Target validation:switching domains

Chemical probes and drugs often bind to functional domains on disease-relevant proteins. A study suggests a chemical genetic approach to establish on-target effects by swapping the targeted domain, affording resistance to pharmacological inhibition while retaining functionality

Study of Bc+B_c^+ decays to the K+K−π+K^+K^-\pi^+ final state and evidence for the decay Bc+→χc0π+B_c^+\to\chi_{c0}\pi^+

A study of $B_c^+\to K^+K^-\pi^+$ decays is performed for the first time using data corresponding to an integrated luminosity of 3.0 $\mathrm{fb}^{-1}$ collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of $7$ and $8$ TeV. Evidence for the decay $B_c^+\to\chi_{c0}(\to K^+K^-)\pi^+$ is reported with a significance of 4.0 standard deviations, resulting in the measurement of $\frac{\sigma(B_c^+)}{\sigma(B^+)}\times\mathcal{B}(B_c^+\to\chi_{c0}\pi^+)$ to be $(9.8^{+3.4}_{-3.0}(\mathrm{stat})\pm 0.8(\mathrm{syst}))\times 10^{-6}$. Here $\mathcal{B}$ denotes a branching fraction while $\sigma(B_c^+)$ and $\sigma(B^+)$ are the production cross-sections for $B_c^+$ and $B^+$ mesons. An indication of $\bar b c$ weak annihilation is found for the region $m(K^-\pi^+)<1.834\mathrm{\,Ge\kern -0.1em V\!/}c^2$, with a significance of 2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html, link to supplemental material inserted in the reference

Live Imaging at the Onset of Cortical Neurogenesis Reveals Differential Appearance of the Neuronal Phenotype in Apical versus Basal Progenitor Progeny

The neurons of the mammalian brain are generated by progenitors dividing either at the apical surface of the ventricular zone (neuroepithelial and radial glial cells, collectively referred to as apical progenitors) or at its basal side (basal progenitors, also called intermediate progenitors). For apical progenitors, the orientation of the cleavage plane relative to their apical-basal axis is thought to be of critical importance for the fate of the daughter cells. For basal progenitors, the relationship between cell polarity, cleavage plane orientation and the fate of daughter cells is unknown. Here, we have investigated these issues at the very onset of cortical neurogenesis. To directly observe the generation of neurons from apical and basal progenitors, we established a novel transgenic mouse line in which membrane GFP is expressed from the beta-III-tubulin promoter, an early pan-neuronal marker, and crossed this line with a previously described knock-in line in which nuclear GFP is expressed from the Tis21 promoter, a pan-neurogenic progenitor marker. Mitotic Tis21-positive basal progenitors nearly always divided symmetrically, generating two neurons, but, in contrast to symmetrically dividing apical progenitors, lacked apical-basal polarity and showed a nearly randomized cleavage plane orientation. Moreover, the appearance of beta-III-tubulin–driven GFP fluorescence in basal progenitor-derived neurons, in contrast to that in apical progenitor-derived neurons, was so rapid that it suggested the initiation of the neuronal phenotype already in the progenitor. Our observations imply that (i) the loss of apical-basal polarity restricts neuronal progenitors to the symmetric mode of cell division, and that (ii) basal progenitors initiate the expression of neuronal phenotype already before mitosis, in contrast to apical progenitors

Structural basis of PROTAC cooperative recognition for selective protein degradation

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation

"I am becoming more and more like my eldest brother!": the relationship between older siblings, adolescent gambling severity, and the attenuating role of parents in a large-scale nationally representative survey study

The present study examined the association between having older siblings who gamble and adolescent at-risk/problem gambling and how parents (i.e., parental knowledge of their whereabouts) and peers might moderate such effects. Data were drawn from the ESPAD®Italia2012 survey (European School Survey Project on Alcohol and Other Drugs) comprising a nationally representative Italian sample of adolescents. The analysis was carried out on a subsample of 10,063 Italian students aged 15–19 years (average age = 17.10; 55 % girls) who had at least one older sibling and who had gambled at some point in their lives. Respondents’ problem gambling severity, older gambler sibling, gambler peers, parental knowledge, and socio-demographic characteristics were individually assessed. Multinomial logistic regression analyses including two- and three-way interactions were conducted. The odds of being an at-risk/problem gambler were higher among high school students with older siblings that gambled and those with peers who gambled. Higher parental knowledge (of who the adolescent was with and where they were in their leisure time) was associated with lower rates of at-risk/problem gambling. There was also an interaction between gamblers with older siblings and parental knowledge. The combination of having siblings who gambled and a greater level of parental knowledge was associated with lower levels of problem gambling. The present study confirmed the occurrence of social risk processes (older siblings and peers who gambled) and demonstrated that gambling among older siblings and peers represents an important contextual factor for increased at-risk/problem gambling. However, parental knowledge appears to be sufficient to counterbalance the influence of older siblings

Observation of Bc+ →j /ψD (∗)K (∗) decays

A search for the decays B+c→J/ψD(*)0K+ and B+c→J/ψD(*)+K*0 is performed with data collected at the LHCb experiment corresponding to an integrated luminosity of 3 fb−1. The decays B+c→J/ψ0K+ and B+c→J/ψD*0K+ are observed for the first time, while first evidence is reported for the B+c→JψD*+K*0 and B+c→J/ψD+K*0 decays. The branching fractions of these decays are determined relative to the B+c→J/ψπ+ decay. The B+c mass is measured, using the J/ψD0K+ final state, to be 6274.28±1.40(stat)±0.32(syst) MeV/c2. This is the most precise single measurement of the B+c mass to date

An update on vitamin B12-related gene polymorphisms and B12 status.

