Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes

Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting

DANGO (Doings and Goings On) - Vol. 22 | Issue 11

ACU Department of Engineering and Physics Summer Research Newsletterhttps://digitalcommons.acu.edu/dango/1010/thumbnail.jp

Serum albumin and muscle strength: a longitudinal study in older men and women

OBJECTIVES: To examine whether low serum albumin is associated with low muscle strength and future decline in muscle strength in community-dwelling older men and women. DESIGN: Population-based cohort study. SETTING: The Longitudinal Aging Study Amsterdam. PARTICIPANTS: Six hundred seventy-six women and 644 men aged 65 to 88. MEASUREMENTS: Serum albumin was determined at baseline. Muscle strength was assessed using grip strength at baseline, after 3 (n = 1,009), and 6 (n = 741) years. The outcomes were continuous baseline muscle strength, 3- and 6-year change in muscle strength, and a dichotomous indicator for substantial decline (a decrease if ≥1 standard deviations for women = 11 kg, for men = 12 kg) in muscle strength. RESULTS: Mean serum albumin concentration ± standard deviation was 45.0 ± 3.3 g/L for women and 45.2 ± 3.2 g/L for men. At baseline, adjusting for age, lifestyle factors, and chronic conditions, lower serum albumin was cross-sectionally associated with weaker muscle strength (P < .001) in women and men. After 3 years of follow-up, mean decline in muscle strength was -5.6 ± 10.9 kg in women and -9.6 ± 11.9 kg in men. After adjustment for potential confounders, lower serum albumin was associated with muscle strength decline over 3 years (P < .01) in women and men (β = 0.57, standard error (SE) = 0.18; β = 0.37, SE = 0.16, respectively). Lower serum albumin was also associated with substantial decline in muscle strength in women (per unit albumin (g/L) adjusted odds ratio (OR) = 1.14, one-sided 95% confidence limit (CL) = 1.07) and men (per unit albumin (g/L) adjusted OR = 1.14, 95% CL = 1.08). Similar but slightly weaker associations were found between serum albumin and 6-year change in muscle strength (P < .05). CONCLUSION: These results suggest that low serum albumin, even within the normal range, is independently associated with weaker muscle strength and future decline in muscle strength in older women and men. © 2005 by the American Geriatrics Society

Murine model for Fusarium oxysporum invasive fusariosis reveals organ-specific structures for dissemination and long-term persistence

Peer reviewedPublisher PD

A molten salt test loop for component and instrumentation testing

Molten salt is an effective coolant for a wide range of applications, including nuclear reactors, concentrated solar power, and other high temperature industrial heat transfer processes. The technical readiness level of components and instrumentation for high-temperature molten salt applications needs improvement for molten salt to be more widely adopted. A molten salt test loop was designed, built, and commissioned as a test bed to address these issues. The molten salt test loop at Abilene Christian University was built out of 316 stainless steel with a forced flow centrifugal-type pump, and was instrumented for remote operation. A low-temperature molten nitrate salt was used in this system, which was designed to operate at temperatures up to 300 ◦C and flow rates up to 90 liters per minute. This paper describes the loop design, computational fluid dynamics modeling, construction, and commissioning details. An outline of the data acquisition and control systems is presented. Salt samples were taken before and after introduction into the loop, and melting points were measured both before and after salt circulation. Performance of the system is discussed as well as improvements required for higher temperature loops envisioned for the future

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper

BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5\u2009ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with 65 5 CTCs were classified as Stage IVaggressive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggressive (36.3 months vs. 16.0 months, P\u2009<\u20090.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggressive, p\u2009<\u20090.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P\u2009<\u20090.0001), HER2-positive (36.7 months vs. 20.4 months, P\u2009<\u20090.0001), and triple negative (23.8 months vs. 9.0 months, P\u2009<\u20090.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggressive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials

A miRNA Signature of Prion Induced Neurodegeneration

MicroRNAs (miRNAs) are small, non-coding RNA molecules which are emerging as key regulators of numerous cellular processes. Compelling evidence links miRNAs to the control of neuronal development and differentiation, however, little is known about their role in neurodegeneration. We used microarrays and RT-PCR to profile miRNA expression changes in the brains of mice infected with mouse-adapted scrapie. We determined 15 miRNAs were de-regulated during the disease processes; miR-342-3p, miR-320, let-7b, miR-328, miR-128, miR-139-5p and miR-146a were over 2.5 fold up-regulated and miR-338-3p and miR-337-3p over 2.5 fold down-regulated. Only one of these miRNAs, miR-128, has previously been shown to be de-regulated in neurodegenerative disease. De-regulation of a unique subset of miRNAs suggests a conserved, disease-specific pattern of differentially expressed miRNAs is associated with prion–induced neurodegeneration. Computational analysis predicted numerous potential gene targets of these miRNAs, including 119 genes previously determined to be also de-regulated in mouse scrapie. We used a co-ordinated approach to integrate miRNA and mRNA profiling, bioinformatic predictions and biochemical validation to determine miRNA regulated processes and genes potentially involved in disease progression. In particular, a correlation between miRNA expression and putative gene targets involved in intracellular protein-degradation pathways and signaling pathways related to cell death, synapse function and neurogenesis was identified

Etoricoxib - preemptive and postoperative analgesia (EPPA) in patients with laparotomy or thoracotomy - design and protocols

<p>Abstract</p> <p>Background and Objective</p> <p>Our objective was to report on the design and essentials of the <it>Etoricoxib </it>protocol<it>- Preemptive and Postoperative Analgesia (EPPA) </it>Trial, investigating whether preemptive analgesia with cox-2 inhibitors is more efficacious than placebo in patients who receive either laparotomy or thoracotomy.</p> <p>Design and Methods</p> <p>The study is a 2 × 2 factorial armed, double blinded, bicentric, randomised placebo-controlled trial comparing (a) etoricoxib and (b) placebo in a pre- and postoperative setting. The total observation period is 6 months. According to a power analysis, 120 patients scheduled for abdominal or thoracic surgery will randomly be allocated to either the preemptive or the postoperative treatment group. These two groups are each divided into two arms. Preemptive group patients receive etoricoxib prior to surgery and either etoricoxib again or placebo postoperatively. Postoperative group patients receive placebo prior to surgery and either placebo again or etoricoxib after surgery (2 × 2 factorial study design). The Main Outcome Measure is the cumulative use of morphine within the first 48 hours after surgery (measured by patient controlled analgesia PCA). Secondary outcome parameters include a broad range of tests including sensoric perception and genetic polymorphisms.</p> <p>Discussion</p> <p>The results of this study will provide information on the analgesic effectiveness of etoricoxib in preemptive analgesia and will give hints on possible preventive effects of persistent pain.</p> <p>Trial registration</p> <p>NCT00716833</p