Structural insights into a StART-like domain in Lam4 and its interaction with sterol ligands

Sterols are essential components of cellular membranes and shape their biophysical properties. The recently discovered family of Lipid transfer proteins Anchored at Membrane contact sites (LAMs) has been suggested to carry out intracellular sterol traffic using StART-like domains. Here, we studied the second StART-like domain of Lam4p from S. cerevisiae by NMR. We show that NMR data are consistent with the StART-like domain structure, and that several functionally important regions within the domain exhibit significant conformational dynamics. NMR titration experiments confirm sterol binding to the canonical sterol-binding site and suggest a role of membrane interactions on the thermodynamics and kinetics of sterol binding

Quantised Vortices in an Exciton-Polariton Fluid

One of the most striking quantum effects in a low temperature interacting Bose gas is superfluidity. First observed in liquid 4He, this phenomenon has been intensively studied in a variety of systems for its amazing features such as the persistence of superflows and the quantization of the angular momentum of vortices. The achievement of Bose-Einstein condensation (BEC) in dilute atomic gases provided an exceptional opportunity to observe and study superfluidity in an extremely clean and controlled environment. In the solid state, Bose-Einstein condensation of exciton polaritons has now been reported several times. Polaritons are strongly interacting light-matter quasi-particles, naturally occurring in semiconductor microcavities in the strong coupling regime and constitute a very interesting example of composite bosons. Even though pioneering experiments have recently addressed the propagation of a fluid of coherent polaritons, still no conclusive evidence is yet available of its superfluid nature. In the present Letter, we report the observation of spontaneous formation of pinned quantised vortices in the Bose-condensed phase of a polariton fluid by means of phase and amplitude imaging. Theoretical insight into the possible origin of such vortices is presented in terms of a generalised Gross-Pitaevskii equation. The implications of our observations concerning the superfluid nature of the non-equilibrium polariton fluid are finally discussed.Comment: 14 pages, 4 figure

Perforated carcinoma of the caecum presenting as necrotising fasciitis of the abdominal wall, the key to early diagnosis and management

BACKGROUND: Necrotising Fasciitis is a life threatening soft tissue infection which requires aggressive, early surgical management. CASE PRESENTATION: We present a rare case of a retroperitoneal perforation of a carcinoma of the caecum presenting as a necrotising fasciitis of the anterior abdominal wall. CONCLUSION: This case highlights the importance of early aggressive debridement to healthy tissue limits, the consideration of a rare underlying cause, and the scope for plastic surgical reconstruction in order that aggressive initial surgery can be adequately performed

The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma.

CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition

Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures

<p>Abstract</p> <p>Background</p> <p>Latinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance.</p> <p>Methods</p> <p>We utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 ± 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function.</p> <p>Results</p> <p>Mean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non-Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA-IR were no longer observed after controlling for adiponectin levels.</p> <p>Conclusions</p> <p>Among patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations.</p

Into Thick(er) Air? Oxygen Availability at Humans’ Physiological Frontier on Mount Everest

Global audiences are captivated by climbers pushing themselves to the limits in the hypoxic environment of Mount Everest. However, air pressure sets oxygen abundance, meaning it varies with the weather and climate warming. This presents safety issues for mountaineers, but also an opportunity for public engagement around climate change. Here we blend new observations from Everest with ERA5 reanalysis (1979- 2019) and climate model results to address both perspectives. We find that plausible warming could generate subtle but physiologically relevant changes in summit oxygen availability, including an almost 5% increase in annual minimum VO 2 max for 2°C warming since pre-industrial. In the current climate we find evidence of swings in pressure sufficient to change Everest’s apparent elevation by almost 750 m. Winter pressures can also plunge lower than previously reported, highlighting the importance of air pressure forecasts for the safety of those trying to push the physiological frontier on Mt. Everest

Analysis of single nucleotide polymorphism in the promoter and protein expression of the chemokine Eotaxin-1 in colorectal cancer patients

<p>Abstract</p> <p>Background</p> <p>Previous studies suggest that chemokines (chemotactic cytokines) promote and regulate neoplastic progression including metastasis and angiogenesis. The chemokine eotaxin-1 is a powerful eosinophil attractant but also exerts chemotaxis of other leukocytes. Eotaxin-1 has been implicated in gastrointestinal disorders and may play an important role in colorectal mucosal immunity.</p> <p>Patients and methods</p> <p>The objective of this study was to assess the role of eotaxin-1 in colorectal cancer (CRC). Levels of eotaxin-1 protein in CRC tissues (n = 86) and paired normal mucosa were compared after determination by ELISA. Plasma eotaxin-1 levels from CRC patients (n = 67) were also compared with controls (n = 103) using the same method. Moreover, a TaqMan system was used to evaluate the -384A>G eotaxin-1 gene variant in CRC patients (n = 241) and in a control group (n = 253).</p> <p>Results</p> <p>Eotaxin-1 protein levels in colorectal tumours were significantly (P < 0.0001) higher than in normal tissue. Immunohistochemistry revealed eotaxin-1 expression in stromal cells such as fibroblasts and leukocytes of the CRC tissue. The plasma eotaxin-1 level in CRC patients was lower compared with controls (P < 0.0001). Patients with tumours classified as Dukes' stage B and C had lower levels than patients with tumours in Dukes' stage A. We found no difference in genotype distribution but noted a difference regarding allele distribution (P = 0.036) and a dominance of allele G in rectal cancer patients.</p> <p>Conclusion</p> <p>The up-regulated eotaxin-1 protein expression in cancer tissue may reflect an eotaxin-1 mediated angiogenesis and/or a recruitment of leukocytes with potential antitumourigenic role. We noticed a dominance of the G allele in rectal cancer patients compared with colon cancer patients that was independent of eotaxin-1 expression.</p

