Early life programming and the risk of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, type 2 diabetes and cardiovascular disease and can be considered the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of disease, from the relatively benign simple steatosis to the more serious non-alcoholic steatohepatitis, which can progress to liver cirrhosis, hepatocellular carcinoma and end-stage liver failure, necessitating liver transplantation. Although the increasing prevalence of NAFLD in developed countries has substantial implications for public health, many of the precise mechanisms accounting for the development and progression of NAFLD are unclear. The environment in early life is an important determinant of cardiovascular disease risk in later life and studies suggest this also extends to NAFLD. Here we review data from animal models and human studies which suggest that fetal and early life exposure to maternal under- and overnutrition, excess glucocorticoids and environmental pollutants may confer an increased susceptibility to NAFLD development and progression in offspring and that such effects may be sex-specific. We also consider studies aimed at identifying potential dietary and pharmacological interventions aimed at reducing this risk. We suggest that further human epidemiological studies are needed to ensure that data from animal models are relevant to human health.

Planktonic marine iron oxidizers drive iron mineralization under low-oxygen conditions.

Observations of modern microbes have led to several hypotheses on how microbes precipitated the extensive iron formations in the geologic record, but we have yet to resolve the exact microbial contributions. An initial hypothesis was that cyanobacteria produced oxygen which oxidized iron abiotically; however, in modern environments such as microbial mats, where Fe(II) and O2 coexist, we commonly find microaerophilic chemolithotrophic iron-oxidizing bacteria producing Fe(III) oxyhydroxides. This suggests that such iron oxidizers could have inhabited niches in ancient coastal oceans where Fe(II) and O2 coexisted, and therefore contributed to banded iron formations (BIFs) and other ferruginous deposits. However, there is currently little evidence for planktonic marine iron oxidizers in modern analogs. Here, we demonstrate successful cultivation of planktonic microaerophilic iron-oxidizing Zetaproteobacteria from the Chesapeake Bay during seasonal stratification. Iron oxidizers were associated with low oxygen concentrations and active iron redox cycling in the oxic-anoxic transition zone (<3 µm O2 , <0.2 µm H2 S). While cyanobacteria were also detected in this transition zone, oxygen concentrations were too low to support significant rates of abiotic iron oxidation. Cyanobacteria may be providing oxygen for microaerophilic iron oxidation through a symbiotic relationship; at high Fe(II) levels, cyanobacteria would gain protection against Fe(II) toxicity. A Zetaproteobacteria isolate from this site oxidized iron at rates sufficient to account for deposition of geologic iron formations. In sum, our results suggest that once oxygenic photosynthesis evolved, microaerophilic chemolithotrophic iron oxidizers were likely important drivers of iron mineralization in ancient oceans.

The role of microaerophilic Fe-oxidizing micro-organisms in producing banded iron formations.

Despite the historical and economic significance of banded iron formations (BIFs), we have yet to resolve the formation mechanisms. On modern Earth, neutrophilic microaerophilic Fe-oxidizing micro-organisms (FeOM) produce copious amounts of Fe oxyhydroxides, leading us to wonder whether similar organisms played a role in producing BIFs. To evaluate this, we review the current knowledge of modern microaerophilic FeOM in the context of BIF paleoenvironmental studies. In modern environments wherever Fe(II) and O2 co-exist, microaerophilic FeOM proliferate. These organisms grow in a variety of environments, including the marine water column redoxcline, which is where BIF precursor minerals likely formed. FeOM can grow across a range of O2 concentrations, measured as low as 2 µm to date, although lower concentrations have not been tested. While some extant FeOM can tolerate high O2 concentrations, many FeOM appear to prefer and thrive at low O2 concentrations (~3-25 µm). These are similar to the estimated dissolved O2 concentrations in the few hundred million years prior to the 'Great Oxidation Event' (GOE). We compare biotic and abiotic Fe oxidation kinetics in the presence of varying levels of O2 and show that microaerophilic FeOM contribute substantially to Fe oxidation, at rates fast enough to account for BIF deposition. Based on this synthesis, we propose that microaerophilic FeOM were capable of playing a significant role in depositing the largest, most well-known BIFs associated with the GOE, as well as afterward when global O2 levels increased.

Mechanisms of extracellular S0 globule production and degradation in Chlorobaculumtepidum via dynamic cell-globule interactions.

