Store-operated Ca entry regulatory factor alters murine metabolic state in an age-dependent manner via hypothalamic pathways.

Store-operated calcium entry (SOCE) is a vital process aimed at refilling cellular internal Ca stores and a primary cellular signaling driver for transcription factors' entry to the nucleus. SOCE-associated regulatory factor (SARAF)/TMEM66 is an endoplasmic reticulum (ER)-resident transmembrane protein that promotes SOCE inactivation and prevents Ca overfilling of the cell. Here, we demonstrate that mice deficient in SARAF develop age-dependent sarcopenic obesity with decreased energy expenditure, lean mass, and locomotion without affecting food consumption.

Quinone Methide-Based Organophosphate Hydrolases Inhibitors: Trans Proximity Labelers versus Cis Labeling Activity-Based Probes.

Quinone methide (QM) chemistry is widely applied including in enzyme inhibitors. Typically, enzyme-mediated bond breaking releases a phenol product that rearranges into an electrophilic QM that in turn covalently modifies protein side chains. However, the factors that govern the reactivity of QM-based inhibitors and their mode of inhibition have not been systematically explored.

Presenilin 1 Regulates [Ca]i and Mitochondria/ER Interaction in Cultured Rat Hippocampal Neurons.

Mutations in the presenilin 1 (PS1) gene are a major trigger of familial Alzheimer's disease (AD), yet the mechanisms affected by mutated PS1 causing cognitive decline are not yet elucidated. In the present study, we compared rat hippocampal neurons in culture, transfected with PS1 or with mutant (M146V) PS1 (mPS1) plasmids in several neuronal functions. Initially, we confirmed earlier observations that mPS1-expressing neurons are endowed with fewer mature "mushroom" spines and more filopodial immature protrusions.

SARAF Luminal Domain Structure Reveals a Novel Domain-Swapped β-Sandwich Fold Important for SOCE Modulation.

Store-Operated Calcium Entry (SOCE) plays key roles in cell proliferation, muscle contraction, immune responses, and memory formation. The coordinated interactions of a number of proteins from the plasma and endoplasmic reticulum membranes control SOCE to replenish internal Ca stores and generate intracellular Ca signals. SARAF, an endoplasmic reticulum resident component of the SOCE pathway having no homology to any characterized protein, serves as an important brake on SOCE.

Importin α5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1.

Importins mediate transport from synapse to soma and from cytoplasm to nucleus, suggesting that perturbation of importin-dependent pathways should have significant neuronal consequences. A behavioral screen on five importin α knockout lines revealed that reduced expression of importin α5 (KPNA1) in hippocampal neurons specifically decreases anxiety in mice. Re-expression of importin α5 in ventral hippocampus of knockout animals increased anxiety behaviors to wild-type levels.

Altered lysosome distribution is an early neuropathological event in neurological forms of Gaucher disease.

In the lysosomal storage disorder Gaucher disease (GD), glucosylceramide (GlcCer) accumulates due to the defective activity of glucocerebrosidase. A subset of GD patients develops neuropathology. We now show mislocalization of Limp2-positive puncta and a large reduction in the number of Lamp1-positive puncta, which are associated with impaired tubulin.

Delineating pathological pathways in a chemically induced mouse model of Gaucher disease.

Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently discovered genetic relationship with Parkinson's disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid β-glucosidase (GCase) using the irreversible inhibitor conduritol B-epoxide (CBE) is particularly attractive, although few systematic studies examining the effect of CBE on the development of symptoms associated with neurological forms of GD have been performed.

Identification of a biomarker in cerebrospinal fluid for neuronopathic forms of Gaucher disease.

Gaucher disease, a recessive inherited metabolic disorder caused by defects in the gene encoding glucosylceramidase (GlcCerase), can be divided into three subtypes according to the appearance of symptoms associated with central nervous system involvement. We now identify a protein, glycoprotein non-metastatic B (GPNMB), that acts as an authentic marker of brain pathology in neurological forms of Gaucher disease. Using three independent techniques, including quantitative global proteomic analysis of cerebrospinal fluid (CSF) in samples from Gaucher disease patients that display neurological symptoms, we demonstrate a correlation between the severity of symptoms and GPNMB levels.

