ToxoDB (http://ToxoDB.org) is a genome and functional genomic database for the protozoan parasite Toxoplasma gondii. It incorporates the sequence and annotation of the T. gondii ME49 strain, as well ...as genome sequences for the GT1, VEG and RH (Chr Ia, Chr Ib) strains. Sequence information is integrated with various other genomic-scale data, including community annotation, ESTs, gene expression and proteomics data. ToxoDB has matured significantly since its initial release. Here we outline the numerous updates with respect to the data and increased functionality available on the website.
Offering innovative ideas that explore how strategy and management methodology can be developed, Methods to Improve Our Field considers approaches that range from the re-imagining of secondary data ...in the digital age and Interpretive Phenomenological Analysis (IPA) to Machine Learning and Artificial Intelligence.
Research Methodology in Strategy and Managementadvances understanding of the methods used to study organizations - including managers, strategies, and how firms succeed.
Matings among different species of animals or plants often result in sterile or lethal hybrids. Identifying the evolutionary forces that create hybrid incompatibility alleles is fundamental to ...understanding the process of speciation, but very few such alleles have been identified, particularly in model organisms that are amenable to experimental manipulation. We report here the cloning of the first, to our knowledge, Drosophila melanogaster gene involved in hybrid incompatibilities, Hybrid male rescue (Hmr). Hmr causes lethality and female sterility in hybrids among D. melanogaster and its sibling species. We have found that Hmr encodes a protein with homology to a family of MYB-related DNA-binding transcriptional regulators. The HMR protein has evolved both amino acid substitutions and insertions and deletions at an extraordinarily high rate between D. melanogaster and its sibling species, including in its predicted DNA-binding domain. Our results suggest that hybrid lethality may result from disruptions in gene regulation, and we also propose that rapid evolution may be a hallmark of speciation genes in general.
Hospitalized infants have the highest rates of invasive Staphylococcus aureus disease of any population and infection control strategies such as decolonization have been insufficient. For decades, ...researchers began studying the microbiome in search of new prevention strategies. The resident microbiota was found to be closely associated with susceptibility and at times, resistance to S. aureus colonization. The evolution of nucleic acid based techniques has enhanced our understanding of the complex relationship between the nasal microbiota and S. aureus colonization. We review what is known about bacterial communities in the nasal cavity of infants and discuss how future microbiome studies may help identify novel interventions to protect high-risk infants from S. aureus disease.
The diagnosis of amyloidosis is important for early intervention, disease monitoring, and prevention of complications and progression. Carpal tunnel syndrome (CTS) and trigger digit (TD) are two ...common conditions associated with early disease. The purpose of this study was to define disease prevalence among patients with bilateral CTS and multiple TDs and assess for an increased rate of diagnosis in the presence of both.
Men older than 50 years and women older than 60 years of age diagnosed with bilateral CTS, multiple TDs, or a combination of the 2 were prospectively enrolled in our study. Tenosynovial biopsy samples taken at the time of surgery were tested for the presence of amyloid using Congo red staining. Demographic and medical covariates were also collected and analyzed for differences between amyloid-positive and -negative patients.
Fifty-six patients were enrolled in the study, and nine patients tested positive for amyloid deposition. The demographics and medical comorbidities were similar between amyloid-positive and -negative patients. Thirty patients with bilateral CTS were enrolled, and four tested positive for amyloid. For patients with multiple TDs, a total of 17 patients were enrolled, and 4 tested positive for amyloid. Among patients with multiple TDs, only men tested positive for amyloid and were, on average, younger than those who tested negative (61 and 73 years, respectively). Patients presenting with a combination of CTS and TD did not exhibit increased amyloid discovery.
Hand surgeons should consider tenosynovial biopsy in men older than 50 years and women older than 60 years presenting with either bilateral CTS or multiple TDs.
Prognostic IV.
Anti-drug antibody (ADA) responses are a concern for both drug efficacy and safety, and high drug concentrations in patient samples may inhibit ADA assays. We evaluated strategies to improve drug ...tolerance of surface plasmon resonance (SPR) assays that detect ADAs against a bispecific Adnectin drug molecule that consists of an anti-VEGFR2 domain linked to an anti-IGF-1R domain (V-I-Adnectin). Samples containing ADAs against V-I-Adnectin and various drug concentrations were tested in the presence of 1M guanidine hydrochloride (Gdn), at pH values ranging from 4.5 to 7.4 and temperatures of up to 37°C. Temperature had a negligible effect in weakening the affinity of interaction of monoclonal antibodies with polyethylene glycol(PEG)–V-I-Adnectin and did not increase drug tolerance of the ADA assay. Low pH increased drug tolerance of the assay relative to pH 7.4 but caused nonspecific binding of the drug during competition experiments. The chaotropic agent Gdn lowered the affinity of interaction between an anti-V-Adnectin monoclonal antibody and the drug (from KD=0.93nM to KD=348nM). That decrease in the affinity of drug–ADA interaction correlated with an increase of assay drug tolerance. Conditions that lower drug–ADA interaction affinity could also be used to develop drug-tolerant SPR assays for other systems.
Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse ...drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints. Our analyses replicate 75% of known GWAS associations (P < 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.
The authors evaluated the relation between consumption of alcoholic beverages and incidence of coronary heart disease in White and African-American participants in the Atherosclerosis Risk in ...Communities Study. The average duration of follow-up was 9.8 years between 1987 and 1998. The association was analyzed by means of Cox proportional hazards regression models. The authors found a positive association between ethanol consumption and incident coronary heart disease for Black men (for a 13-g/day increment in ethanol consumption, adjusted hazard ratio (HR) = 1.13, 95% confidence interval (CI): 1.01, 1.28) and an inverse association for White men (HR = 0.88, 95% CI: 0.79, 0.99). There was an inverse association of coronary heart disease with rare drinking (HR = 0.47, 95% CI: 0.28, 0.80) and with consumption of > or =70 g of ethanol per week (HR = 0.49, 95% CI: 0.24, 0.98) in White women and with consumption of > or =210 g/week (HR = 0.56, 95% CI: 0.33, 0.95) in White men. In Black men, the association was positive for consumption of 140-<210 g/week (HR = 2.61, 95% CI: 1.11, 6.17). The contrasting findings in Whites and Black men in this cohort raise the question of whether the cardioprotective effect of alcohol is real or may be confounded by lifestyle characteristics of drinkers.
Objectives/Hypothesis
The purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis ...(RRP), and to provide preliminary guidance surrounding the use of this treatment modality.
Study Design
Delphi method‐based survey series.
Methods
A multidisciplinary, multi‐institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work‐up.
Results
The international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18).
Conclusion
This consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best‐practice applications of systemic bevacizumab for patients with early‐onset or less‐severe disease phenotypes.
Level of Evidence
5 Laryngoscope, 131:E1941–E1949, 2021
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