Regulated translocation of neutral sphingomyelinase-2 to the plasma membrane drives insulin resistance in steatotic hepatocytes.

Obesity-associated diabetes is linked to the accumulation of ceramide in various organs, including the liver. The exact mechanisms by which ceramide contributes to diabetic pathology are unclear, but one proposed scenario is that ceramide accumulation may inhibit insulin signaling pathways. It is unknown however whether the excess ceramide is generated proximal to the insulin receptor, that is, at the plasma membrane (PM), where it could affect the insulin signaling pathway directly, or the onset of insulin resistance is due to ceramide-induced mitochondrial dysfunction and/or lipotoxicity. Using hepatic cell lines and primary cultures, gain- and loss- of function approach, and state-of-the art lipid imaging, this study shows that PM-associated neutral sphingomyelinase 2 (nSMase2) regulates ceramide homeostasis in fat-loaded hepatocytes and drives the onset of insulin resistance. Our results provide evidence of a regulated translocation of nSMase2 to the PM which leads to local generation of ceramide and insulin resistance in cells treated with palmitic acid (PAL), a type of fat commonly found in diabetogenic diets. Oleic acid, which also causes accumulation of lipid droplets, does not induce nSMase2 translocation and insulin resistance. Experiments using the acyl-biotin exchange method to quantify protein palmitoylation show that cellular PAL abundance regulates the rate of nSMase2 palmitoylation. Furthermore, while inhibition of nSMase2 with GW4869 prevents PAL-induced insulin resistance, the overexpression of wild type nSMase2 but not palmitoylation-defective mutant protein potentiates the suppressive effect of PAL on insulin signaling. Overall, this study identifies nSMase2 as a novel component of the mechanism of insulin resistance onset in fat-loaded hepatocytes, that is, cell-autonomous and driven by PAL.

Direct regulation of IGF-binding protein 1 promoter by interleukin-1ß via an insulin- and FoxO-1-independent mechanism.

The level of insulin-like growth factor-binding protein 1 (IGFBP1), a liver-produced serum protein that regulates insulin-like growth factor-I bioactivity, glucose homeostasis, and tissue regeneration, increases during inflammation. This manuscript describes a novel pathway for the regulation of hepatic IGFBP1 mRNA and protein levels by interleukin (IL)-1ß. Experiments with the luciferase reporter system show that IL-1ß stimulates transcriptional activity from the 1-kb promoter region of IGFBP1. Although IL-1ß stimulation suppresses the insulin activation of protein kinase B, the major upstream regulator of IGFBP1 mRNA transcription, the induction of IGFBP1 by IL-1ß did not require an intact insulin response element. Furthermore, neither overexpression nor silencing of FoxO-1 had any effect on the IL-1ß-induced increase in IGFBP1 mRNA levels and promoter activity. However, inhibition of the ERK MAP kinases effectively prevented the IL-1ß effects. Inhibition of neutral sphingomyelinase, a key player in the IL-1ß signaling cascade that acts upstream of ERK, also suppressed the IL-1ß effects, while increasing the ceramide, through the addition of C2-ceramide or via treatment with exogenous sphingomyelinase, was sufficient to induce IGFBP1 promoter-driven luciferase activity. Studies in primary rat hepatocytes where the levels of neutral sphingomyelinase were either elevated or suppressed using adenoviral constructs affirmed the key role of neutral sphingomyelinase and ceramide (exerted likely through ERK activation) in the IL-1ß-induced IGFBP1 production. Finally, the IL-1ß effects on IGFBP1 mRNA production and protein secretion could be abolished by the addition of insulin, either at very late time points or at very high doses.

[Cancer morbidity risks among workers of asbestos-cement productions].

The retrospective assessment of morbidity rates and cancer pathology risks in workers of asbestosis-cement enterprises of Ukraine has been made. It was established that annual cancer morbidity among workers makes 88,1 per 100 000 of workers (RR = 0.26, CI 95 % 0.06-1.01). The most often cancer pathology was located in digestive organs (48.1%), respiratory organs (18.5%) (lung cancer--11.1%). The mesothelioma of pleura, peritoneum and pericardium were not found. The risks (odds ratio--OR) of cancer morbidity were increased for such organs as: respiratory organs (OR = 2.37), skin (OR = 1.78), digestive organs (OR = 1.34).

[Hygienic characteristics of work conditions for main occupations in asbestos cement production of Ukraine].

Studies covered of work conditions for main occupations in asbestos cement production of Ukraine. Studies covered work conditions and occupational features of workers engaged into main occupations in asbestos cement enterprises of Ukraine. Parameters presented characterize ambient air state, microclimate conditions, levels of noise and vibration, work intensity and hardness.

