status: published

OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. METHODS: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a. ispartof: ANNALS OF NEUROLOGY vol:90 issue:6 pages:887-900 ispartof: location:United States status: published

Cell penetrating peptides (CPPs) hold immense potential for the transport of therapeutic agents to their active targets, due to their low cytotoxicity and high transduction efficiency. Adoption of CPPs as delivery systems, and development of novel peptides has been hampered by the variety of mechanisms and complexity of factors involved in cellular uptake. Quantitatively analyzing these systems is further hindered by the inability to compare data among reports due to varying experimental conditions. In this study we investigate the translocation of seventeen CPPs, representing cationic, amphipathic and hydrophobic physicochemical classes, through a DOPC membrane using molecular dynamics simulations. Free energy profiles for individual peptides inserting into the lipid bilayer were generated giving insight into both the approach and adsorption of different CPPs to cell membranes, and the feasibility of their direct translocation. The control of physical conditions and composition allows objective comparison of different peptides and analyze the effect of sequence on the adsorption and translocation energetics. Our results indicate that positively charged residues impart repulsion, while hydrophobic residues increase bilayer interaction. This study is the first step in fully understanding the processes and energetics involved in the passive translocation mechanisms of CPPs, which usually involve multiple peptides.

Cyclodextrins (CDs) are cyclic oligosaccharides composed of glucopyranose units bonded together to form a truncated cone that can make inclusion complexes with guest molecules. The α, β, and γ-CDs, which respectively comprise six, seven or eight glucopyranose units, are used extensively in pharmaceutical formulations as functional excipients. The cavity sizes of all three natural CDs have been approximated using static structures but a growing consensus is that the CDs are flexible; moreover, the size range of molecules that CDs can accommodate has not been systematically studied. Here the results of molecular dynamics simulations performed using spherical continuum probe particles of different sizes to observe the complex-forming behaviour of CDs are presented. Results revealed that CDs can make dynamic complexes with guest molecules that are larger than their reported cavity sizes. Probe particle with intermediate hydrophilicity (ϵ = 0.2 kcal mol-1), with nominal radius in the range of 0.5 - 1.1 Å (effective radius of 2.61 - 3.41 Å), makes the complexes with α-CD. For β-CD, these values range from 0.9 - 1.9 Å (3.75 - 4.26 Å) and for γ-CD 1.4 - 2.8 Å (3.72 - 5.09 Å) respectively.

Mycoplasma bovis is an economically important disease in dairy and feedlot cattle; the annual loss was calculated as 140 million USD in the USA. Mycoplasma bovis is a common bacterium found in mucous membranes in different animal species, including the respiratory tract, urogenital tract, and gastrointestinal tract. Mycoplasma bovis is a highly contagious disease with an over 70% infection rate. The disease prevalence of M. bovis infection is varied widely and high nasal prevalence was reported among young calves. The mortality were reported in 2-6 weeks of old calves while the peak clinical incidence was at the age of one month. Mycoplasma bovis is colonized in normal respiratory mucosae and tonsils. The clearance of the organism takes for a long period in cattle, it is for a couple of months to a number of years in the mammary gland. Mortality of Mycoplasma bovis infection is varied from herd to herd and location to location. Mycoplasma bovis has been isolated from milk, conjunctiva, semen, and vaginal secretions. The organism is excreted through milk either intermittently or continuously, even in sub-clinical infection. Airborne transmission is the main route of infection in the susceptible bovine host. An animal that sheds M. bovis is the main source of infection within a herd. The bacterium is excreted in colostrum, vaginal secretion and in respiratory secretion of infected cows. The pathogenesis of Mycoplasma bovis has been poorly understood or partly investigated in cattle. Both conventional and molecular methods are there to identify the organism with high analytical sensitivity and specificity. Both 16S rDNA and 23S rDNA targets are used to differentiate Mycoplasma from other possible microorganisms. The immunohistochemistry, in situ hybridization and histopathology, have also been optimized as diagnosis of Mycoplasm bovis infection in cattle. Serological diagnosis is also considered a cost-effective method to identify the seropositive animal. ELISA test has been optimized for field samples of both serum and milk. Three main mechanisms have been able to control or prevent Mycoplasma bovis infection in cattle farming such as sanitary control measures, antimicrobial therapy and vaccination.

