Adenovirus-based phospholamban antisense expression as a novel approach to improve cardiac contractile dysfunction: comparison of a constitutive viral versus an endothelin-1-responsive cardiac promoter

BACKGROUND: A decrease in sarcoplasmic reticulum Ca(2+) pump (SERCA2) activity is believed to play a role in the impairment of diastolic function of the failing heart. Because the expression ratio of phospholamban (PL) to SERCA2 may be a target to improve contractile dysfunction, a PL antisense RNA strategy was developed under the control of either a constitutive cytomegalovirus (CMV) or an inducible atrial natriuretic factor (ANF) promoter. The latter is upregulated in hypertrophied and failing heart, allowing "induction-by-disease" gene therapy. METHODS AND RESULTS: Part of the PL cDNA was cloned in antisense and sense directions into adenovectors under the control of either a CMV (Ad5CMVPLas and Ad5CMVPLs, respectively) or ANF (Ad5ANFPLas and Ad5ANFPLs, respectively) promoter. Infection of cultured rat neonatal cardiomyocytes with Ad5CMVPLas reduced PL mRNA to 30+/-7% of baseline and PL protein to 24+/-3% within 48 and 72 hours, respectively. The effects were vector dose dependent. Ad5CMVPLas increased the Ca(2+) sensitivity of SERCA2 and reduced the time to 50% recovery of the Ca(2+) transient. A decrease of PL protein was also achieved by infection with Ad5ANFPLas, and the presence of the hypertrophic stimulus, endothelin-1, led to enhanced downregulation of PL. The adenovectors expressing PL sense RNA had no effect on any of the tested parameters. CONCLUSIONS: Vector-mediated PL antisense RNA expression may become a feasible approach to modulate myocyte Ca(2+) homeostasis in the failing heart. The inducible ANF promoter for the first time offers the perspective for induction-by-disease gene therapy, ie, selective expression of therapeutic genes in hypertrophied and failing cardiomyocytes

cGMP stimulation of cystic fibrosis transmembrane conductance regulator Cl- channels co-expressed with cGMP-dependent protein kinase type II but not type Ibeta

In order to investigate the involvement of cGMP-dependent protein kinase (cGK) type II in cGMP-provoked intestinal Cl- secretion, cGMP-dependent activation and phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels was analyzed after expression of cGK II or cGK Ibeta in intact cells. An intestinal cell line which stably expresses CFTR (IEC-CF7) but contains no detectable endogenous cGK II was infected with a recombinant adenoviral vector containing the cGK II coding region (Ad-cGK II) resulting in co-expression of active cGK II. In these cells, CFTR was activated by membrane-permeant analogs of cGMP or by the cGMP-elevating hormone atrial natriuretic peptide as measured by 125I- efflux assays and whole-cell patch clamp analysis. In contrast, infection with recombinant adenoviruses expressing cGK Ibeta or luciferase did not convey cGMP sensitivity to CFTR in IEC-CF7 cells. Concordant with the activation of CFTR by only cGK II, infection with Ad-cGK II but not Ad-cGK Ibeta enabled cGMP analogs to increase CFTR phosphorylation in intact cells. These and other data provide evidence that endogenous cGK II is a key mediator of cGMP-provoked activation of CFTR in cells where both proteins are co-localized, e. g. intestinal epithelial cells. Furthermore, they demonstrate that neither the soluble cGK Ibeta nor cAMP-dependent protein kinase are able to substitute for cGK II in this cGMP-regulated function

Deep learning to represent sub-grid processes in climate models

The representation of nonlinear sub-grid processes, especially clouds, has been a major source of uncertainty in climate models for decades. Cloud-resolving models better represent many of these processes and can now be run globally but only for short-term simulations of at most a few years because of computational limitations. Here we demonstrate that deep learning can be used to capture many advantages of cloud-resolving modeling at a fraction of the computational cost. We train a deep neural network to represent all atmospheric sub-grid processes in a climate model by learning from a multi-scale model in which convection is treated explicitly. The trained neural network then replaces the traditional sub-grid parameterizations in a global general circulation model in which it freely interacts with the resolved dynamics and the surface-flux scheme. The prognostic multi-year simulations are stable and closely reproduce not only the mean climate of the cloud-resolving simulation but also key aspects of variability, including precipitation extremes and the equatorial wave spectrum. Furthermore, the neural network approximately conserves energy despite not being explicitly instructed to. Finally, we show that the neural network parameterization generalizes to new surface forcing patterns but struggles to cope with temperatures far outside its training manifold. Our results show the feasibility of using deep learning for climate model parameterization. In a broader context, we anticipate that data-driven Earth System Model development could play a key role in reducing climate prediction uncertainty in the coming decade.Comment: View official PNAS version at https://doi.org/10.1073/pnas.181028611

Электроснабжение установки перекачки нефти п. Пионерный ОАО «Томскнефть»

РЕФЕРАТ Выпускная квалификационная работа 149 с., 23 рис., 32 табл., 29 источников, 6 прил. Ключевые слова: нефтепровод, насос, электрооборудование, схема электроснабжения, линия, сеть, электроприемник, нагрузка, оборудование, защита, ток, напряжение, мощность. Объектом исследования является электрическая часть УПН п. Пионерный ОАО «Томскенефть». Цель работы – проектирование схемы электроснабжения предприятия, выбор оборудования. В процессе исследования проводился сбор исходных данных в ходе производственной практики на объекте исследования. В результате была спроектирована схема электроснабжения от подстанции энергосистемы, до конечного электроприемника. Были выбраны кабели и провода, коммутационное оборудование, были сделаны необходимые проверки. Также результатом работы сталESSAY Final qualifying work 149 p., 23 fig., 32 tab., 29 sources, 6 adj. Keywords: oil, pump, electrical equipment, power supply circuit, line, network, power-consuming equipment, load equipment, protection, current, voltage, power. The object of research is the electrical part of UPN claim. Pionerny of "Tomskeneft". The purpose of work - designing enterprise power scheme, the choice of equipment. The study was conducted to collect baseline data in the course of practical training on the subject of the study. As a result, power supply circuit has been designed from the substation grid, appliance, to the end. Were selected cables and wires, switching equipment, the necessary checks have been made. It is also the result of the work became an economic calculation of capital costs for the con

Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis

Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75432/1/j.1365-2222.2006.02498.x.pd

Eozinofilna upala u alergijskom rinitisu i nosnoj polipozi

On histopathological examination, nasal polyps and nasal mucosa in allergic rhinitis show different forms of pseudostratified respiratory epithelium, whereas the dominant characteristic of lamina propria is an eosinophilic infiltration. The aim of this study was to compare interleukin (IL)-5 and eosinophilic cationic protein (ECP) levels in the nasal fluid of 42 patients: 12 with allergic rhinitis and nasal septal deviation, 17 non-atopic patients with nasal polyposis, and 13 atopic nasal polyp patients were enrolled in this cross-sectional study. Nasal secretion samples were collected a few days before surgery. The levels of IL-5 were measured using fl ow cytometry and the ECP using a commercial ELISA kit. In addition, we counted eosinophils in hematoxylin-and-eosin-stained sections of all nasal polyp and all nasal mucosa samples taken from the inferior nasal turbinates during septoplasty. A significantly higher concentration of IL-5 was found in the nasal fluid of atopic patients with nasal polyposis than in non-atopic nasal polyp patients (p=0.025) and patients with allergic rhinitis (p=0.05). ECP was higher in atopic nasal polyp patients than in patients with allergic rhinitis (p<0.0001) and than in non-atopic nasal polyp patients (p<0.0001). Polyp eosinophils were higher in atopic’ than in non-atopic patients (p<0.0001) and higher than in the mucosa of patients with allergic rhinitis (p<0.0001). These however had signifi cantly more mucosal eosinophils than was found in the polyps of non-atopic patients’ (p=0.025). ECP levels in nasal fl uid and eosinophil counts in tissue specimens correlated well in all three groups of patients. Our study has shown that atopic nasal polyp patients have a higher level of eosinophilic inflammation than non-atopic patients with nasal polyps and patients with allergic rhinitis.Na histopatološkim pregledima nosni polipi, kao i nosna sluznica u alergijskom rinitisu pokazuju različite oblike pseudoslojevitog respiracijskog epitela, dok je osnovna karakteristika lamine proprije infiltracija eozinofilima. Cilj ove studije bio je usporediti koncentracije interleukina 5 (IL-5) i eozinofilnoga kationskog proteina (ECP) u nosnome sekretu pacijenata s alergijskim rinitisom, neatopičnih i atopičnih pacijenata s nosnom polipozom, kao i usporediti broj eozinofi la u tkivu nosnih polipa/nosne sluznice ovih pacijenata. Četrdeset dvoje (n=42) pacijenata, 12-ero s alergijskim rinitisom i devijacijom nosnog septuma, 17-ero neatopičnih pacijenata s nosnom polipozom i 13-ero atopičnih pacijenata s nosnom polipozom bilo je uključeno u ovu presječnu studiju. Uzorci nosnog sekreta bili su skupljeni iz nosnih šupljina svih ispitanika nekoliko dana prije kirurškog liječenja. Koncentracije IL-5 mjerene su metodom protočne citometrije, dok su koncentracije ECP mjerene komercijalnim ELISA-kitom. Eozinofi li su brojeni u svim uzorcima tkiva nosnih polipa, kao i u svim uzorcima tkiva sluznice uzetih s donje nosne školjke tijekom septoplastike. Značajno više koncentracije IL-5 izmjerene su u nosnom sekretu atopičnih pacijenata s nosnom polipozom u usporedbi s neatopičnim pacijentima s nosnom polipozom (p=0,025) i pacijentima s alergijskim rinitisom (p=0,05). Naši su rezultati pokazali više koncentracije ECP u atopičnih pacijenata s nosnom polipozom nego u pacijenata s alergijskim rinitisom (p<0,0001) i u usporedbi s nealergičnim pacijentima s nosnom polipozom (p<0,0001). Veći broj eozinofi la izbrojen je u tkivu polipa atopičnih pacijenata nego u tkivu polipa neatopičnih pacijenata (p<0,0001), kao i u sluznici pacijenata s alergijskim rinitisom (p<0,0001). U nosnoj sluznici pacijenata s alergijskim rinitisom našli smo značajno veći broj eozinofila nego u polipima neatopičnih pacijenata s nosnim polipima (p=0,025). Konačno, našli smo pozitivnu korelaciju između nivoa ECP u nosnom sekretu i broja eozinofila u uzorcima tkiva u sve tri skupine ispitanika. Zaključili smo da atopični pacijenti s nosnom polipozom imaju viši stupanj eozinofilne upale u usporedbi s neatopičnim pacijentima s nosnim polipima i s pacijentima s alergijskim rinitisom

Introduction to the special issue on the statistical mechanics of climate

We introduce the special issue on the Statistical Mechanics of Climate by presenting an informal discussion of some theoretical aspects of climate dynamics that make it a topic of great interest for mathematicians and theoretical physicists. In particular, we briefly discuss its nonequilibrium and multiscale properties, the relationship between natural climate variability and climate change, the different regimes of climate response to perturbations, and critical transitions