Cloning of the rat Slc14a2 gene and genomic organization of the UT-A urea transporter.

We cloned the Slc14a2 gene and determined the genomic organization of the rat urea transporter UT-A. Slc14a2, the gene encoding the rat UT-A transporter, extends for more that 300 kb. The four known rat mRNA isoforms: UT-A1, UT-A2, UT-A3, and UT-A4 are transcribed from 24 exons. The Slc14a2 genomic map also accounts for 3'-untranslated sequences expressed alternatively in UT-A1, UT-A2, and UT-A3. We previously identified a TATA-less, tonicity-responsive promoter controlling the transcription of UT-A1, UT-A3, and UT-A4 from a single initiation site in the 5'-flanking region of the gene. Here, we describe a second, internal promoter in intron 12, which controls the transcription of UT-A2 starting from exon 13. This region contains a TATA motif upstream from the UT-A2 transcription start site, and shows consensus sequences for the cAMP response element (CRE) and for the tonicity enhancer (TonE) motif. Stimulation by cAMP induces UT-A2 mRNA expression in mIMCD3 cells, and luciferase activity in mIMCD3 cells transfected with those pGL3 constructs including the CRE sequences. Although long-term exposure to hypertonicity induces UT-A2 expression in mIMCD3 cells, hypertonicity does not induce significantly the activity of the promoter in intron 12. In summary, we describe the genomic structure of the rat UT-A urea transporter, encoded by the Slc14a2 gene. Our findings suggest that two promoters regulate transcription of the four UT-A isoforms, and that stimulation of transcription by vasopressin, mediated by cAMP and CRE sequences, and controlled by an intronic promoter, may contribute to the increase in UT-A2 expression during water deprivation.

[The medical aspects of agricultural production and rural ecology under the new management conditions]. / Meditsinskie aspekty sel'skokhoziaistvennogo proizvodstva i ékologii sela v novykh usloviiakh khoziaistvovaniia.

Problems of rural hygiene are evaluated related to new conditions of agricultural production, technization of working processes, development of microbiological industry. Working conditions of women are emphasized. Medical aspects of ecology are discussed in detail. Socio-hygienic problems are evaluated.

[A retrospective analysis of aborted pregnancy in women engaged in agricultural production in controlled areas of Ukraine]. / Retrospektivnyi analiz nedonoshennoi beremennosti u zhenshchin, zaniatykh v sel'skokhoziaistvennom proizvodstve kontroliruemykh territorii Ukrainy.

A retrospective analysis was carried out of failure for a woman to be delivered of a child at the natural time in those female workers engaged in agricultural production in controlled territories of Ukraine (Narodichi and Ovruch districts of Zhytomir Province). Data files were studied of 5371 histories of labor (2440 those before and 2931 after the Chernobyl accident) and 525 records of spontaneous abortion (255 those before and 27 after the ChNPP breakdown). There has been found relationship between the frequency of incomplete pregnancies and density of contamination of soil with cesium-137 in certain settlements.

[The social hygiene problems in the operator work of hydroelectric power station workers and the means for enhancing work capacity]. / Sotsial'no-gigienicheskie voprosy operatorskogo truda rabochikh GES i puti povysheniia rabotosposobnosti.

Weight, tension and harmfulness of professional activity, peculiarities of labour conditions and characteristics of work, shift dynamics of operative personnel's working capacity were studied in the course of 8-hour working day currently accepted at hydroelectric power stations (HEPS) and experimental 12-hour schedule. Working conditions classified as "admissible", positive dynamics of operators' state, their social and material contentment were a basis for 12-hour two-shift schedule to be recommended as more appropriate. At the same time, problem of optimal shift schedules for operative personnel of HEPS remains unsolved and needs to be further explored.

[Labor of women workers engaged in different fields of national economics (a sociological study)]. / Trud zhenshchin-rabotnits v razlichnykh otrasliakh narodnogo khoziaistva (sotsiologicheskoe issledovanie).

Under the conditions of complex socio-hygienic studies of labour and living conditions and health status of the working women it is also reasonable to find the degree of their satisfaction with work. It gives a most complete idea of how important the mood of a person is in the sphere of the working activity. It has been shown, that psychological factors (satisfaction with work, interrelations in a collective of people etc.) constitute an important reserve in the elevation of labour productivity, health preservation.

[Reproductive health of women in rural areas of Ukraine]. / Reproduktivnoe zdorov'e zhenshchin sel'skikh raionov Ukrainy.

