The naked truth: Sphynx and Devon Rex cat breed mutations in KRT71

Hair is a unique structure, characteristic of mammals, controlling body homeostasis, as well as cell and tissue integration. Previous studies in dog, mouse, and rat have identified polymorphisms in Keratin 71 (KRT71) as responsible for the curly/wavy phenotypes. The coding sequence and the 3′ UTR of KRT71 were directly sequenced in randomly bred and pedigreed domestic cats with different pelage mutations, including hairless varieties. A SNP altering a splice site was identified in the Sphynx breed and suggested to be the hairless (hr) allele, and a complex sequence alteration, also causing a splice variation, was identified in the Devon Rex breed and suggested to be the curly (re) allele. The polymorphisms were genotyped in approximately 200 cats. All the Devon Rex were homozygous for the complex alterations and most of the Sphynx were either homozygous for the hr allele or compound heterozygotes with the Devon-associated re allele, suggesting that the phenotypes are a result of the identified SNPs. Two Sphynx carrying the proposed hr mutation did not carry the Devon-associated alteration. No other causative mutations for eight different rexoid and hairless cat phenotypes were identified. The allelic series KRT71 ⁺  > KRT71 ^hr  > KRT71 ^re is suggested.     

A novel small-molecule inhibitor of IL-6 signalling

A small library of pyrrolidinesulphonylaryl molecules has been synthesized via an efficient 4-step route, and members evaluated for their ability to inhibit IL-6 signalling. One molecule (6a) was found to have promising activity against IL-6/STAT3 signalling at the low micromolar level, and to selectively inhibit phosphorylation of STAT3 (but not STAT1) in IL-6 stimulated MDA-MB-231 breast cancer and HeLa cell lines. It was also selectively cytostatic in MDA-MB-231 (STAT3-dependent) versus A4 (STAT3-null) cells suggesting STAT3-specific inhibitory properties.     

Boron,a Trace Mineral,Alleviates Gentamicin-Induced Nephrotoxicity in Rats

Biological Trace Element Research - The present study was considered to assess the protective effects of boron (B) on gentamicin-induced oxidative stress, proinflammatory cytokines, and...     

In vitro effects of standard antioxidants on lactoperoxidase enzyme–A molecular docking approach

Lactoperoxidase (LPO), an antioxidant enzyme, is a natural antimicrobial system that eliminates the harmful effects of microorganisms in milk. It has a wide range of applications and is also preferred in cosmetic and clinical applications, as well as used in foods. The use of antioxidants is well recognized in the food and feed industries to improve the shelf life of products. This study aimed to determine the in vitro inhibition effects of Trolox, α‐tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate, which are commonly used as antioxidants in food and pharmaceutical products. For this purpose, LPO was first purified in a single step using sepharose‐4B‐l ‐tyrosine‐sulfanilamide affinity gel chromatography. Also, some inhibition parameters, including half‐maximal inhibitory concentration (IC₅₀), K_i values, and inhibition types, were calculated for each antioxidant molecule. The IC₅₀ values of these molecules, which exhibited competitive inhibition, varied between 377.7 and 3397.8 nM. Molecular docking studies were also performed for all compounds. According to the binding scores, α‐tocopherol was shown to exhibit the most effective inhibitor property (IC₅₀: 377.7 nM and K_i: 635.8 ± 16.8 nM) among the standard antioxidants used in this study. Inhibiting the LPO activity by standard antioxidants results in the weakening of the immune system during lactation, which is important for metabolism.     

Isolation and characterization of the chemical constituents from Plumeria rubra

Rubranonoside (=7-O-α-l-rhamnopyranosyl-4′-O-β-d-glucopyranosylnaringenin; (1), a new flavanone glycoside, rubranin (=(2S,3S,4R)-2-{[(2R,16E)-2-hydroxyhexaeico-16-en]amino}octadecane-1,3,4-triol-1-O-β-d-glucopyranoside; (2), a new sphingolipid, rubradoid (plumieridine-1-O-β-d-galactopyranoside; (3), a new iridoid galactoside, rubrajaleelol (4) and rubrajaleelic acid (5), two new nor-terpenoids together with known iridoids: 1-α-plumieride (6), plumieride p-Z-coumarate (7) and plumieride-p-E-coumarate (8) have been isolated from the EtOAc-soluble fraction of the MeOH extract of Plumeria rubra. Their structures were assigned from ¹H, ¹³C NMR spectra and 2D NMR analyses (COSY, NOESY, HMQC and HMBC experiments) in combination with HRMS experiments and comparison with literature data of related compounds. All the isolates (1–8) were tested for their antioxidant, antiurease, cytotoxic and phytotoxic activities and were found almost inactive.     

The Association between Histamine 2 Receptor Antagonist Use and Clostridium difficile Infection: A Systematic Review and Meta-analysis

Background

Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI.

Purpose

We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H₂RAs) and CDI.

Data source

We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H₂RAs and CDI.

Study selection

Two authors independently reviewed the studies for eligibility.

Data extraction

Data about studies characteristics, adjusted effect estimates and quality were extracted.

Data synthesis

Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H₂RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22–1.7), I² = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15–1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H₂RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097).