Impacto da exposição académica no estado de saúde de estudantes universitários

OBJECTIVE: To assess the impact of academic life on health status of university students. METHODS: Longitudinal study including 154 undergraduate students from the Universidade de Aveiro, Portugal, with at least two years of follow-up observations. Sociodemographic and behavioral characteristics were collected using questionnaires. Students' weight, height, blood pressure, serum glucose, serum lipids and serum homocysteine levels were measured. Regression analysis was performed using linear mixed-effect models, allowing for random effects at the participant level. RESULTS: A higher rate of dyslipidemia (44.0% vs. 28.6%), overweight (16.3% vs. 12.5%) and smoking (19.3% vs. 0.0%) was found among students exposed to the academic life when compared to freshmen. Physical inactivity was about 80%. Total cholesterol, high density lipoprotein-cholesterol (HDL-C), triglycerides, systolic blood pressure, and physical activity levels were significantly associated with gender (p<0.001). Academic exposure was associated with increased low density lipoprotein-cholesterol (LDL-C) levels (about 1.12 times), and marginally with total cholesterol levels (p=0.041). CONCLUSIONS: High education level does not seem to have a protective effect favoring a healthier lifestyle and being enrolled in health-related areas does not seem either to positively affect students' behaviors. Increased risk factors for non-transmissible diseases in university students raise concerns about their well-being. These results should support the implementation of health promotion and prevention programs at universities.OBJETIVO: Avaliar a influência da vida académica na saúde de estudantes universitários. MÉTODOS: Estudo longitudinal envolvendo 154 estudantes de graduação da Universidade de Aveiro, Portugal, por pelo menos dois anos de acompanhamento. Características sociodemográfi cas e comportamentais foram recordados, por meio de questionários. Foram medidos peso, altura,pressão arterial, glicemia, perfil lipídico e os níveis séricos de homocisteína dos alunos. Foi realizada análise de regressão com modelos lineares mistos considerando as medidas repetidas de cada sujeito. RESULTADOS: Estudantes expostos à vida académica, quando comparados àqueles de ingresso recente à universidade apresentaram proporção mais elevada de dislipidemia (44,0% versus 28,6%), sobrepeso (16,3% versus 12,5%) e tabagismo (19,3% versus 0,0%). No geral, foi observada alta proporção de sedentarismo (cerca de 80%). O colesterol total, lipoproteína de alta densidade, triglicérides, pressão arterial sistólica e níveis de atividade física apresentaram associação signifi cativa com o género (p < 0,001). A exposição académica apresentou-se associada com o aumento dos níveis das lipoproteínas de baixa densidade (cerca de 1,12 vezes), e marginalmente com os níveis de colesterol total (p = 0,041). CONCLUSÕES: Nem o alto nível de instrução parece ter papel protetor na adoção de estilo de vida saudável, tampouco o envolvimento com áreas de saúde muda o comportamento dos estudantes. Altas proporções de fatores de risco para doenças não-transmissíveis em jovens universitários podem afetar seu bem-estar. Os resultados podem servir de apoio às universidades no desenvolvimento de programas de prevenção e promoção da saúde

Snapshot photoacoustic topography through an ergodic relay of optical absorption in vivo

Photoacoustic tomography (PAT) has demonstrated versatile biomedical applications, ranging from tracking single cells to monitoring whole-body dynamics of small animals and diagnosing human breast cancer. Currently, PAT has two major implementations: photoacoustic computed tomography (PACT) and photoacoustic microscopy (PAM). PACT uses a multi-element ultrasonic array for parallel detection, which is relatively complex and expensive. In contrast, PAM requires point-by-point scanning with a single-element detector, which has a limited imaging throughput. The trade-off between the system cost and throughput demands a new imaging method. To this end, we have developed photoacoustic topography through an ergodic relay (PATER). PATER can capture a wide-field image with only a single-element ultrasonic detector upon a single laser shot. This protocol describes the detailed procedures for PATER system construction, including component selection, equipment setup and system alignment. A step-by-step guide for in vivo imaging of a mouse brain is provided as an example application. Data acquisition, image reconstruction and troubleshooting procedures are also elaborated. It takes ~130 min to carry out this protocol, including ~60 min for both calibration and snapshot wide-field data acquisition using a laser with a 2-kHz pulse repetition rate. PATER offers low-cost snapshot wide-field imaging of fast dynamics, such as visualizing blood pulse wave propagation and tracking melanoma tumor cell circulation in mice in vivo. We envision that PATER will have wide biomedical applications and anticipate that the compact size of the setup will allow it to be further developed as a wearable device to monitor human vital signs