Cosmological bounds on tachyonic neutrinos

Recent time-of-flight measurements on muon neutrinos in the OPERA neutrino oscillation experiment have found anomalously short times compared to the light travel-times, corresponding to a superluminal velocity, $v-1=2.37\pm0.32\times 10^{-5}$ in units where $c=1$. We show that cosmological bounds rule out an explanation involving a Lorentz invariant tachyonic neutrino. At the OPERA energy scale, nucleosynthesis constraints imply $v-1<0.86\times 10^{-12}$ and the Cosmic Microwave Background observations imply $v-1<7.1\times 10^{-23}$. The CMB limit on the velocity of a tachyon with an energy of 10 MeV is stronger than the SN1987A limit. Superluminal neutrinos that could be observed at particle accelerator energy scales would have to be associated with Lorentz symmetry violation.Comment: LaTeX, 4 page

Relationship between lipoproteins, thrombosis and atrial fibrillation

The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow’s triad of hypercoagulability, structural abnormalities, and blood stasis. More recently, there is emerging evidence that lipoproteins are implicated in this process, beyond their traditional role in atherosclerosis. In this review, we provide an overview of the various lipoproteins and explore the association between lipoproteins and AF, the effects of lipoproteins on haemostasis, and the potential contribution of lipoproteins to thrombogenesis in AF. There are several types of lipoproteins based on size, lipid composition, and apolipoprotein category, namely: chylomicrons, very low-density lipoprotein, low-density lipoprotein (LDL), intermediate-density lipoprotein, and high-density lipoprotein. Each of these lipoproteins may contain numerous lipid species and proteins with a variety of different functions. Furthermore, the lipoprotein particles may be oxidized causing an alteration in their structure and content. Of note, there is a paradoxical inverse relationship between total cholesterol and LDL cholesterol (LDL-C) levels, and incident AF. The mechanism by which this occurs may be related to the stabilizing effect of cholesterol on myocardial membranes, along with its role in inflammation. Overall, specific lipoproteins may interact with haemostatic pathways to promote excess platelet activation and thrombin generation, as well as inhibiting fibrinolysis. In this regard, LDL-C has been shown to be an independent risk factor for thromboembolic events in AF. The complex relationship between lipoproteins, thrombosis and AF warrants further research with an aim to improve our knowledge base and contribute to our overall understanding of lipoprotein-mediated thrombosis

Relationship between Renal Function, Fibrin Clot Properties and Lipoproteins in Anticoagulated Patients with Atrial Fibrillation

Background: Mechanisms by which chronic kidney disease (CKD) influences fibrin clot properties in atrial fibrillation (AF) remain ill-defined. We aimed to investigate the effects of AF and CKD on fibrin clot properties and lipoproteins, and determine the relationship between these factors. Methods: Prospective cross-sectional study of patients recruited from cardiology services in Liverpool between September 2019 and October 2021. Primary groups consisted of anticoagulated AF patients with and without CKD in a 1:1 ratio. Control group comprised anticoagulated patients without AF or CKD. Fibrin clot properties were analysed using turbidity and permeation assays. Detailed lipoprotein characteristics, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), small dense LDL and oxidised LDL, were measured. Results: Fifty-six anticoagulated patients were enrolled (median age 72.5; 34% female); 46 with AF (23 with CKD and 23 without CKD) and 10 controls. AF was associated with changes in three indices of fibrin clot properties using PTT (T(lag) 314 vs. 358 s, p = 0.047; Abs(peak) 0.153 vs. 0.111 units, p = 0.031; T(lysis50%) 884 vs. 280 s, p = 0.047) and thrombin reagents (T(lag) 170 vs. 132 s, p = 0.031; T(max) 590 vs. 462 s, p = 0.047; T(peak50%) 406 vs. 220 s, p = 0.005) while the concomitant presence of CKD led to changes in fibrin clot properties using kaolin (T(lag) 1072 vs. 1640 s, p = 0.003; T(max) 1458 vs. 1962 s, p = 0.005; T(peak50%) 1294 vs. 2046, p = 0.008) and PPP reagents (T(lag) 566 vs. 748 s, p = 0.044). Neither of these conditions were associated with changes in fibrin clot permeability. Deteriorating eGFR was significantly correlated to the speed of clot formation, and CKD was independently associated with unfavourable clot properties (T(lag) −778, p = 0.002; T(max) −867, p = 0.004; T(peak50%) −853, p = 0.004 with kaolin reagent). AF alone was not associated with changes in lipoprotein distribution while AF patients with CKD had lower total cholesterol, LDL-C and small dense LDL due to the presence of other risk factors. No significant relationship was observed between fibrin clot properties and lipoprotein distribution. Conclusions: There are important changes that occur in fibrin clot properties with AF and CKD that may account for the increased risk of thromboembolic complications. However, these changes in fibrin clot properties were not attributable to alterations in lipoprotein distribution

‘Fit for surgery’:the relationship between cardiorespiratory fitness and postoperative outcomes

