Search

Die Modellierung von Prozessen findet bereits in fast allen metallurgischen Bereichen breite Anwendung. Insbesondere Prozessmodelle, die auf thermodynamischen Grundlagen basieren, ermoglichen eine tiefgehende Verbesserung des allgemeinen Prozessverstandnisses. Dadurch bieten derartige Modelle die Moglichkeit, die Prozesssteuerung zu verbessern oder die Feuerfestzustellung in Hochtemperaturanlagen zu optimieren. Das vorgestellte Modell simuliert den Walzprozess in SimuSageTM, einer Software zur Erstellung von benutzerdefinierten Flowsheets. Die Menge sowie die chemische Zusammensetzung des Eingangsmaterials und des Luftvolumens sowie die fur die Warmeubertragung relevanten Randbedingungen bilden die Eingangsparameter des Modells. Damit lassen sich die chemische Zusammensetzung und die Temperatur der erzeugten Walzschlacke und des mit Walzoxid beladenen Abgasstromes bestimmen. Weiterhin werden die Profile der Schlackenzusammensetzung, der Festphasentemperatur und der Gasphasentemperatur in Abhangigkeit der Walzofenlange modelliert.

Inflammasomes are cytosolic supramolecular organizing centers that, in response to pathogen-derived molecules and endogenous danger signals, assemble and activate innate immune responses. Bacterial lipopolysaccharide (LPS) is an inflammasome trigger and a major mediator of inflammation during infection, including during the potentially lethal condition sepsis. Activation of most inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein (NLRP) or other sensor protein that in turn activates a pro-inflammatory caspase. LPS that accesses the cell cytosol (cLPS) induces cell-autonomous activation of a non-canonical inflammasome that contains caspases-4/5 in humans or caspase-11 in mice1-3. Whereas the NLRPs that sense most pathogen triggers have been identified, no NLRP is known to sense cLPS, which together with the observation that caspases-4, -5, and -11 bind LPS in vitro4, has led to the postulate that inflammasome activation by cLPS occurs independent of an NLRP. Here we show that primate-specific NLRP11 senses cLPS and promotes the activation of caspase-4. We found that in response to infection by each of several gram-negative intracellular bacterial pathogens or to LPS transfection, efficient activation of the non-canonical pathway in human-derived macrophages depends on NLRP11. Further, we found that in both immortalized human-derived macrophages and primary human macrophages, the dependence of the non-canonical pathway on NLRP11 is due to detection of cLPS. Moreover, in cell lysates, NLRP11 binds LPS independently of caspase-4 and binds caspase-4 independently of LPS. Our results demonstrate that NLRP11 senses cLPS and promotes LPS-dependent activation of caspase-4. NLRP11 is a previously missing link in the human non-canonical inflammasome activation pathway.

The main purpose of this article was to highlight the potential for enhancing positive silvicultural effects and their dependency on the management method in Scots pine Pinus sylvestris L. stands. We therefore assessed the impact of natural and artificial regeneration on vitality and health, compaction, surface coverage and seedlings height. Another important goal was to assess the severity of damage in the selected forest sites. A comparative analysis was carried out based on results from field work conducted in the autumn 2010 in the Forest District Nowa Dęba. As part of this field work, also the breeding quality of the analyzed pine renewals was assessed. The obtained results indicate that natural regeneration of Scots pine under the conditions of a fresh coniferous forest as well as a fresh mixed coniferous forest is the most reasonable management practice. In wet mixed coniferous forests however, the naturally regenerating Scots pine seedlings are of lower silvicultural quality and growth parameter values compared to those in artificially regenerated stands. In fresh mixed broadleaved forests, naturally regenerated Scot pine trees showed slightly lower silvicultural quality and vitality than artificially regenerated trees. Our results indicate furthermore that there are indeed conditions under which the restoration of Scots pine in the Nowa Dęba Forest District using natural regeneration is preferable. We also found that the employed method of renewing has a significant impact on pine growth parameters in the moist mixed coniferous forest habitat. Naturally renewing pines are characterized by a lower overall viability, but at the same time natural regeneration provides a larger number of individuals with the best viability (1st vitality class), which can be a valuable selection basis for trees used in breeding. *The article is based on the doctoral thesis of Justyna Długosiewicz titled ‘The Economic and breeding effectiveness of the natural and artificial regeneration of pine stands’ conducted at the Faculty of Forestry of the Warsaw University of Life Sciences SGGW.

