Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy.

BackgroundHistone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac diseases. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle (SV) heart disease of right ventricular morphology, as well as in a rodent model of right ventricular hypertrophy (RVH).MethodsHomogenates of right ventricle (RV) explants from non-failing controls and children born with a SV were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day-old rat pups were placed in hypoxic conditions, and echocardiographic analysis, gene expression, HDAC catalytic activity, and isoform expression studies of the RV were performed.ResultsClass I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in the hearts of children born with a SV. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression, elevated class I and class IIb HDAC catalytic activity, and protein expression in the RV compared with those in the control.ConclusionsThese data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. Although further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for preclinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies

Particle velocity in noncommutative space-time

We investigate a particle velocity in the $\kappa$-Minkowski space-time, which is one of the realization of a noncommutative space-time. We emphasize that arrival time analyses by high-energy $\gamma$-rays or neutrinos, which have been considered as powerful tools to restrict the violation of Lorentz invariance, are not effective to detect space-time noncommutativity. In contrast with these examples, we point out a possibility that {\it low-energy massive particles} play an important role to detect it.Comment: 16 pages, corrected some mistake

Have we already detected astrophysical symptoms of space-time noncommutativity ?

We discuss astrophysical implications of $\kappa$-Minkowski space-time, in which there appears space-time noncommutativity. We first derive a velocity formula for particles based on the motion of a wave packet. The result is that a massless particle moves at a constant speed as in the usual Minkowski space-time, which implies that an arrival time analysis by $\gamma$-rays from Markarian (Mk) 421 does not exclude space-time noncommutativity. Based on this observation, we analyze reaction processes in $\kappa$-Minkowski space-time which are related to the puzzling detections of extremely high-energy cosmic rays above the Greisen-Zatsepin-Kuzmin cutoff and of high-energy ($\sim$20 TeV) $\gamma$-rays from Mk 501.Comment: 10 pages, 6 figures, submitted to PRD, corrected some mistake

Expression of OATP Family Members in Hormone-Related Cancers: Potential Markers of Progression

The organic anion transporting polypeptide (OATP) family of transporters has been implicated in prostate cancer disease progression probably by transporting hormones or drugs. In this study, we aimed to elucidate the expression, frequency, and relevance of OATPs as a biomarker in hormone-dependent cancers. We completed a study examining SLCO1B3, SLCO1B1 and SLCO2B1 mRNA expression in 381 primary, independent patient samples representing 21 cancers and normal tissues. From a separate cohort, protein expression of OATP1B3 was examined in prostate, colon, and bladder tissue. Based on expression frequency, SLCO2B1 was lower in liver cancer (P = 0.04) which also trended lower with decreasing differentiation (P = 0.004) and lower magnitude in pancreatic cancer (P = 0.05). SLCO2B1 also had a higher frequency in thyroid cancer (67%) than normal (0%) and expression increased with stage (P = 0.04). SLCO1B3 was expressed in 52% of cancerous prostate samples and increased SLCO1B3 expression trended with higher Gleason score (P = 0.03). SLCO1B3 expression was also higher in testicular cancer (P = 0.02). SLCO1B1 expression was lower in liver cancer (P = 0.04) which trended lower with liver cancer grade (P = 0.0004) and higher with colon cancer grade (P = 0.05). Protein expression of OATP1B3 was examined in normal and cancerous prostate, colon, and bladder tissue samples from an independent cohort. The results were similar to the transcription data, but showed distinct localization. OATPs correlate to differentiation in certain hormone-dependent cancers, thus may be useful as biomarkers for assessing clinical treatment and stage of disease