The Chlorobiales are anoxygenic phototrophs that produce solid, extracellular elemental sulfur globules as an intermediate step in the oxidation of sulfide to sulfate. These organisms must export sulfur while preventing cell encrustation during S0 globule formation; during globule degradation they must find and mobilize the sulfur for intracellular oxidation to sulfate. To understand how the Chlorobiales address these challenges, we characterized the spatial relationships and physical dynamics of Chlorobaculum tepidum cells and S0 globules by light and electron microscopy. Cba. tepidum commonly formed globules at a distance from cells. Soluble polysulfides detected during globule production may allow for remote nucleation of globules. Polysulfides were also detected during globule degradation, probably produced as an intermediate of sulfur oxidation by attached cells. Polysulfides could feed unattached cells, which made up over 80% of the population and had comparable growth rates to attached cells. Given that S0 is formed remotely from cells, there is a question as to how cells are able to move toward S0 in order to attach. Time-lapse microscopy shows that Cba. tepidum is in fact capable of twitching motility, a finding supported by the presence of genes encoding type IV pili. Our results show how Cba. tepidum is able to avoid mineral encrustation and benefit from globule degradation even when not attached. In the environment, Cba. tepidum may also benefit from soluble sulfur species produced by other sulfur-oxidizing or sulfur-reducing bacteria as these organisms interact with its biogenic S0 globules.

Measuring Activity Performance of Continuing Care Residents Using the activPAL: An Exploratory Study.

Few studies have measured the activity patterns of continuing care residents using objective, uniaxial, accelerometers such as the activPAL. This exploratory study described the activity performance of continuing care residents and explored the correlation of activity performance with grip strength, falls and mobility. Data were gathered from 24 continuing care residents. Participants (82.3 ± 5.8 years of age), wore the activPAL an average of 12.60 hours per day (SD = 0.96) and were stepping for a median of 0.47 hours (25th and 75th percentiles = 0.31, 0.81) with a median step count of 1906 steps (25th and 75th percentiles = 1216, 3420). Participants were inactive (sitting/lying/standing) for a mean 11.99 hours (SD = 1.03). No statistically significant correlations were identified between activity performance (active time, inactive time or step count) and grip strength, falls or mobility. Ambulatory older adults in continuing care centres were more sedentary compared to community-dwelling older adults or older adults with cancer.

Involvement of tumor suppressors PTEN and p53 in the formation of multiple subtypes of liposarcoma.

Liposarcoma (LPS) is a type of soft tissue sarcoma that mostly occurs in adults, and in humans is characterized by amplifications of MDM2 and CDK4. The molecular pathogenesis of this malignancy is still poorly understood and, therefore, we developed a mouse model with conditional inactivation of PTEN and p53 to investigate these pathways in the progression of the disease. We show that deletion of these two tumor suppressors cooperate in the formation of multiple subtypes of LPS (from well-differentiated LPS to pleomorphic LPS). In addition, progression of the tumors is further characterized by the expression of D cyclins and CDK4/6, which allow for continued cell division. Microarray analysis also revealed novel genes that are differentially expressed between different subtypes of LPS, which could aid in understanding the disease and to unravel potential new therapeutic targets.

The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors.

Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three-dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well.

Development of anti-influenza A compounds: a pilot study.

1. There is no effective anti-H5N1 avian influenza agent. 2. A chemical compound­ BFDBSC­can inhibit H5N1 virus infection in cell cultures, and such inhibition might be attributable to its halogenated benzoyl residues. 3. This pilot study assessed anti- H5N1 activity and toxicity of four chemical compounds with halogenated benzoyl residues in cell culture system. 4. Two compounds­FPBFDBSC and BFB-gallate­ showed higher antiviral effectsthan BFDBSC, whearas the other two­BFB-borneol and BFB-menthol­showed lower antiviral effects. These compounds did not show toxicity. 5. The halogenated benzoyl residues may play a key role in anti-H5N1 effects. However, all these compounds showed poor solubility, which may limit their utility

Morphology of biogenic iron oxides records microbial physiology and environmental conditions: toward interpreting iron microfossils.