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease., Graphical abstract, Filbin et al. use plasma proteomics in 306 coronavirus disease 2019 (COVID-19) patients and 78 symptomatic controls over time to better understand the role of circulating immune cells and tissue cells in inflammation, disease severity, and survival. They propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage.

SummaryCOVID-19 has caused over 1 million deaths globally, yet the cellular mechanisms underlying severe disease remain poorly understood. By analyzing several thousand plasma proteins in 306 COVID-19 patients and 78 symptomatic controls over serial timepoints using two complementary approaches, we uncover COVID-19 host immune and non-immune proteins not previously linked to this disease. Integration of plasma proteomics with nine published scRNAseq datasets shows that SARS-CoV-2 infection upregulates monocyte/macrophage, plasmablast, and T cell effector proteins. By comparing patients who died to severely ill patients who survived, we identify dynamic immunomodulatory and tissue-associated proteins associated with survival, providing insights into which host responses are beneficial and which are detrimental to survival. We identify intracellular death signatures from specific tissues and cell types, and by associating these with angiotensin converting enzyme 2 (ACE2) expression, we map tissue damage associated with severe disease and propose which damage results from direct viral infection rather than from indirect effects of illness. We find that disease severity in lung tissue is driven by myeloid cell phenotypes and cell-cell interactions with lung epithelial cells and T cells. Based on these results, we propose a model of immune and epithelial cell interactions that drive cell-type specific and tissue-specific damage in severe COVID-19.

Membrane trafficking and receptor signaling are two fundamental cellular processes that interact constantly. Although how trafficking regulates signaling is well studied, how signaling pathways regulate trafficking is less well understood. Here, we use the mu opioid receptor (MOR), the primary target for opioid analgesics, to define a signaling pathway that dynamically regulates postendocytic receptor recycling. By directly visualizing individual MOR recycling events, we show that agonist increases MOR recycling. Inhibition of G(βγ,) phospholipase C, or protein kinase C mimicked agonist removal, whereas activation of G(βγ) increased recycling even after agonist removal. Phosphorylation of serine 363 on the C-terminal tail of MOR was required and sufficient for agonist-mediated regulation of MOR recycling. Our results identify a feedback loop that regulates MOR recycling via G(βγ), protein kinase C, and receptor phosphorylation. This could serve as a general model for how signaling regulates postendocytic trafficking of G protein–coupled receptors. SIGNIFICANCE STATEMENT: G protein–coupled receptor (GPCR) localization in the endosome is being increasingly recognized as an important and distinct component of GPCR signaling and physiology. This study identifies a G protein–dependent and protein kinase C–dependent signaling pathway that dynamically regulates the endosomal localization of the mu opioid receptor, the primary target of opioid analgesics and abused drugs. This pathway could provide a mechanism to manipulate spatial encoding of opioid signaling and physiology.

The Standard Model does not explain the hierarchy problem. Before the discovery of nonzero lepton mixing angle {\theta}13 high hopes in explanation of the shape of the lepton mixing matrix were combined with non abelian symmetries. Nowadays, assuming one Higgs doublet, it is unlikely that this is still valid. Texture zeroes, that are combined with abelian symmetries, are intensively studied. The neutrino mass matrix is a natural way to study such symmetries., Comment: 11 pages, 2 figures, the topic presented at the IX International Symposium :" Quantum Theory and Symmetries" in Yerevan, Armenia (July 2015)

Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation encoding an expanded polyglutamine tract in the huntingtin protein, which leads to cognitive, psychiatric and motor dysfunction. Exposure to environmental enrichment (EE), which enhances levels of cognitive stimulation and physical activity, has therapeutic effects on cognitive, affective and motor function of transgenic HD mice. The present study investigated gene expression changes and behavioral pharmacology in male and female R6/1 transgenic HD mice at an early time-point in HD progression associated with onset of cognitive and affective abnormalities, following EE and exercise (wheel running) interventions. We have demonstrated changes in expression levels of the serotonin (5-HT) receptor Htr1a, Htr1b, Htr2a and Htr2c genes (encoding the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors, respectively) in HD brains at 8 weeks of age, using quantitative real-time PCR. In contrast, expression of the serotonin transporter (SerT, also known as 5-HTT or Slc6a4) was not altered in these brains. Furthermore, we identified region-specific, sex-specific and environmentally regulated (comparing EE, exercise and standard housing conditions) impacts on gene expression of particular 5-HT receptors, as well as SerT. For example, SerT gene expression was upregulated by exercise (wheel running from 6 to 8 weeks of age) in the hippocampus. Interestingly, when EE was introduced from 6 to 8 weeks of age, Htr2a gene expression was upregulated in the cortex, striatum and hippocampus of male mice. EE also rescued the functional activity of 5-HT2 receptors as observed in the head-twitch test, reflecting sexually dimorphic effects of environmental stimulation. These findings demonstrate that disruption of the serotonergic system occurs early in HD pathogenesis and, together with previous findings, show that the timing and duration of environmental interventions are critical in terms of their ability to modify gene expression. This study is the first to show that EE is able to selectively enhance both gene expression of a neurotransmitter receptor and the functional consequences on behavioral pharmacology, and links this molecular modulation to the therapeutic effects of environmental stimulation in this neurodegenerative disease.

Within the framework of the two-Higgs Doublet Model (2HDM), we attempt to find some discrete, non-abelian flavour symmetry which could provide an explanation for the masses and mixing matrix elements of leptons. Unlike the Standard Model, currently there is no need for the flavour symmetry to be broken. With the GAP program we investigate all finite subgroups of the U3 group up to the order of 1025. Up to such an order there is no group for which it is possible to select free model parameters in order to match the masses of charged leptons, masses of neutrinos, and the Pontecorvo-Maki-Nakagawa-Sakata mixing matrix elements in a satisfactory manner.

Huntington's disease is caused by polyglutamine (polyQ)-expansion mutations in the CAG tandem repeat of the Huntingtin gene. The central feature of Huntington's disease pathology is the aggregation of mutant Huntingtin (Htt) protein into micrometer-sized inclusion bodies. Soluble mutant Htt states are most proteotoxic and trigger an enhanced risk of death whereas inclusions confer different changes to cellular health, and may even provide adaptive responses to stress. Yet the molecular mechanisms underpinning these changes remain unclear. Using the flow cytometry method of pulse-shape analysis (Pu1SA) to sort neuroblastoma (Neuro2a) cells enriched with mutant or wild-type Htt into different aggregation states, we clarified which transcriptional signatures were specifically attributable to cells before versus after inclusion assembly. Dampened CREB signalling was the most striking change overall and invoked specifically by soluble mutant Httexl states. Toxicity could be rescued by stimulation of CREB signalling. Other biological processes mapped to different changes before and after aggregation included NF-kB signalling, autophagy, SUMOylation, transcription regulation by histone deacetylases and BRD4, NAD + biosynthesis, ribosome biogenesis and altered HIF-1 signalling. These findings open the path for therapeutic strategies targeting key molecular changes invoked prior to, and subsequently to, Httexl aggregation.

Molluscs are the most diverse group in respect of sexual systems and strategies. They can be dioecious with separate sexes or hermaphroditic. Within hermaphroditism, it is possible to distinguish a number of modifications of this type of reproduction, such as protandry, protogyny, sex reversal, or protandry with some overlap. It is thought that dioecy was ancestral because it occurs in most classes of molluscs. Hermaphroditism evolved independently several times, and sequential and simultaneous hermaphroditism are more closely related to each other than to dioecy. This publication presents a general review of sexual systems and strategies in terrestrial gastropods with special emphasis on mating, fertilization, presence of love darts, reproductive strategies (semelparity vs. iteroparity) and modes (oviparity, ovoviviparity, viviparity), production of eggs and egg cannibalism., Invertebrate Survival Journal, Vol 14 No 1 (2017)

In order to explain the fermions masses and mixing parameters appearing in the lepton sector of the Standard Model, one proposes the extension of its symmetry. A discrete, non-abelian subgroup of $U(3)$ is added to the gauge group $SU(3)_{C}\times SU(2)_{L}\times U(1)_{Y}$ . Apart from that, one assumes the existence of one extra Higgs doublet. This article focuses mainly on the mathematical theorems and computational techniques which brought us to the results., 10 pages, the topic presented at the IX International Symposium :" Quantum Theory and Symmetries" in Yerevan, Armenia (July 2015)