Instabilities of Black Strings and Branes

We review recent progress on the instabilities of black strings and branes both for pure Einstein gravity as well as supergravity theories which are relevant for string theory. We focus mainly on Gregory-Laflamme instabilities. In the first part of the review we provide a detailed discussion of the classical gravitational instability of the neutral uniform black string in higher dimensional gravity. The uniform black string is part of a larger phase diagram of Kaluza-Klein black holes which will be discussed thoroughly. This phase diagram exhibits many interesting features including new phases, non-uniqueness and horizon-topology changing transitions. In the second part, we turn to charged black branes in supergravity and show how the Gregory-Laflamme instability of the neutral black string implies via a boost/U-duality map similar instabilities for non- and near-extremal smeared branes in string theory. We also comment on instabilities of D-brane bound states. The connection between classical and thermodynamic stability, known as the correlated stability conjecture, is also reviewed and illustrated with examples. Finally, we examine the holographic implications of the Gregory-Laflamme instability for a number of non-gravitational theories including Yang-Mills theories and Little String Theory.Comment: 119 pages, 16 figures. Invited review for Classical and Quantum Gravit

Cryptochrome 1 in Retinal Cone Photoreceptors Suggests a Novel Functional Role in Mammals

Cryptochromes are a ubiquitous group of blue-light absorbing flavoproteins that in the mammalian retina have an important role in the circadian clock. In birds, cryptochrome 1a (Cry1a), localized in the UV/violet-sensitive S1 cone photoreceptors, is proposed to be the retinal receptor molecule of the light-dependent magnetic compass. The retinal localization of mammalian Cry1, homologue to avian Cry1a, is unknown, and it is open whether mammalian Cry1 is also involved in magnetic field sensing. To constrain the possible role of retinal Cry1, we immunohistochemically analysed 90 mammalian species across 48 families in 16 orders, using an antiserum against the Cry1 C-terminus that in birds labels only the photo-activated conformation. In the Carnivora families Canidae, Mustelidae and Ursidae, and in some Primates, Cry1 was consistently labeled in the outer segment of the shortwave-sensitive S1 cones. This finding would be compatible with a magnetoreceptive function of Cry1 in these taxa. In all other taxa, Cry1 was not detected by the antiserum that likely also in mammals labels the photo-activated conformation, although Western blots showed Cry1 in mouse retinal cell nuclei. We speculate that in the mouse and the other negative-tested mammals Cry1 is involved in circadian functions as a non-light-responsive protein

Sustained favorable long-term outcome in the treatment of schizophrenia: a 3-year prospective observational study

<p>Abstract</p> <p>Background</p> <p>This study of chronically ill patients with schizophrenia aimed to identify patients who achieve sustained favorable long-term outcome - when the outcome incorporates severity of symptoms, level of functioning, and use of acute care services - and to identify the best baseline predictors of achieving this sustained favorable long-term outcome.</p> <p>Methods</p> <p>Using data from the United States Schizophrenia Care and Assessment Program (US-SCAP) (N = 2327), a large 3-year prospective, multisite, observational study of individuals treated for schizophrenia in the US, a hierarchical cluster analysis was performed to group patients based upon baseline symptom severity. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) scores, level of functioning, and use of acute care services. Level of functioning reflected patient-reported productivity and clinician-rated occupational role functioning. Use of acute care services reflected self-reported psychiatric hospitalization and emergency service use. Change of health state was determined over the 3-year period. A patient was classified as having a sustained favorable long-term outcome if their health state values had the closest distance to the defined "best baseline cluster" at each point over the length of the study. Stepwise logistic regression was used to determine baseline predictors of sustained favorable long-term outcome.</p> <p>Results</p> <p>At baseline, 5 distinct health state clusters were identified, ranging from "best" to "worst." Of 1635 patients with sufficient data, only 157 (10%) experienced sustained favorable long-term outcome during the 2-years postbaseline. The baseline predictors associated with sustained favorable long-term outcome included better quality of life, more daily activities, patient-reported clearer thinking from medication, better global functioning, being employed, not being a victim of a crime, not having received individual therapy, and not having received help with shopping and leisure activities.</p> <p>Conclusions</p> <p>Only a small percentage of patients achieved sustained favorable long-term outcome in this study, suggesting there continues to be a great need for improvement in the treatment of schizophrenia. Findings suggest that clinicians could make early projections of health states and identify those patients more likely to achieve favorable long-term outcomes enabling early therapeutic interventions to enhance benefits for patients.</p

