The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits

A carboxypeptidase E (CPE) knockout ( KO) mouse was generated by deletion of exons 4 and 5 from the CPE gene, and its phenotype was characterized. KO mice became obese by 10 - 12 wk of age and reached 60 - 80 g by 40 wk. At this age, body fat content was more than double that in the wild-type (WT) controls. The null animals consumed more food overall, were less physically active during the light phase of the light-dark cycle, and burned fewer calories as fat than WT littermates. Fasting levels of glucose and insulin-like immunoreactivity in plasma were elevated in both male and female KO mice at approximately 20 wk; males recovered fully and females partially from this state by 32 wk. At this time, insulin-like immunoreactivity in the plasma, identified as proinsulin, was 50 - 100 times higher than that of the WT animals. The KO mice showed impaired glucose clearance and were insulin resistant. High levels of leptin and no circulating fully processed cocaine- and amphetamine-related transcript, a peptide that is responsive to leptin-induced feedback inhibition of feeding, were found in serum. The KO mice were subfertile and showed deficits in GnRH processing in the hypothalamus. Behavioral analyses revealed that KO animals showed diminished reactivity to stimuli and had reduced muscle strength and coordination, as well as visual placing and toe-pinch reflexes. These data demonstrate that CPE KO mice display a wide range of neural and endocrine abnormalities and suggest that CPE may have additional physiological roles beyond those ascribed to peptide processing and sorting of prohormones in cells

Investigating causal relationships between obesity and skin barrier function in a multi-ethnic Asian general population cohort

BACKGROUND: Skin diseases impact significantly on the quality of life and psychology of patients. Obesity has been observed as a risk factor for skin diseases. Skin epidermal barrier dysfunctions are typical manifestations across several dermatological disturbances. OBJECTIVES: We aim to establish the association between obesity and skin physiology measurements and investigate whether obesity may play a possible causal role on skin barrier dysfunction. METHODS: We investigated the relationship of obesity with skin physiology measurements, namely transepidermal water loss (TEWL), skin surface moisture and skin pH in an Asian population cohort (n = 9990). To assess for a possible causal association between body mass index (BMI) and skin physiology measurements, we performed Mendelian Randomization (MR), along with subsequent additional analyses to assess the potential causal impact of known socioeconomic and comorbidities of obesity on TEWL. RESULTS: Every 1 kg/m2 increase in BMI was associated with a 0.221% (95%CI: 0.144-0.298) increase in TEWL (P = 2.82E-08), a 0.336% (95%CI: 0.148-0.524) decrease in skin moisture (P = 4.66E-04) and a 0.184% (95%CI: 0.144-0.224) decrease in pH (P = 1.36E-19), adjusting for age, gender, and ethnicity. Relationships for both TEWL and pH with BMI remained strong (Beta 0.354; 95%CI: 0.189-0.520 and Beta -0.170; 95%CI: -0.253 to -0.087, respectively) even after adjusting for known confounders, with MR experiments further supporting BMI's possible causal relationship with TEWL. Based on additional MR performed, none of the socioeconomic and comorbidities of obesity investigated are likely to have possible causal relationships with TEWL. CONCLUSION: We establish strong association of BMI with TEWL and skin pH, with MR results suggestive of a possible causal relationship of obesity with TEWL. It emphasizes the potential impact of obesity on skin barrier function and therefore opportunity for primary prevention

The South Asian genome

Genetics of disease Microarrays Variant genotypes Population genetics Sequence alignment AllelesThe genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.Whole genome sequencing to discover genetic variants underlying type-2 diabetes, coronary heart disease and related phenotypes amongst Indian Asians. Imperial College Healthcare NHS Trust cBRC 2011-13 (JS Kooner [PI], JC Chambers)

Systematic evaluation of library preparation methods and sequencing platforms for high-throughput whole genome bisulfite sequencing

Whole genome bisulfte sequencing (WGBS), with its ability to interrogate methylation status at single CpG site resolution epigenome-wide, is a powerful technique for use in molecular experiments. Here, we aim to advance strategies for accurate and efcient WGBS for application in future largescale epidemiological studies. We systematically compared the performance of three WGBS library preparation methods with low DNA input requirement (Swift Biosciences Accel-NGS, Illumina TruSeq and QIAGEN QIAseq) on two state-of-the-art sequencing platforms (Illumina NovaSeq and HiSeq X), and also assessed concordance between data generated by WGBS and methylation arrays. Swift achieved the highest proportion of CpG sites assayed and efective coverage at 26x(P<0.001). TruSeq sufered from the highest proportion of PCR duplicates, while QIAseq failed to deliver across all quality metrics. There was little diference in performance between NovaSeq and HiSeq X, with the exception of higher read duplication rate on the NovaSeq (P<0.05), likely attributable to the higher cluster densities on its fow cells. Systematic biases exist between WGBS and methylation arrays, with lower precision observed for WGBS across the range of depths investigated. To achieve a level of precision broadly comparable to the methylation array, a minimum coverage of 100x is recommended

Higher media multi-tasking activity is associated with smaller gray-matter density in the anterior cingulate cortex