BACKGROUND AND PURPOSE Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5-hydroxytryptaminergic (serotonergic) dysregulation. EXPERIMENTAL APPROACH We performed tests of depression-related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT1A and 5-HT2A receptors were performed by measuring behavioural and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation. KEY RESULTS Female HD mice recorded increased immobility time in the forced-swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild-type animals. These alterations were improved by chronic sertraline treatment. Wheel-running also resulted in similar improvements with the exception of saccharin preference but failed to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5-HT1A autoreceptor function, as demonstrated by modulation of the exaggerated 8-OH-DPAT-induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5-HT1A and 5-HT2 heteroceptor function observed in HD animals. CONCLUSIONS AND IMPLICATIONS We report for the first time a crucial role for 5-HT1A autoreceptor function in mediating the sex-specific depressive-like phenotype of female R6/1 HD mice. Our data further support a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioural benefits.

An important characteristic of an antenna is the radiation pattern, which determines in which direction(s) radiation is concentrated. Typical antenna radiation-pattern-measurement systems consist of measurement equipment and a controlled environment. Both of these elements can individually be prohibitively expensive, in terms of both cost and laboratory space. This paper outlines a low-cost (less than $1500) system for use at 2.4 GHz that is portable and requires a limited amount of space. Measurements are accomplished using a self-contained RF system, a simply constructed antenna rotator, a readily available data-acquisition and motor-controller circuit, and MA TLAB. A key feature of this system is an extremely low-cost and simple rotary joint, which eliminates cable twisting.

The subjects of the paper are the likelihood method (LM) and the expected Fisher information (FI) considered from the point od view of the construction of the physical models which originate in the statistical description of phenomena. The master equation case and structural information principle are derived. Then, the phenomenological description of the information transfer is presented. The extreme physical information (EPI) method is reviewed. As if marginal, the statistical inter-pretation of the amplitude of the system is given. The formalism developed in this paper would be also applied in quantum information processing and quantum game theory.

Dysregulation of the serotonergic signaling system has been implicated in the pathology of mood disorders including depression, and various rodent models of disrupted serotonergic signaling display depression-related behavioral phenotypes. Depression is a common neuropsychiatric feature of preclinical Huntington's disease (HD) but the underlying changes in the HD brain contributing to the development of depression are unknown. Using the R6/1 transgenic mouse model of HD, we show that pre-motor symptomatic HD mice display sex-specific depressive-related behaviors on the forced-swim (FST), tail-suspension (TST) and novelty-suppressed feeding (NSFT) tests while having muted responses to acute anti-depressant administration. The baseline behaviors of HD mice were similar to the behavioral phenotypes of serotonin (5-HT) receptor and transporter null mutants, and gene expression of specific serotonin receptors were subsequently found to be reduced in the hippocampus and cortex of HD mice. Female HD mice had an additional deficit in cortical expression of serotonin transporter (SerT). Environmental enrichment normalized the FST behavioral response of female HD mice corresponding with increased gene expression of specific 5-HT receptors in the hippocampus and cortex. Our findings implicate altered serotonergic signaling as the basis for the development of depression during the preclinical stages of HD.

The ordered probit model was used to evaluate the effect of roadway and area type features on injury severity of pedestrian crashes in rural Connecticut. Injury severity was coded on the KABCO scale and crashes were limited to those in which the pedestrians were attempting to cross two-lane highways that were controlled by neither stop signs nor traffic signals. Variables that significantly influenced pedestrian injury severity were clear roadway width (the distance across the road including lane widths and shoulders, but excluding the area occupied by on-street parking), vehicle type, driver alcohol involvement, pedestrian age 65 years or older, and pedestrian alcohol involvement. Seven area types were identified: downtown, compact residential, village, downtown fringe, medium-density commercial, low-density commercial, and low-density residential. Two groups of these area types were found to experience significantly different injury severities. Downtown, compact residential, and medium- and low-density commercial areas generally experienced lower pedestrian injury severity than village, downtown fringe, and low-density residential areas.