Protective Efficacy of Neutralizing Monoclonal Antibodies in a Nonhuman Primate Model of Ebola Hemorrhagic Fever

Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF

Human Natural Killer T Cells Are Heterogeneous in Their Capacity to Reprogram Their Effector Functions

BACKGROUND: Natural killer T (NKT) cells are a subset of T cells that help potentiate and regulate immune responses. Although human NKT cell subsets with distinct effector functions have been identified, it is unclear whether the effector functions of these subsets are imprinted during development or can be selectively reprogrammed in the periphery. RESULTS: We found that neonatal NKT cells are predominantly CD4+ and express higher levels of CCR7 and CD62L and lower levels of CD94 and CD161 than adult CD4+ or CD4− NKT cell subsets. Accordingly, neonatal NKT cells were more flexible than adult CD4+ NKT cells in their capacity to acquire Th1- or Th2-like functions upon either cytokine-mediated polarization or ectopic expression of the Th1 or Th2 transcription factors T-bet and GATA-3, respectively. Consistent with their more differentiated phenotype, CD4- NKT cells were predominantly resistant to functional reprogramming and displayed higher cytotoxic function. In contrast to conventional T cells, neither the expression of CXCR3 nor the cytotoxic capacity of neonatal NKT cells could be reprogrammed. CONCLUSIONS AND SIGNIFICANCE: Together, these results suggest that neonatal CD4+, adult CD4+, and adult CD4− NKT may represent unique states of maturation and that some functions of human NKT cells may be developmentally imprinted, while others are acquired similar to conventional T cell subsets during peripheral maturation and differentiation. Given the potent immuno-regulatory functions of NKT cells, these findings have important implications for the development of novel NKT cell-based therapeutics and vaccines

Cilostazol Activates Function of Bone Marrow-Derived Endothelial Progenitor Cell for Re-endothelialization in a Carotid Balloon Injury Model

BACKGROUND: Cilostazol(CLZ) has been used as a vasodilating anti-platelet drug clinically and demonstrated to inhibit proliferation of smooth muscle cells and effect on endothelial cells. However, the effect of CLZ on re-endothelialization including bone marrow (BM)-derived endothelial progenitor cell (EPC) contribution is unclear. We have investigated the hypothesis that CLZ might accelerate re-endothelialization with EPCs. METHODOLOGY/PRINCIPAL FINDINGS: Balloon carotid denudation was performed in male Sprague-Dawley rats. CLZ group was given CLZ mixed feed from 2 weeks before carotid injury. Control group was fed normal diet. CLZ accelerated re-endothelialization at 2 weeks after surgery and resulted in a significant reduction of neointima formation 4 weeks after surgery compared with that in control group. CLZ also increased the number of circulating EPCs throughout the time course. We examined the contribution of BM-derived EPCs to re-endothelialization by BM transplantation from Tie2/lacZ mice to nude rats. The number of Tie2-regulated X-gal positive cells on injured arterial luminal surface was increased at 2 weeks after surgery in CLZ group compared with that in control group. In vitro, CLZ enhanced proliferation, adhesion and migration activity, and differentiation with mRNA upregulation of adhesion molecule integrin αvβ3, chemokine receptor CXCR4 and growth factor VEGF assessed by real-time RT-PCR in rat BM-derived cultured EPCs. In addition, CLZ markedly increased the expression of SDF-1α that is a ligand of CXCR4 receptor in EPCs, in the media following vascular injury. CONCLUSIONS/SIGNIFICANCE: CLZ promotes EPC mobilization from BM and EPC recruitment to sites of arterial injury, and thereby inhibited neointima formation with acceleration of re-endothelialization with EPCs as well as pre-existing endothelial cells in a rat carotid balloon injury model. CLZ could be not only an anti-platelet agent but also a promising tool for endothelial regeneration, which is a key event for preventing atherosclerosis or restenosis after vascular intervention