Sri Lanka occupies a strategic position in the Indian Ocean, making the surrounding ocean one of the busiest in the region. The lack of fundamental studies has created a void regarding the physical and chemical behaviour of the fouling community. A few studies have been conducted to assess the subtidal biofouling communities and invasive threats in key ports and surrounding coastal waters. This study explores the chemical diversity and environmental resilience of nine marine macrofouling organisms through secondary metabolite-induced impacts on biofilm formation and volatile component analysis. The anti-settlement assay revealed thatSchizoporella errata, Botrylloides violaceus, Callyspongia diffusa, andAcanthella cavernosashowed significant resistance againstEscherichia colisettlement within the first 12 h (OD600< 0.1). The identification of known compounds with a higher degree of antimicrobial activity, such as dodecanoic acid, methyl palmitate, β-caryophyllene and β-asarone, further supports the findings of anti-settlement activity of macrofouling organisms and likely plays a role in environmental resilience.

Composite materials have excellent in-plane mechanical properties. However, they have a low resistance to impact damage. Low-velocity impacts (LVI) produce barely visible impact damage (BVID) on the surface of the laminate but with the potential to produce significant internal damage, such as delamination and matrix cracking. Composite materials' impact damage evaluation still largely relies on experimental results rather than numerical simulations because of the material's multiple damage mechanisms. In an attempt to mitigate cost and time requirements for large-scale experimental studies, there have been significant strides toward enhancing computational simulations to incorporate and predict damage mechanisms observed in composite structures. However, current computational models have limitations in how they capture the impact response and damage spread in laminated composites. The present study compares the predictive capabilities of two commercially available software, ABAQUS and LS-Dyna, to assess their feasibility in capturing the impact response and damage spread on laminated composites. The computational responses will also be compared with the responses obtained experimentally. To the authors' best knowledge, there has not been any report in the literature that compares the predicting capabilities of these two softwares. IM7/977-3 graphite epoxy unidirectional laminates with a 32-ply layup [-45/0/45/90]4S were manufactured according to the ASTM D7136/D7136M-12. Drop weight impact tests were performed in an Instron CEAST 9350. The samples were subjected to LVI energies of 30 J. From each test, the contact force, displacement, velocity, energy and impact duration time were recorded to compare with the predicted responses from the computational models. To evaluate the internal damage area, nondestructive inspection (NDI) was performed on all the samples with X-ray. The objective is to compare the internal damage per layer of each experiment with the internal damage obtained from the ABAQUS and LS-Dyna computational models. For the ABAQUS model, the intralaminar damage (ply failure) model consisted of a continuum damage model, Hashin failure criterion, and a damage evolution model based on equivalent displacement. The interlaminar damage (delamination) was incorporated through a cohesive surface interaction with a bilinear traction-separation law. In the LS-Dyna model, MAT261 Laminated Fracture Daimler-Pinho material card was used as the intralaminar damage model. MAT261 is a continuum damage model with linear softening evolution based on fracture toughness. The interlaminar damage was incorporated through a Tiebreak contact algorithm with a bilinear traction-separation behavior. Preliminary studies have shown that the ABAQUS/Explicit model showed a good correlation with the experimental results in terms of contact force, impact duration time, and displacement. On the other hand, the LS-Dyna MAT261 material model underpredicted the contact force, impact duration time, and displacement. The extreme differences in the LS-Dyna simulation are attributed to MAT261’s algorithm requiring element deletion during the simulation to maintain stability. Therefore, the striker never rebounded and continued penetrating the laminate. Further impact energies will be explored with the ABAQUS computational model. For LS-Dyna, different venues need to be explored in calibration for MAT261’s material model to account for the element deletion’s energy loss or use a different material model.