We present multiple epochs of near-IR spectroscopy for a sample of 25 young stars, including T Tauri, Herbig Ae/Be, and FU Ori objects. Using the FSPEC instrument on the Bok 90-inch telescope, we obtained K-band spectra of the BrGamma transition of hydrogen, with a resolution of ~3500. Epochs were taken over a span of >1 year, sampling time-spacings of roughly one day, one month, and one year. The majority of our targets show BrGamma emission, and in some cases these are the first published detections. Time-variability is seen in approximately half of the targets showing BrGamma emission. We compare the observed variability with expectations for rotationally-modulated accretion onto the central stars and time-variable continuum emission or extinction from matter in the inner disk. Our observations are not entirely consistent with models of rotationally-modulated magnetospheric accretion. Further monitoring, over a larger number of epochs, will facilitate more quantitative constraints on variability timescales and amplitudes, and a more conclusive comparison with theoretical models., Comment: 16 pages in emulateapj format. Accepted for publication in MNRAS

The solubility of niobium in microalloyed austenite has been analyzed using a thermodynamic description of the Fe-Nb-C-N system. The description of this system forms an important basis for calculations of precipitation of niobium carbonitrides in microalloyed steels. Previously presented thermodynamic descriptions are combined with a new description of the Fe-Nb-N system, and equilibria in the quaternary system are calculated. New experiments were performed on Nb, Nb-Ti, and Nb-Ti-V microalloyed steels to confirm the calculated results. The results of theoretical calculations show good agreement with the experimental data on dissolution/precipitation of Nb carbonitrides in microalloyed austenite.

Pulsatile blood flow using incompressible newtonian fluid is investigated numerically in abdominal aortic aneurysm models with the aid of transient Navier-Stokes equations for axisymmetric geometry. The arterial wall is assumed to be rigid. The actual arterial pressure-velocity pulse at the abdominal aorta is used as the inlet boundary condition to the aneurysm. The corresponding velocity at every time-step is assumed to be fully developed parabolic profile at the inlet. Time-dependent formation of vortices and occurrence of stagnation zones are analyzed in this numerical study. It has been found that the distal end of the aneurysm is subjected to maximum shear stress and pressure during the entire cycle. This analysis also confirms that the mechanical forces on the arterial wall, developed by the blood flow which is pulsatile in nature, may play an important role in both development and growth of aneurysms. It has also been found that a quasi-steady state may be used to explain sufficiently the basic flow characteristic within the aneurysm. The wall shear stress in the quasi-steady state at the distal end of the aneurysm during the most adverse condition was approximately the same as in the pulsatile state for a similar situation.

We present near-IR spectra of a sample of T Tauri, Herbig Ae/Be, and FU Ori objects. Using the FSPEC instrument on the Bok 90-inch telescope, we obtained K-band spectra with a resolution of ~3500. Here we present spectra of the v=2->0 and v=3->1 bandheads of ro-vibrational transitions of carbon monoxide. We observed these spectra over multiple epochs spaced by a few days and approximately one month. Several of our targets show CO emission or absorption features. However we see little evidence of variability in these features across multiple epochs. We compare our results with previous observations, and discuss the physical implications of non-variable CO emission across the sampled timescales., 30 pages, 13 figures; Accepted for publication in MNRAS

The effects of environmental enrichment on synaptic spine density in hippocampal area CAI were examined in rats exposed prenatally to alcohol. Pregnant dams were given ethanol via intragastric intubation (6 g/kg/day) from gestational days 8 through 19, or given isocaloric sucrose. An untreated control group was also used. After weaning, offspring from the three groups were then reared for 10 weeks in either isolated (caged alone, not handled) or enriched (group housed with “toys,” handled) conditions. Animals were then sacrificed, the brains Golgi impregnated, and CA1 pyramidal cell apical and basilar spine densities quantified. Among isolated animals there were no significant differences between control and alcohol-exposed groups. In general, environmental enrichment increased apical or basilar spine densities in untreated and sucrose controls. However, in prenatal alcohol-exposed animals, environmental enrichment did not increase spine densities. Because the environmental enrichment acted postnatally, these findings suggest that the effects of prenatal alcohol exposure include decreased neural plasticity enduring into early adulthood. Such a reduction in neuroanatomical plasticity in Hppocampus may be associated with cognitive impairments found following prenatal alcohol exposure.

A brief discussion about the current status of the search for the possible finite symmetry of a leptonic mass matrix is presented. Possible extensions of the models of leptons that can describe the masses and mixing elements are discussed.

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A) receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A) receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.