Despite the abundance of Fe and its significance in Earth history, there are no established robust biosignatures for Fe(II)-oxidizing micro-organisms. This limits our ability to piece together the history of Fe biogeochemical cycling and, in particular, to determine whether Fe(II)-oxidizers played a role in depositing ancient iron formations. A promising candidate for Fe(II)-oxidizer biosignatures is the distinctive morphology and texture of extracellular Fe(III)-oxyhydroxide stalks produced by mat-forming microaerophilic Fe(II)-oxidizing micro-organisms. To establish the stalk morphology as a biosignature, morphologic parameters must be quantified and linked to the microaerophilic Fe(II)-oxidizing metabolism and environmental conditions. Toward this end, we studied an extant model organism, the marine stalk-forming Fe(II)-oxidizing bacterium, Mariprofundus ferrooxydans PV-1. We grew cultures in flat glass microslide chambers, with FeS substrate, creating opposing oxygen/Fe(II) concentration gradients. We used solid-state voltammetric microelectrodes to measure chemical gradients in situ while using light microscopy to image microbial growth, motility, and mineral formation. In low-oxygen (2.7-28 µm) zones of redox gradients, the bacteria converge into a narrow (100 µm-1 mm) growth band. As cells oxidize Fe(II), they deposit Fe(III)-oxyhydroxide stalks in this band; the stalks orient directionally, elongating toward higher oxygen concentrations. M. ferrooxydans stalks display a narrow range of widths and uniquely biogenic branching patterns, which result from cell division. Together with filament composition, these features (width, branching, and directional orientation) form a physical record unique to microaerophilic Fe(II)-oxidizer physiology; therefore, stalk morphology is a biosignature, as well as an indicator of local oxygen concentration at the time of formation. Observations of filamentous Fe(III)-oxyhydroxide microfossils from a ~170 Ma marine Fe-Si hydrothermal deposit show that these morphological characteristics can be preserved in the microfossil record. This study demonstrates the potential of morphological biosignatures to reveal microbiology and environmental chemistry associated with geologic iron formation depositional processes.

Near-neutral surface charge and hydrophilicity prevent mineral encrustation of Fe-oxidizing micro-organisms.

Microbial survival in mineralizing environments depends on the ability to evade surface encrustation by minerals, which could obstruct nutrient uptake and waste output. Some organisms localize mineral precipitation away from the cell; however, cell surface properties - charge and hydrophobicity - must also play a role in preventing surface mineralization. This is especially relevant for iron-oxidizing bacteria (FeOB), which face an encrustation threat from both biotic and abiotic mineralization. We used electron microscopy and surface characterization techniques to study the surfaces of two stalk-forming neutrophilic FeOB: the marine Zetaproteobacterium Mariprofundus ferrooxydans PV-1 and the recently isolated freshwater Betaproteobacterium Gallionellales strain R-1. Both organisms lack detectable iron on cell surfaces. Live and azide-inhibited M. ferrooxydans PV-1 cells had small negative zeta potentials (-0.34 to -2.73 mV), over the pH range 4.2-9.4; Gallionellales strain R-1 cells exhibited an even smaller zeta potential (-0.10 to -0.19 mV) over pH 4.2-8.8. Cells have hydrophilic surfaces, according to water contact angle measurements and microbial adhesion to hydrocarbons tests. Thermodynamic and extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) calculations showed that as low charge causes low electrostatic attraction, hydrophilic repulsion dominates cell-mineral interactions. Therefore, we conclude that surface properties help enable these FeOB to survive in highly mineralizing environments. Given both mineral-repelling surface properties and the ability to sequester Fe(III) biominerals in an organomineral stalk, these two FeOB have a well-coordinated system to localize both biotic and abiotic mineral distribution.

Ultra-diffuse hydrothermal venting supports Fe-oxidizing bacteria and massive umber deposition at 5000 m off Hawaii.

A novel hydrothermal field has been discovered at the base of Loihi Seamount, Hawaii, at 5000 mbsl. Geochemical analyses demonstrate that 'FeMO Deep', while only 0.2 °C above ambient seawater temperature, derives from a distal, ultra-diffuse hydrothermal source. FeMO Deep is expressed as regional seafloor seepage of gelatinous iron- and silica-rich deposits, pooling between and over basalt pillows, in places over a meter thick. The system is capped by mm to cm thick hydrothermally derived iron-oxyhydroxide- and manganese-oxide-layered crusts. We use molecular analyses (16S rDNA-based) of extant communities combined with fluorescent in situ hybridizations to demonstrate that FeMO Deep deposits contain living iron-oxidizing Zetaproteobacteria related to the recently isolated strain Mariprofundus ferroxydans. Bioenergetic calculations, based on in-situ electrochemical measurements and cell counts, indicate that reactions between iron and oxygen are important in supporting chemosynthesis in the mats, which we infer forms a trophic base of the mat ecosystem. We suggest that the biogenic FeMO Deep hydrothermal deposit represents a modern analog for one class of geological iron deposits known as 'umbers' (for example, Troodos ophilolites, Cyprus) because of striking similarities in size, setting and internal structures.

α8-integrins are required for hippocampal long-term potentiation but not for hippocampal-dependent learning.