Conclusion

In this rigorous systematic review and meta-analysis, we observed an association between H₂RAs and CDI. The absolute risk of CDI associated with H₂RAs is highest in hospitalized patients receiving antibiotics.     

Oblique Bile Duct Predisposes to the Recurrence of Bile Duct Stones

Background and Study Aims

Bile stones represent a highly prevalent condition and abnormalities of the biliary tree predispose to stone recurrence due to development of biliary stasis. In our study, we assessed the importance of an altered bile duct course for stone formation.

Patients and Methods

1,307 patients with choledocholithiasis in the absence of any associated hepatobiliary disease who underwent endoscopic retrograde cholangiopancreatography (ERCP) between 2002 and 2009 were analysed. The angle enclosed between the horizontal portion of the common bile duct (CBD) and the horizontal plane was measured (angle α). Oblique common bile duct (OCBD) was defined as a CBD with angle α<45°.

Results

103 patients (7.9%) were found to harbour OCBD and these were compared to 104 randomly selected control subjects. Compared to controls, OCBD patients were (i) significantly older (72±13 vs. 67±13, p<0.00001); (ii) more frequently underwent a cholecystectomy (p = 0.02) and biliary surgery (p = 0.003) prior to the diagnosis and (iii) more often developed chronic pancreatitis (p = 0.04) as well as biliary fistulae (p = 0.03). Prior to and after ERCP, OCBD subjects displayed significantly elevated cholestatic parameters and angle α negatively correlated with common bile duct diameter (r = -0.29, p = 0.003). OCBD subjects more often required multiple back-to-back ERCP sessions to remove bile stones (p = 0.005) as well as more ERCPs later on due to recurrent stone formation (p<0.05).

Conclusion

OCBD defines a novel variant of the biliary tree, which is associated with chronic cholestasis, hampers an efficient stone removal and predisposes to recurrence of bile duct stones.     

Knockdown of CDKN1C (p57kip2) and PHLDA2 Results in Developmental Changes in Bovine Pre-implantation Embryos

Imprinted genes have been implicated in early embryonic, placental, and neonatal development and alterations in expression levels of these genes can lead to growth abnormalities and embryonic lethality. However, little is known about the functions of bovine imprinted genes during the pre-implantation period. Therefore, the objective of this study was to assess the influence of altered expression of imprinted genes on developmental progress of embryos using small interfering RNA (siRNA). Expression levels of 18 imprinted genes (MAGEL2, UBE3A, IGF2R, NAP1L5, TSSC4, PEG3, NDN, CDKN1C, PHLDA2, MKRN3, USP29, NNAT, PEG10, RTL1, IGF2, H19, MIM1, and XIST) were compared between embryos reaching the blastocyst stage and growth-arrested embryos (degenerates) using quantitative real-time PCR (qRT-PCR). Ten genes were found to be differentially expressed between blastocysts and degenerates. The CDKN1C gene showed the highest upregulation in blastocysts whereas PHLDA2 was highly expressed in degenerates. To assess whether the observed differential gene expression was causative or resultant of embryo degeneration, these genes were selected for functional analysis using siRNA. Injection of siRNA specific to PHLDA2 into one-cell zygotes resulted in a substantial increase in blastocyst development, whereas injection of CDKN1C-specific siRNA resulted in a 45% reduction (P = 0.0006) in blastocyst development. RNA-Seq analysis of CDKN1C-siRNA-injected vs. non-injected embryos revealed 51 differentially expressed genes with functions in apoptosis, lipid metabolism, differentiation, and cell cycle regulation. Gene ontology analysis revealed nine pathways related to cell signaling, metabolism, and nucleic acid processing. Overall, our results show that proper expression levels of the imprinted genes CDKN1C and PHLDA2 are critical for embryo development, which suggests that these genes can be used as markers for normal blastocyst formation.     

New natural cholinesterase inhibiting and calcium channel blocking quinoline alkaloids

During this study, one new coumarin; 7-O-β-D-glucopyranoside-2H-1-benzopyran-2-one (1) and three quinoline alkaloids; 3-hydroxy, 2, 2, 6-trimethyl–3, 4, 5, 6-tetrahydro-2H-pyrano[3,2-c] quinoline 5-one (2), ribalinine (3) and methyl isoplatydesmine (4) were isolated from the aerial parts of Skimmia laureola and their structures established by spectroscopic studies. Compounds 2-4 were found to be linear mixed type inhibitors of acetylcholinesterase (K_i = 110.0, 30.0 and 30.0 μM, respectively). Compounds 2 and 3 were also found to be linear mixed type inhibitors of butyrylcholinesterase, while compound 4 was a noncompetitive inhibitor of the enzyme (K_i = 90.0, 70.0 and 19.0 μM, respectively). The inhibition of acetyl- and butyryl-cholinesterase enzymes persists as the most promising therapeutic strategy for activating the impaired cholinergic functions in Alzheimer's disease and related dementias.

Compound 4 also showed dose-dependent spasmolytic activity in the isolated rabbit jejunum intestinal preparation by relaxing the spontaneous (EC₅₀ = 0.1 mg/mL) and K⁺-induced contractions (EC₅₀ = 0.4 mg/mL), suggesting that the spasmolytic effect of compound 4 is mediated through the blockade of voltage-dependent Ca^{2 +} channels.