Animals exposed prenatally to alcohol (4 g/kg/day) via maternal peroral intubation or control offspring were reared after weaning either alone in standard steel/wire cages or in groups of eight, for 6 weeks. Rats exposed prenatally to alcohol and reared in isolation had a dysmetric stride length indicative of an ataxic gait. However, following postweaning environmental enrichment, prenatal alcohol-exposed rats showed no evidence of ataxia. In addition, the prenatal alcohol-exposed rats showed the same magnitude of improved Morris maze performance after enrichment as did the control offspring. These preliminary results suggest that postnatal environment can influence the expression of alcohol-related birth defects in rats, that rats exposed prenatally to alcohol can benefit from the effects of enriched postweaning environment and that postnatal factors can attenuate some of the deficits due to prenatal alcohol exposure.

Since the first reports of fetal alcohol syndrome (FAS), thousands of studies have examined the effects of antenatal alcohol exposure in humans and in animal models. Research with animal models has led to discoveries which would be difficult if not impossible in human subjects. Most importantly, these models have resulted in valuable insights into the actions of alcohol on various parts of the developing embryo and have helped researchers come closer to identifying the mechanisms of its teratogenic action. Both the direct and indirect biological effects of alcohol exposure in utero appear to work in conjunction with other concurrent and predisposing factors such as genotype, nutritional status, pattern of exposure and use of other drugs such as nicotine and cocaine. At present animal research indicates a multifactorial mechanism of the teratogenicity of alcohol resulting from nutrient deficiencies, fetal hypoxia and alterations in enzyme activities and cell function important in cell division and membrane integrity. This review examines how animal models are used to clarify issues associated with alcohol-related birth defects and to shed light on the underlying mechanisms.

Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin and regulation of its expression is complex due to multiple 5′ untranslated exons which are separately spliced to a common coding exon to form unique mRNA transcripts. Disruption of BDNF gene expression is a key to the development of symptoms in Huntington's disease (HD), a fatal neurodegenerative condition. Abnormal epigenetic modifications are associated with reduced gene expression in late-stage HD but such regulation of BDNF gene expression has yet to be investigated. We hypothesized that BDNF gene expression is altered in the HD hippocampus of pre-motor symptomatic R6/1 transgenic HD mice, correlating with a change in the DNA methylation profile. The effects of wheel-running and environmental enrichment on wild-type mice, in association with a proposed environment-mediated correction of BDNF gene expression deficits in HD mice, were also investigated. Using real-time PCR, levels of total BDNF mRNA were found to be reduced in the hippocampus of both male and female HD mice. Wheel-running significantly increased total BDNF gene expression in all groups of mice except male HD mice. In contrast, environmental enrichment significantly increased expression only in male wild-type animals. Further quantification of BDNF exon-specific transcripts revealed sex-specific changes in relation to the effect of the HD mutation and differential effects on gene expression by wheel-running and environmental enrichment. The HD-associated reduction of BDNF gene expression was not due to increased methylation of the gene sequence. Furthermore, environment-induced changes in BDNF gene expression in the wild-type hippocampus were independent of the extent of DNA methylation. Overall, the results of this study provide new insight into the role of BDNF in HD pathogenesis in addition to the mechanisms regulating normal BDNF gene expression. © 2009 Wiley-Liss, Inc.

Effects of prenatal ethanol exposure on postnatal renal function and structure in the rat. Renal function and morphology were studied in 90-day-old offspring of ethanol-fed (E) rats and were compared to pair-fed control (C) animals. Compared to C rats, E rats were smaller at birth, had higher fractional sodium excretion (p less than 0.01) and lower fractional potassium excretion (p less than 0.01). In E rats, sodium (Na) restriction resulted in a significant increase in urine flow and Na wastage, whereas C rats remained in Na balance. E rats developed hyperkalemia, when potassium (K) intake was increased from 2.8 to 14 mEq/day. Baseline creatinine clearance, urine and blood osmolalities and pH, plasma electrolytes and aldosterone concentrations were similar in both groups. There was no significant difference in wet or dry kidney weight, renal water content, or renal tissue concentrations of Na or K between the two groups. No difference was found in gross morphology or light microscopic appearances of the kidneys between E and C rats. Thus rats exposed to ethanol during fetal life have a defect in urine concentration and Na conservation when fed a low Na diet and a defect in K excretion when given a K load without evidence of any gross or light microscopic renal structural abnormalities at 90 days of age.

