Biallelic Variants in Seven Different Genes Associated with Clinically Suspected Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. The primary clinical and diagnostic features include six different hallmarks, such as rod-cone dystrophy, learning difficulties, renal abnormalities, male hypogonadism, post-axial polydactyly, and obesity. Here, we report nine consanguineous families and a non-consanguineous family with several affected individuals presenting typical clinical features of BBS. In the present study, 10 BBS Pakistani families were subjected to whole exome sequencing (WES), which revealed novel/recurrent gene variants, including a homozygous nonsense mutation (c.94C>T; p.Gln32Ter) in the IFT27 (NM_006860.5) gene in family A, a homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B, a homozygous nonsense variant (c.720C>A; p.Cys240Ter) in the WDPCP (NM_015910.7) in family C, a homozygous nonsense variant (c.505A>T; p.Lys169Ter) in the LZTFL1 (NM_020347.4) in family D, pathogenic homozygous 1 bp deletion (c.775delA; p.Thr259Leufs*21) in the MKKS/BBS5 (NM_170784.3) gene in family E, a pathogenic homozygous missense variant (c.1339G>A; p.Ala447Thr) in BBS1 (NM_024649.4) in families F and G, a pathogenic homozygous donor splice site variant (c.951+1G>A; p?) in BBS1 (NM_024649.4) in family H, a pathogenic bi-allelic nonsense variant in MKKS (NM_170784.3) (c.119C>G; p.Ser40*) in family I, and homozygous pathogenic frameshift variants (c.196delA; p.Arg66Glufs*12) in BBS5 (NM_152384.3) in family J. Our findings extend the mutation and phenotypic spectrum of four different types of ciliopathies causing BBS and also support the importance of these genes in the development of multi-systemic human genetic disorders

Evaluation of gut modulatory and bronchodilator activities of Amaranthus spinosus Linn.

Background The aqueous-methanolic extract of Amaranthus spinosus (A. spinosus Linn.,) whole plant, was studied for its laxative, spasmolytic and bronchodilator activities to validate some of its medicinal uses. Methods The crude extract of A. spinosus was studied in-vivo for bronchodilator and laxative activities and in-vitro using isolated tissue preparations which were mounted in tissue baths assembly containing physiological salt solutions, maintained at 37°C and aerated with carbogen, to assess the spasmolytic effect and to find out the possible underlying mechanisms. Results In the in-vivo experiments in mice, the administration of A. spinosus increased fecal output at doses of 100 and 300 mg/kg showing laxative activity. It also inhibited carbachol-induced bronchospasm in anesthetized rats at 1, 3, 10 and 30 mg/kg indicative of bronchodilator activity. When tested on isolated gut preparations, the plant extract showed a concentration-dependent (0.01-10.0 mg/ml) spasmogenic effect in spontaneously contracting rabbit jejunum and guinea-pig ileum. The spasmogenic effect was partially blocked in tissues pretreated with atropine (0.1 μM). When tested on K+ (80 mM)-induced sustained contractions in isolated rabbit jejunum, the plant extract caused complete relaxation and also produced a shift in the Ca++ concentration-response curves (CRCs) towards right, similar to diltiazem. In rabbit trachea, the plant extract completely inhibited K+ (80 mM) and carbachol (CCh, 1 μM)-induced contractions at 1 mg/ml but pretreatment of tissue with propranolol (1 μM), caused around 10 fold shift in the inhibitory CRCs of the plant extract constructed against CCh-induced contraction. The plant extract (up to 0.3 mg/ml) also increased both force and rate of spontaneous contractions of isolated guinea-pig atria, followed by relaxation at higher concentration (1.0-5.0 mg/ml). The cardio-stimulant effect was abolished in the presence of propranolol, similar to that of isoprenaline. Activity-directed fractionation revealed that the spasmolytic component(s) was separated in the organic fraction, whereas the spasmogenic component was concentrated in the aqueous fraction. Conclusion These results indicate that A. spinosus possesses laxative activity partially mediated through cholinergic action. The spasmolytic effect was mediated through calcium channel blocking (CCB), while bronchodilator activity through a combination of β-adrenergic and CCB pathways, which may explain the traditional uses of A. spinosus in gut and airways disorders

Engineering and construction expertise transfusion at the U.S. Army Corps of Engineers: A KM case study

Knowledge Management (KM) is the collection and transfusion of the organization's critical information, skills, experience, and identity, held by senior individuals, to successor generations for action. A great deal of the technical expertise in the U.S. Army Corps of Engineers (USACE) has been departing through the retirement of the most experienced employees over the last several years and continues to do so today. Without robust technical competency, an organization as large as USACE cannot continue to perform design and construction functions effectively. This research study defines KM, reviews best practices from industry and assesses how USACE is performing at the working level. The research data obtained identified key needs and subsequent recommendations for additional efforts or improvements to existing initiatives. Data was collected through interviews of eight managers at a USACE District Office to make assessments and determine steps to be taken to ensure critical expertise is retained and mission execution continues effectively. This study found that at the working level the current KM program is primarily based on mentoring and informal communities of practice, and not in top-down information systems based approaches. USACE would benefit greatly from reconciling different approaches, eliminating redundant items, and a coordinated approach at all levels of leadership to champion processes that work