The phonon theory of liquid thermodynamics

Heat capacity of matter is considered to be its most important property because it holds information about system's degrees of freedom as well as the regime in which the system operates, classical or quantum. Heat capacity is well understood in gases and solids but not in the third state of matter, liquids, and is not discussed in physics textbooks as a result. The perceived difficulty is that interactions in a liquid are both strong and system-specific, implying that the energy strongly depends on the liquid type and that, therefore, liquid energy can not be calculated in general form. Here, we develop a phonon theory of liquids where this problem is avoided. The theory covers both classical and quantum regimes. We demonstrate good agreement of calculated and experimental heat capacity of 21 liquids, including noble, metallic, molecular and hydrogen-bonded network liquids in a wide range of temperature and pressure.Comment: 7 pages, 4 figure

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing

BACKGROUND: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. METHODS: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. RESULTS: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. CONCLUSIONS: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. FUNDING: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study

BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes

BACKGROUND: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic. METHODS: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome. RESULTS: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients. CONCLUSIONS: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation

Brettanomyces bruxellensis yeasts: impact on wine and winemaking

Yeasts belonging to the Brettanomyces/Dekkera genus are non-conventional yeasts, which affect winemaking by causing wine spoilage all over the world. This mini-review focuses on recent results concerning the presence of Brettanomyces bruxellensis throughout the wine processing chain. Here, culture-dependent and independent methods to detect this yeast on grapes and at the very early stage of wine production are encompassed. Chemical, physical and biological tools, devised for the prevention and control of such a detrimental species during winemaking are also presented. Finally, the mini-review identifies future research areas relevant to the improvement of wine safety and sensory profiles

Targeting BRAF for patients with melanoma

The prognosis of patients with metastatic melanoma is poor and not influenced by systemic therapy with cytotoxic drugs. New targeted agents directed against the RAS-RAF-MEK-ERK pathway show promising activity in early clinical development and particular interest is focused on selective inhibitors of mutant BRAF, which is present in one half of the cases of metastatic melanoma. The majority of patients on early trials of these drugs develop secondary resistance and subsequent disease progression and it is, therefore, critical to understand the underlying escape mechanisms leading to resistance

Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training

The purpose of this study was to investigate associations between acute exercise-induced hormone responses and adaptations to high intensity resistance training in a large cohort (n = 56) of young men. Acute post-exercise serum growth hormone (GH), free testosterone (fT), insulin-like growth factor (IGF-1) and cortisol responses were determined following an acute intense leg resistance exercise routine at the midpoint of a 12-week resistance exercise training study. Acute hormonal responses were correlated with gains in lean body mass (LBM), muscle fibre cross-sectional area (CSA) and leg press strength. There were no significant correlations between the exercise-induced elevations (area under the curve—AUC) of GH, fT and IGF-1 and gains in LBM or leg press strength. Significant correlations were found for cortisol, usually assumed to be a hormone indicative of catabolic drive, AUC with change in LBM (r = 0.29, P < 0.05) and type II fibre CSA (r = 0.35, P < 0.01) as well as GH AUC and gain in fibre area (type I: r = 0.36, P = 0.006; type II: r = 0.28, P = 0.04, but not lean mass). No correlations with strength were observed. We report that the acute exercise-induced systemic hormonal responses of cortisol and GH are weakly correlated with resistance training-induced changes in fibre CSA and LBM (cortisol only), but not with changes in strength

Kinetics and Ligand-Binding Preferences of Mycobacterium tuberculosis Thymidylate Synthases, ThyA and ThyX

Mycobacterium tuberculosis kills approximately 2 million people each year and presents an urgent need to identify new targets and new antitubercular drugs. Thymidylate synthase (TS) enzymes from other species offer good targets for drug development and the M. tuberculosis genome contains two putative TS enzymes, a conventional ThyA and a flavin-based ThyX. In M. tuberculosis, both TS enzymes have been implicated as essential for growth, either based on drug-resistance studies or genome-wide mutagenesis screens. To facilitate future small molecule inhibitors against these proteins, a detailed enzymatic characterization was necessary.After cloning, overexpression, and purification, the thymidylate-synthesizing ability of ThyA and ThyX gene products were directly confirmed by HPLC analysis of reaction products and substrate saturation kinetics were established. 5-Fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) was a potent inhibitor of both ThyA and ThyX, offering important clues to double-targeting strategies. In contrast, the folate-based 1843U89 was a potent inhibitor of ThyA but not ThyX suggesting that it should be possible to find ThyX-specific antifolates. A turnover-dependent kinetic assay, combined with the active-site titration approach of Ackermann and Potter, revealed that both M. tuberculosis enzymes had very low k(cat) values. One possible explanation for the low catalytic activity of M. tuberculosis ThyX is that its true biological substrates remain to be identified. Alternatively, this slow-growing pathogen, with low demands for TMP, may have evolved to down-regulate TS activities by altering the turnover rate of individual enzyme molecules, perhaps to preserve total protein quantities for other purposes. In many organisms, TS is often used as a part of larger complexes of macromolecules that control replication and DNA repair.Thus, the present enzymatic characterization of ThyA and ThyX from M. tuberculosis provides a framework for future development of cell-active inhibitors and the biological roles of these TS enzymes in M. tuberculosis