Integrins are heterodimeric transmembrane cell adhesion receptors that are essential for a wide range of biological functions via cell-matrix and cell-cell interactions. Recent studies have provided evidence that some of the subunits in the integrin family are involved in synaptic and behavioral plasticity. To further understand the role of integrins in the mammalian central nervous system, we generated a postnatal forebrain and excitatory neuron-specific knockout of alpha8-integrin in the mouse. Behavioral studies showed that the mutant mice are normal in multiple hippocampal-dependent learning tasks, including a T-maze, non-match-to-place working memory task for which other integrin subunits like alpha3- and beta1-integrin are required. In contrast, mice mutant for alpha8-integrin exhibited a specific impairment of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, whereas basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD) remained unaffected. Because LTP is also impaired in the absence of alpha3-integrin, our results indicate that multiple integrin molecules are required for the normal expression of LTP, and different integrins display distinct roles in behavioral and neurophysiological processes like synaptic plasticity.

Major haemoptysis in Hong Kong: aetiologies, angiographic findings and outcomes of bronchial artery embolisation.

SETTING: Tertiary referral centres. OBJECTIVE: To provide comprehensive updates on the aetiologies, angiographic findings and outcomes of bronchial artery embolisation (BAE) for life-threatening haemoptysis in Hong Kong. DESIGN: Retrospective review of clinical records of consecutive patients presenting with life-threatening haemoptysis from 2000 to 2006. RESULTS: There were 3006 admissions due to haemoptysis involving 2260 patients during the study period; of these, 251 patients had life-threatening haemoptysis. Pulmonary tuberculosis (PTB) (active or inactive) and bronchiectasis were the main underlying causes. BAE was attempted in 167 patients. There was a high prevalence of bilateral bronchial arterial abnormalities (31.7%), presence of abnormal non-bronchial arteries (41.3%) and presence of broncho-pulmonary shunt (38.9%). BAE had a high immediate success rate of 95.7%, with a 5-year recurrence rate of 45.0%. Recurrent life-threatening haemoptysis was independently associated with past history of haemoptysis (P = 0.024), presence of broncho-pulmonary shunt (P = 0.013), and incomplete embolisation (P = 0.002). Complications were uncommon (<5%) and self-limiting. CONCLUSIONS: In Hong Kong, about one tenth of admissions due to haemoptysis were life-threatening. PTB and bronchiectasis were the major causes. Complications due to BAE were uncommon and self-limiting, with super-selective catheters.

Molecular and genetic characterisation of the SARS coronavirus auxiliary protein X1 in Drosophila.

1. We have generated monoclonal antibodies against the SARS coronavirus (SARS-CoV) X1/3a protein (3a), which are suitable for western blotting, immunocytochemistry, and immunohistochemistry. 2. We have established and characterised an in-vivo 3a transgenic Drosophila model, and demonstrated its usefulness in studying SARS-CoV 3a gene function. 3. We validated our in-vivo findings on 3a gene function in mammalian Vero E6 cells. 4. Our findings raise the possibility of using ion channel blockers as a novel approach to suppress SARS-CoV-induced cell death.

Change in bone mineral density and its determinants in pre- and perimenopausal Chinese women: the Hong Kong Perimenopausal Women Osteoporosis Study.

UNLABELLED: This 30-month study investigating bone change and its determinants in 438 perimenopausal Chinese women revealed that the fastest bone loss occurred in women undergoing menopausal transition but maintenance of body weight and physical fitness were beneficial for bone health. Soy protein intake also seemed to exert a protective effect. INTRODUCTION: This 30-month follow-up study aims to investigate change in bone mineral density and its determinants in Hong Kong Chinese perimenopausal women. METHODS: Four hundred and thirty-eight women aged 45 to 55 years were recruited through random telephone dialing and primary care clinic. Bone mass, body composition, lifestyle measurements were obtained at baseline and at 9-, 18- and 30-month follow-ups. Univariate and stepwise multiple regression analyses were performed with the regression coefficients of BMD/C (derived from baseline and follow-up measurements) as the outcome variables. Menopausal status was classified as pre- or postmenopausal or transitional. RESULTS: Menopausal status was the strongest determinant of bone changes. An annual bone loss of about 0.5% was observed among premenopausal, 2% to 2.5% among transitional, and about 1.5% in postmenopausal women. Multiple regression analyses, revealed that a positive regression slope of body weight was protective for follow-up bone loss at all sites. Number of pregnancy, soy protein intake and walking were protective for total body BMC. Higher baseline LM was also protective for neck of femur BMD. CONCLUSION: Maintenance of body weight and physical fitness were observed to have a protective effect on for bone loss in Chinese perimenopausal women.