Vitamin B12 is an essential micronutrient in humans needed for health maintenance. Deficiency of vitamin B12 has been linked to dietary, environmental and genetic factors. Evidence for the genetic basis of vitamin B12 status is poorly understood. However, advancements in genomic techniques have increased the knowledge-base of the genetics of vitamin B12 status. Based on the candidate gene and genome-wide association (GWA) studies, associations between genetic loci in several genes involved in vitamin B12 metabolism have been identified. The objective of this literature review was to identify and discuss reports of associations between single-nucleotide polymorphisms (SNPs) in vitamin B12 pathway genes and their influence on the circulating levels of vitamin B12. Relevant articles were obtained through a literature search on PubMed through to May 2017. An article was included if it examined an association of a SNP with serum or plasma vitamin B12 concentration. Beta coefficients and odds ratios were used to describe the strength of an association, and a  < 0.05 was considered as statistically significant. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data. From 23 studies which fulfilled the selection criteria, 16 studies identified SNPs that showed statistically significant associations with vitamin B12 concentrations. Fifty-nine vitamin B12-related gene polymorphisms associated with vitamin B12 status were identified in total, from the following populations: African American, Brazilian, Canadian, Chinese, Danish, English, European ancestry, Icelandic, Indian, Italian, Latino, Northern Irish, Portuguese and residents of the USA. Overall, the data analyzed suggests that ethnic-specific associations are involved in the genetic determination of vitamin B12 concentrations. However, despite recent success in genetic studies, the majority of identified genes that could explain variation in vitamin B12 concentrations were from Caucasian populations. Further research utilizing larger sample sizes of non-Caucasian populations is necessary in order to better understand these ethnic-specific associations

Polymorphisms in MTHFR, MS and CBS Genes and Homocysteine Levels in a Pakistani Population

Background: Hyperhomocysteinemia (\u3e15 mol/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes--methylenetetrahydrofolate reductase (MTHFR, C677T, A1298C), methionine synthase (MS, A2756G), cystathionine-beta-synthase (CBS, T833C/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population. Methodology/Principal Findings: In a cross-sectional survey, 872 healthy adults (355 males and 517 females, age 18-60 years) were recruited from a low-income urban population in Karachi. Fasting venous blood was obtained and assessed for plasma/serum homocysteine, folate, vitamin B12, pyridoxal phosphate and blood lead. DNA was isolated and genotyping was performed by PCR-RFLP (restriction-fragment-length-polymorphism) based assays. The average changes in homocysteine levels for MTHFR 677CT and TT genotypes were positive [beta(SE beta), 2.01(0.63) and 16.19(1.8) mol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [beta(SE beta), -0.56(0.58) and -0.83(0.99) mol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was -1.88(0.81) mol/L. The combined effect of MTHFR C677T, MS A2756G and CBS 844ins68 genotypes for plasma homocysteine levels was additive (p valu

Cardiovascular magnetic resonance for the assessment of patients undergoing transcatheter aortic valve implantation: a pilot study

<p>Abstract</p> <p>Background</p> <p>Before trans-catheter aortic valve implantation (TAVI), assessment of cardiac function and accurate measurement of the aortic root are key to determine the correct size and type of the prosthesis. The aim of this study was to compare cardiovascular magnetic resonance (CMR) and trans-thoracic echocardiography (TTE) for the assessment of aortic valve measurements and left ventricular function in high-risk elderly patients submitted to TAVI.</p> <p>Methods</p> <p>Consecutive patients with severe aortic stenosis and contraindications for surgical aortic valve replacement were screened from April 2009 to January 2011 and imaged with TTE and CMR.</p> <p>Results</p> <p>Patients who underwent both TTE and CMR (n = 49) had a mean age of 80.8 ± 4.8 years and a mean logistic EuroSCORE of 14.9 ± 9.3%. There was a good correlation between TTE and CMR in terms of annulus size (R²= 0.48, p < 0.001), left ventricular outflow tract (LVOT) diameter (R²= 0.62, p < 0.001) and left ventricular ejection fraction (LVEF) (R²= 0.47, p < 0.001) and a moderate correlation in terms of aortic valve area (AVA) (R²= 0.24, p < 0.001). CMR generally tended to report larger values than TTE for all measurements. The Bland-Altman test indicated that the 95% limits of agreement between TTE and CMR ranged from -5.6 mm to + 1.0 mm for annulus size, from -0.45 mm to + 0.25 mm for LVOT, from -0.45 mm²to + 0.25 mm²for AVA and from -29.2% to 13.2% for LVEF.</p> <p>Conclusions</p> <p>In elderly patients candidates to TAVI, CMR represents a viable complement to transthoracic echocardiography.</p