[Species and quantitative characteristics of pharyngeal mucosa microflora in pregnant women].

Aim: Species and quantitative characteristics of upper respiratory tract (URT) mucosa microflora in women at gestation period.

Materials And Methods: The results of a bacteriological study of 68 samples of mucus from posterior pharyngeal wall in women at gestation period (from 14 weeks), 52 of those--from pregnant women with acute respiratory infection (ARI) symptoms and 16--from women without signs of disease, are presented. Qualitative and quantitative composition of microflora was studied by a generally accepted bacteriological method.

From sheep to mice to cells: tools for the study of the sphingolipidoses.

The sphingolipidoses are a group of inherited lysosomal storage diseases in which sphingolipids accumulate due to the defective activity of one or other enzymes involved in their degradation. For most of the sphingolipidoses, little is known about the molecular mechanisms that lead to disease, which has negatively impacted attempts to develop therapies for these devastating human diseases. Use of both genetically-modified animals, ranging from mice to larger mammals, and of novel cell culture systems, is of utmost importance in delineating the molecular mechanisms that cause pathophysiology, and in providing tools that enable testing the efficacy of new therapies.

RIPK3 as a potential therapeutic target for Gaucher's disease.

Gaucher's disease (GD), an inherited metabolic disorder caused by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease. Heterozygous mutations in GBA are a major risk factor for Parkinson's disease. GD is divided into three clinical subtypes based on the absence (type 1) or presence (types 2 and 3) of neurological signs.

[The influence of gel-like recombinant interferon α-2b on the clinical course of acute respiratory infection and the state of mucosal immunity in the pregnant women].

The objective of the present study was to evaluate the state of local immunity of the mucous membrane in the nose of the pregnant women presenting with acute respiratory infection (ARI). A total of 55 women with this condition were examined at the outpatient basis starting from week 14 of the gestation period. Viferon gel was administered intranasally to 34 such patients.

[Clinical course of acute respiratory infection and the state of microbiocenosis of upper respiratory tract in pregnant women].

Aim: Evaluate clinical features of the course of acute respiratory infection (ARI) and the state of microbiocenosis of nasopharynx of pregnant women at gestational term of 14 - 26 weeks.

Materials And Methods: At the stage of outpatient therapy of ARI 49 pregnant women at the gestational term of 14 - 26 weeks were examined: group 1--27 individuals consulting at day 1 and receiving Viferon (gel) intranasally for 10 days, group 2--22 individuals consulting at day 2 - 3 and receiving Viferon (gel and suppositorium). Respiratory viral infection was diagnosed by multiplex PCR.

[Comparative characteristics of treatment quality in patients with arterial hypertension in the system of primary health service].

Aim: To compare quality of therapy and examination of target organs in hypertensive patients in the system of primary health service for 1995-1996 and 2003-2004.

Material And Methods: A retrospective analysis of 1301 case histories of outpatients treated in 1995-1996 and 720 patients treated in 2003-2004 has been made. A special chart was compiled for evaluation of diagnosis and treatment quality.

[The immunological aspects of maternal-fetal interrelationships].

The paper deals with different aspects of the relationships occurring between the pregnant woman and the fetus having paternal antigens. Analysis of a great deal of recent information clearly indicates that local uterine immunity plays a great role during pregnancy. The specific features of the gene expression of major histocompatibility by an invasive trophoblast and the immunosuppressive function of placental fibrinoid are discussed.

[Connective tissue pathology in patients with aneurysms of the cerebral arteries (Ehlers-Danlos syndrome)].

Results of morphological examination of the skin and vessels in patients with large and giant brain artery aneurysms are presented. Ehlers-Danlos syndrome (type IV) was diagnosed in half of the cases; very thin skin and vessel walls, the disturbance of the collagen fibril structure in dermis, increased permeability and the tendency to rupture of the inner elastic membrane of brain arteries combined with a severe intimal atrophy. The absence of the III type collagen in the skin biopsies was shown immunohistochemically.