Pregnant Sprague-Dawley rats consumed an ethanol-containing liquid diet containing 0%, 17.5% or 35% ethanol-derived calories (EDC) from gestation day 8 until parturition. A fourth group was fed standard rat chow as an ad lib diet control. Animals prenatally exposed to ethanol had lower birth weights and impaired passive avoidance learning at 17 days of age. At 90 days of age synaptic potentials in area CA1 were characterized electrophysiologically in hippocampal slices. Slices from ethanol-exposed rats had significantly greater paired-pulse facilitation compared to 0% EDC and ad lib controls. Histological examination of brains from litter mates did not indicate altered number, density or nuclear volumes for neurons in area CA1. These data indicate that prenatal ethanol exposure can result in abnormal hippocampal synaptic physiology and suggest that these changes may contribute to the learning impairments observed in rats following such exposure.

Two studies were conducted to evaluate the interactive effects of alcohol and lead during pregnancy in rats. Our purpose was to see if lead, as lead acetate, would influence the alcohol effect already known to exist. In the first study, pregnant Long-Evans rats received lead (as lead acetate), alcohol (20% w/v), or lead plus alcohol once a day on gestation days (GD) 10-20. On GD 20, when animals were sacrificed, mean blood alcohol levels were consistently higher for the lead-plus-alcohol-dosed groups compared to alcohol alone, but these two groups did not differ in maternal weight gain, percent resorptions, litter size, or fetal weight. Mean blood lead levels were not consistently higher in the lead-plus-alcohol groups compared to lead only, but the lead-plus-alcohol groups differed significantly from the lead-only groups at higher doses in the previously mentioned parameters. The lead-only groups did not differ from vehicle controls in any parameter in spite of blood lead levels as high as 300 micrograms/dl. In the second experiment, animals given a combination of alcohol and lead did not differ in activity, passive avoidance, or active avoidance learning compared to animals given alcohol or lead alone. Animals given lead only or the combination of lead plus alcohol had longer first trial latencies in the passive avoidance test. The data indicate that neither lead nor alcohol attenuates or potentiates each other's effects on reproduction or learning behavior in the Long-Evans rat even at high blood lead levels.

We have calculated the paramagnetic susceptibility of rare earth intermetallics in the model of the crystal-field 4f split 4f ions interacting with conduction electrons by exchange coupling. Using the thermodynamic perturbation theory we have derived analytical formulae for the susceptibility to the second order. We have developed scheme to simultaneously optimize fitting of crystal-field and coupling parameters to the experimental data. >

Axisymmetrical large abdominal aortic aneurysms are considered in terms of formulated dimensionless parameters reflecting geometry and the actual arterial waveform under steady state conditions. Numerical solution of the differential equations yields wall shear stresses and normal forces which are verified experimentally in vitro. It is established that, depending on the parameter magnitudes, there are one or two separation regions. It is verified that the maximum stresses are located at the exit neck of the aneurysm. The separation regions found in the experimental and numerical results are observed to be the site for clots formation in a live specimen of an aneurysm removed during surgery.

One of the postoperative complications after strumectomy is hypoparathyroidism. Therefore, the purpose of our study was to evaluate the effect of the surgical technique on the development of parathyroid gland insufficiency in our group of patients. Subtotal, bilateral strumectomies were performed according to Rothmund's suggestions. Randomized controlled trial was performed in two groups. In the first group of 19 patients, main trunk of the inferior thyroid artery was ligated and in the second one consisting of 18 patients, only the branches of this artery were ligated. Total calcium and PTH levels were evaluated pre- and postoperatively. Based on the biochemical and clinical data, no statistically significant differences in the development of postoperative hypoparathyroidism in relation to performed surgical techniques were observed.

The efficacy of mafosfamide purging depends on factors like incubation time, drug and erythrocyte concentration. To determine the influence of protein-bound SH groups in the incubation medium, the cytotoxicity of mafosfamide on G-CSF mobilized CD34+/- cells was evaluated by short-term culture assays and drug concentration measurements. 100 micromol/ml mafosfamide was incubated for 30 min in five buffers (PBS, PBS with 1%, 5% and 10% BSA and plasma). The mean calculated areas under the concentration-time curves (AUC) were 2489 +/- 198, 1561 +/- 286, 976 +/- 201, 585 +/- 62 and 605 +/- 196 micromol/l/min. The mean reductions of CFU-GM growth were 79.4%, 73.0%, 62.5%, 30.3%, 6.2% respectively. Similar results were obtained for BFU-E. Regression analysis showed a good correlation between cytotoxicity and AUCs (CFU-GM: r = 0.8195; BFU-E: r = 0.8207). This effect is well explained by the different concentrations of SH moieties in the incubation medium resulting in a higher drug binding capacity. The profound difference between AUCs and CFU-GMs in plasma and 10% BSA cannot be explained by the quantity of SH-groups. It is probably due to an additional enzymatic drug degeneration by the 3'-5'exonuclease subsite of plasma DNA polymerase. In conclusion, the concentration of albumin-associated SH groups strongly influences the cytotoxicity of mafosfamide. It has to be considered as a new and important aspect in ex vivo bone marrow purging.

Analysis of 208 patients with atherosclerosis of the lower extremities and co-existing diabetes mellitus was performed to document actual symptoms, to propose a classification of extremity ischemic to localisate atherosclerotic changes and to evaluate therapeutic methods and their results. Authors suggest that to improve therapeutic results in this group of patients necessary is as follows: (a) early diagnosis of atherosclerotic ischemia of extremities, (b) proper preparing to revascularization, (c) early reconstruction of ischemic vessels, (d) good specialist controls in after surgery period.

In the recent years a constant increase of the number of surgical patients with associated diabetes mellitus is observed. Surgical risk is still higher and therapeutic results are worse than in patients without diabetes mellitus. Many years of experience of our department in the surgical treatment of lower limb atherosclerosis (A0) in patients with diabetes, and also the previously published results of studies make possible drawing of conclusions and formulating of a general view. The studies were carried out in 208 patients with A0 and diabetes mellitus. On admission, 65.9% of the patients had IV degrees of limb ischaemia according to Fontaine. Vascular operations in these patients accounted only for 25% of all operations and were performed in 37% of patients. Amputations accounted even for 53.7% of all operations, and among them major amputations accounted for 56.3%. The early and remote results of the operations carried out were subjected to statistical analysis and presented using cumulated indices.

Alcohol teratogenesis may be due in part to inhibition of neuronal differentiation by ethanol. We showed previously that alcohol decreased neuronal differentiation (neurite extension) and increased N-myc and c-myc neuronal protein levels. Since Growth-Associated Protein 43 (GAP43/B50) levels must increase for neurons to differentiate, alcohol may decrease GAP43/B50. Alcohol dose-dependently (0-0.5%) decreased GAP43/B50 protein levels by up to 92% in immature LA-N-5 cells. Five nM retinoic acid alone induced differentiation and increased GAP43/B50 levels to 230% of control. These retinoic acid-induced increases in GAP43/B50 and neurite outgrowth, and decreases in N-myc and c-myc, were reversed dose-dependently by alcohol (0-0.5%). Conversely, the adverse effects of 0.25% alcohol on neurite extension, GAP43/B50, N-myc, and c-myc were prevented by 15 and 45 nM retinoic acid. These results suggest that inhibition of neuronal differentiation by alcohol and prevention of such effects by retinoic acid are related to changes in GAP43/B50, N-myc and c-myc.

From the new existing data with not vanishing theta13 mixing angle we determine the possible shape of the Majorana neutrino mass matrix. We assume that CP symmetry is broken and all Dirac and Majorana phases are taken into account. Two possible approaches "bottom-up" and "top down" are presented. The problem of unphysical phases is examined in detail.

Previous studies have implicated renal ultrastructural abnormalities in the pathogenesis of tubular dysfunction in fetal alcohol syndrome. Scanning electron microscopic studies were performed to examine the role of glomerular and tubular structural changes in this syndrome. Pregnant Sprague-Dawley rats were fed a liquid diet in which ethanol constituted 35% of the total calori content or pair-fed an isocaloric control diet from gestational day 8 to the day of birth. After delivery, offspring were housed with the dam and left undisturbed until 18 days of age when they were weaned and given free access to standard chow diet and water. At random, kidneys from 11 offspring of ethanol-fed (E) rats and 7 pair-fed control (C) rats were fixed by in vivo retrograde perfusion at 90 days of age for ultrastructural studies. The E rats showed cytoplasmic mitochondrial atrophy and vacuolar structures of the epithelial cells of the distal tubules and collecting ducts not seen in C rats. No obvious difference was found in the glomerular, proximal tubule, or loop of Henle architecture between the two groups. These findings suggest that rats prenatally exposed to ethanol have renal ultrastructural abnormalities that may be important in the genesis of functional disturbances.