The use of carbon fiber reinforced polymer (CFRP) composites in modern aircraft has become common as a result of the advantage in the strength to weight ratio the material provides. A limitation to using CFRPs on aircraft stem from their low resistance to low velocity impact (LVI) damage. In these instances, LVI causes barely visible impact damage (BVID) such that the indication of impact on the structure is barely noticeable. These impacts have the potential to generate fiber and matrix failure and cause delamination between lamina which ultimately reduces the compressive load carrying capability of the composite. This study performs an experimental analysis on the knockdown in compressive load carrying capability over a range of impact energies that produce BVID on thick composite panels of 40, 48, and 56 plies.

Progressive Damage and Failure Analysis (PDFA) has been shown to effectively predict damage initiation and propagation of composite materials at the lamina length scale when subjected to various forms of structural loading. The MAT299 composite damage model was developed by Boeing and LST/ANSYS and implemented as a native capability within the LS-DYNA explicit FEA suite under the Impact Damage Analysis Tools for Composite Structures (IDAT) program through the Air Force Research Laboratory in 2020. The material model was thoroughly verified and validated for low velocity impact events under the IDAT program using high fidelity ply-by-ply models. This work addresses the scalability of the MAT299 material model by investigating the effectiveness of thick shell elements implemented in an equivalent single layer scheme for low velocity impact of composite structures. Demonstrating the predictive capability of MAT299 with the thick shell implementation is a significant step toward applying PDFA methods at structurally relevant length scales.

TRIT1 defect is a rare, autosomal-recessive disorder of transcription, initially described as a condition with developmental delay, myoclonic seizures, and abnormal mitochondrial function. Currently, only 13 patients have been reported. We reviewed the genetic, clinical, and metabolic aspects of the disease in all known patients, including two novel, unrelated TRIT1 cases with abnormalities in oxidative phosphorylation complexes I and IV in fibroblasts. Taken together the features of all 15 patients, TRIT1 defect could be identified as a potentially recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and variable microcephaly, with normal lactate levels. Half of the patients had oxidative phosphorylation complex measurements and had multiple complex abnormalities.

This study endeavours to investigate empirically how Information and Communications Technology (ICT) usage affects the bounded rationality and business performance of Small and Medium Enterprises (SMEs) in Sri Lanka. The data collection has been done with 400 owners of SMEs in Sri Lanka by employing telephone and face to face interviews using a structured questionnaire. The Partial Least Squares-Structural Equation Modelling (PLS-SEM) was utilized to analyse the data. The empirical results discovered that the different dimensions of ICT usage such as infrastructure, applications, policy, human resources, and mobile technology have a negative impact on bounded rationality and positive effects on the business performance of SMEs in Sri Lanka. Thus, the study recognizes that several dimensions of ICT usage make proper information flow to pull out information asymmetry and reduce the bounded rationality of SMEs, thereby increasing the business performance of SMEs in Sri Lanka.

In this study, we have employed Digital Light Processing (DLP) printing technology for the fabrication of solid microneedle (MN) arrays. Several arrays with various geometries, such as cones, three-sided pyramids and four-sided pyramids, with different height to aspect ratios of 1:1, 2:1 and 3:1, were printed. Post-processing curing optimizations showed that optimal mechanical properties of the photocurable resin were obtained at 40 °C and 60 min. Ex vivo skin studies showed that piercing forces, penetration depth and penetration width were affected by the MN geometry and height to aspect ratio. Cone-shaped MNs required lower applied forces to penetrate skin and showed higher penetration depth with increasing height to aspect ratio, followed by three-sided and four-sided printed arrays. Cytotoxicity studies presented 84% cell viability of human fibroblasts after 2.5 h, suggesting the very good biocompatibility of the photocurable resin. Overall, DLP demonstrated excellent printing capacity and high resolution for a variety of MN designs.