NEW FINDINGS: What is the topic of this review? The relationships and physiological mechanisms underlying the clinical benefits of cardiorespiratory fitness (CRF) in patients undergoing major intra‐abdominal surgery. What advances does it highlight? Elevated CRF reduces postoperative morbidity/mortality, thus highlighting the importance of CRF as an independent risk factor. The vascular protection afforded by exercise prehabilitation can further improve surgical risk stratification and postoperative outcomes. ABSTRACT: Surgery accounts for 7.7% of all deaths globally and the number of procedures is increasing annually. A patient's ‘fitness for surgery’ describes the ability to tolerate a physiological insult, fundamental to risk assessment and care planning. We have evolved as obligate aerobes that rely on oxygen (O(2)). Systemic O(2) consumption can be measured via cardiopulmonary exercise testing (CPET) providing objective metrics of cardiorespiratory fitness (CRF). Impaired CRF is an independent risk factor for mortality and morbidity. The perioperative period is associated with increased O(2) demand, which if not met leads to O(2) deficit, the magnitude and duration of which dictates organ failure and ultimately death. CRF is by far the greatest modifiable risk factor, and optimal exercise interventions are currently under investigation in patient prehabilitation programmes. However, current practice demonstrates potential for up to 60% of patients, who undergo preoperative CPET, to have their fitness incorrectly stratified. To optimise this work we must improve the detection of CRF and reduce potential for interpretive error that may misinform risk classification and subsequent patient care, better quantify risk by expressing the power of CRF to predict mortality and morbidity compared to traditional cardiovascular risk factors, and improve patient interventions with the capacity to further enhance vascular adaptation. Thus, a better understanding of CRF, used to determine fitness for surgery, will enable both clinicians and exercise physiologists to further refine patient care and management to improve survival

Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase

The Vps34 (vacuolar protein sorting 34) class III PI3K (phosphoinositide 3-kinase) phosphorylates PtdIns (phosphatidylinositol) at endosomal membranes to generate PtdIns(3)P that regulates membrane trafficking processes via its ability to recruit a subset of proteins possessing PtdIns(3)P-binding PX (phox homology) and FYVE domains. In the present study, we describe a highly selective and potent inhibitor of Vps34, termed VPS34-IN1, that inhibits Vps34 with 25 nM ICin vitro, but does not significantly inhibit the activity of 340 protein kinases or 25 lipid kinases tested that include all isoforms of class I as well as class II PI3Ks. Administration of VPS34-IN1 to cells induces a rapid dose-dependent dispersal of a specific PtdIns(3)P-binding probe from endosome membranes, within 1 min, without affecting the ability of class I PI3K to regulate Akt. Moreover, we explored whether SGK3 (serum- and glucocorticoid-regulated kinase-3), the only protein kinase known to interact specifically with PtdIns(3)P via its N-terminal PX domain, might be controlled by Vps34. Mutations disrupting PtdIns(3)P binding ablated SGK3 kinase activity by suppressing phosphorylation of the T-loop [PDK1 (phosphoinositide-dependent kinase 1) site] and hydrophobic motif (mammalian target of rapamycin site) residues. VPS34-IN1 induced a rapid ~50-60% loss of SGK3 phosphorylation within 1 min. VPS34-IN1 did not inhibit activity of the SGK2 isoform that does not possess a PtdIns(3)P-binding PX domain. Furthermore, class I PI3K inhibitors (GDC-0941 and BKM120) that do not inhibit Vps34 suppressed SGK3 activity by ~40%. Combining VPS34-IN1 and GDC-0941 reduced SGK3 activity ~80-90%. These data suggest SGK3 phosphorylation and hence activity is controlled by two pools of PtdIns(3)P. The first is produced through phosphorylation of PtdIns by Vps34 at the endosome. The second is due to the conversion of class I PI3K product, PtdIns(3,4,5)P3 into PtdIns(3)P, via the sequential actions of the PtdIns 5-phosphatases [SHIP1/2 (Src homology 2-domain-containing inositol phosphatase 1/2)] and PtdIns 4-phosphatase [INPP4B (inositol polyphosphate 4-phosphatase type II)]. VPS34-IN1 will be a useful probe to delineate physiological roles of the Vps34. Monitoring SGK3 phosphorylation and activity could be employed as a biomarker of Vps34 activity, in an analogous manner by which Akt is used to probe cellular class I PI3K activity. Combining class I (GDC-0941) and class III (VPS34-IN1) PI3K inhibitors could be used as a strategy to better analyse the roles and regulation of the elusive class II PI3K

Results on Finite Density QCD

A brief summary of the formulation of QCD at finite chemical potental, $\mu$, is presented. The failure of the quenched approximation to the problem is reviewed. Results are presented for dynamical simulations of the theory at strong and intermediate couplings. We find that the problems associated with the quenched theory persist: the onset of non-zero quark number does seem to occur at a chemical potential $\approx { {m_{\pi}} \over 2}$. However analysis of the Lee-Yang zeros of the grand canonical partition function in the complex fugacity plane, ($e^{\mu/T}$), does show signals of critical behaviour in the expected region of chemical potential. Results are presented for a simulation at finite density of the Gross-Neveu model on a $16^3$ lattice near to the chiral limit. Contrary to our simulations of QCD no pathologies were found when $\mu$ passed through the value m_{\pi}/2}.Comment: 14 pages, Latex, 18 eps figures, Review for Tsukuba worksho