The authors revealed age and occupation related features of reproductive health, determined the risk factors and specified the prophylactic measures.

[Hygienic evaluation of women's work in radio-manufacturing industry]. / Gigienicheskaia otsenka truda zhenshchin v promyshlennom radioproizvodstve.

Conditions and character of labour of women working in revolver production are determined by exposure to noise, contact with cooling oils, static field, monotony, hypodynamics, tension of the visual analyser, which leads to the stress of the functional systems of the organism, development of fatigue, decrease in labour productivity, increased morbidity level with temporary loss of capacity for work. A complex of health-improving measures on normalization of occupational factors, rationalization of labour and rest regimen, implementation of which would promote increase in the capacity for work of women engaged in revolver production.

[Dynamics in the health of women occupied in agricultural sector of the Ukraine]. / Dinamika zdorov'ia zhenshchin, zaniatykh v sel'skom khoziaistve Ukrainy.

Work conditions of women engaged into crop-raising and animal husbandry are characterized by variable complex of occupational physical, chemical and biologic hazards caused by the production specificity. The latter results in increased prevalence of chronic somatic diseases and reproductive disorders (menstrual dysfunction, higher incidence of miscarriage, etc.). Further dynamic research based on multifactorial approach are required to study health state of rural population.

[Characteristics of the development of attitudes to health among female industrial and agricultural workers]. / Osobennosti formirovaniia otnosheniia k svoemu zdorov'iu rabotnits promyshlennosti i sel'skogo khoziaistva.

Both the occupational and social factors play an equally important role in the formation of the attitude to health among working women. The study of public opinion is an important link in the solution of problems pertaining to the improvement of health care delivery to the working women.

Surface-plasma-enhanced quantum efficiency of a Ag-Ti-n-GaAs grating photodiode.

An array of Ag-Ti-n-GaAs grating photodiodes was designed and fabricated, with each diode having an active area with a diameter of 400 microm. Both electrical and optical characterizations were performed. We have made two experimental observations concerning (1) the surface-plasma-enhanced detectivity as a function of wavelength for 30 degrees angle of incidence and (2) the offset in angle between the reflectivity minimum and the current maximum at the surface-plasma resonance.

Surface plasma-enhanced internal photoemission in gallium arsenide Schottky diodes.

An aluminum on n-type gallium arsenide Schottky diode with a prism coupler on the front face was illuminated by a p-polarized Nd:YAG laser to excite the surface plasma resonance in the aluminum barrier contact. The internal photoemission current and reflectance were measured simultaneously as a function of the angle of incidence. The excitation of the surface plasma resonance was observed by a dip in the reflectance which occurred at the same angle as a peak in the photoemission current. These effects disappeared in the case of s-polarization. Enhancement in the photoemission current by as much as a factor of 3 was obtained.

Cloning and characterization of the human urea transporter UT-A1 and mapping of the human Slc14a2 gene.

We have isolated and characterized the human homolog of the rat largest urea transporter of the UT-A family (hUT-A1). The 4.2-kb hUT-A1 cDNA encodes a 920-amino acid peptide, which is 89% identical to the rat UT-A1 protein. By Northern hybridization, hUT-A1 expression is detected in the human inner medulla as a approximately 4.4-kb mRNA transcript. By Western analysis, hUT-A1 is identified as a approximately 100-kDa protein in the human inner medulla. By immunohistochemistry, hUT-A1 expression is localized to the inner medullary collecting duct (IMCD). When transfected into HEK-293 cells hUT-A1 cDNA is translated into a approximately 98-kDa protein. Expression of hUT-A1 in Xenopus oocytes results in phloretin-inhibitable uptake of (14)C-urea, which shows only modest stimulation by cAMP, suggesting that in the human IMCD vasopressin may have a limited role in the short-term regulation of hUT-A1-mediated urea transport. We determined the organization of the human Slc14a2 gene and identified 20 exons distributed over approximately 67.5 kb on chromosome 18, from which hUT-A1 and the other human urea transporter, hUT-A2, are transcribed.

Genes for CS2 pili of enterotoxigenic Escherichia coli and their interchangeability with those for CS1 pili.

We have cloned and sequenced the DNA needed for production of CS2 pili in Escherichia coli K-12. The four open reading frames, cotB, cotA, cotC, and cotD, show homology with the genes needed for production of CS1 and CFA/I pili, which are also found on enterotoxigenic E. coli associated with human diarrheal disease. We also report that CotA plus CotB interact with the CS1 gene products CooC and CooD to form pili that can be visualized by electron microscopy and, conversely, that the CS1 gene products CooA and CooB interact with CotC and CotD to form pili.