Media multitasking, or the concurrent consumption of multiple media forms, is increasingly prevalent in today’s society and has been associated with negative psychosocial and cognitive impacts. Individuals who engage in heavier media-multitasking are found to perform worse on cognitive control tasks and exhibit more socio-emotional difficulties. However, the neural processes associated with media multi-tasking remain unexplored. The present study investigated relationships between media multitasking activity and brain structure. Research has demonstrated that brain structure can be altered upon prolonged exposure to novel environments and experience. Thus, we expected differential engagements in media multitasking to correlate with brain structure variability. This was confirmed via Voxel-Based Morphometry (VBM) analyses: Individuals with higher Media Multitasking Index (MMI) scores had smaller gray matter density in the anterior cingulate cortex (ACC). Functional connectivity between this ACC region and the precuneus was negatively associated with MMI. Our findings suggest a possible structural correlate for the observed decreased cognitive control performance and socio-emotional regulation in heavy media-multitaskers. While the cross-sectional nature of our study does not allow us to specify the direction of causality, our results brought to light novel associations between individual media multitasking behaviors and ACC structure differences

Arthroscopic evaluation of the ACL double bundle structure

In order to describe the arthroscopic presence of the double bundle structure and to evaluate the value of different portals in knee arthroscopy, we assessed the AM and PL bundle anatomy. We prospectively examined the knees of 60 patients undergoing arthroscopic surgery for pathology unrelated to the ACL. Arthroscopy was performed in a two portal technique using an anterolateral (ALP) and an anteromedial (AMP) portal. With the arthroscope in the ALP, we could distinguish an AM and PL bundle in 28%. Switching the arthroscope to the AMP, differentiation of the bundles was possible in 67%. In all remaining cases visualization of the PL bundle was possible after retraction of the AM bundle. Use of AMP increased visualization of the PL bundle. It seems reasonable to perform arthroscopy for ACL reconstruction with the arthroscope in the AMP and to establish an additional medial working portal to increase the visualization of the femoral ACL insertion sites for optimal femoral tunnel placement

Structure of hadron resonances with a nearby zero of the amplitude

We discuss the relation between the analytic structure of the scattering amplitude and the origin of an eigenstate represented by a pole of the amplitude.If the eigenstate is not dynamically generated by the interaction in the channel of interest, the residue of the pole vanishes in the zero coupling limit. Based on the topological nature of the phase of the scattering amplitude, we show that the pole must encounter with the Castillejo-Dalitz-Dyson (CDD) zero in this limit. It is concluded that the dynamical component of the eigenstate is small if a CDD zero exists near the eigenstate pole. We show that the line shape of the resonance is distorted from the Breit-Wigner form as an observable consequence of the nearby CDD zero. Finally, studying the positions of poles and CDD zeros of the KbarN-piSigma amplitude, we discuss the origin of the eigenstates in the Lambda(1405) region.Comment: 7 pages, 3 figures, v2: published versio

Repeated Radionuclide therapy in metastatic paraganglioma leading to the highest reported cumulative activity of 131I-MIBG

131I-MIBG therapy for neuroendocrine tumours may be dose limited. The common range of applied cumulative activities is 10-40 GBq. We report the uneventful cumulative administration of 111 GBq (= 3 Ci) 131I-MIBG in a patient with metastatic paraganglioma. Ten courses of 131I-MIBG therapy were given within six years, accomplishing symptomatic, hormonal and tumour responses with no serious adverse effects. Chemotherapy with cisplatin/vinblastine/dacarbazine was the final treatment modality with temporary control of disease, but eventually the patient died of progression. The observed cumulative activity of 131I-MIBG represents the highest value reported to our knowledge, and even though 12.6 GBq of 90Y-DOTATOC were added intermediately, no associated relevant bone marrow, hepatic or other toxicity were observed. In an individual attempt to palliate metastatic disease high cumulative activity alone should not preclude the patient from repeat treatment

A method for identifying genetic heterogeneity within phenotypically defined disease subgroups.

Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximizing power in comparison to standard variant-by-variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post hoc identification of the contributing genetic variants. We demonstrate the method on a range of simulated and test data sets, for which expected results are already known. We investigate subgroups of individuals with type 1 diabetes (T1D) defined by autoantibody positivity, establishing evidence for differential genetic architecture with positivity for thyroid-peroxidase-specific antibody, driven generally by variants in known T1D-associated genomic regions.We acknowledge the help of the Diabetes and Inflammation Laboratory Data Service for access and quality control procedures on the data sets used in this study. The JDRF/Wellcome Trust Diabetes and Inflammation Laboratory is in receipt of a Wellcome Trust Strategic Award (107212; J.A.T.) and receives funding from the NIHR Cambridge Biomedical Research Centre. J.L. is funded by the NIHR Cambridge Biomedical Research Centre and is on the Wellcome Trust PhD program in Mathematical Genomics and Medicine at the University of Cambridge. C.W. is funded by the MRC (grant MC_UP_1302/5). We thank M. Simmonds, S. Gough, J. Franklyn, and O. Brand for sharing their AITD genetic association data set and all patients with AITD and control subjects for participating in this study. The AITD UK national collection was funded by the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript