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Objective: To determine whether a dietary intervention in pregnancy had a lasting effect on maternal outcomes of diet, HbA1c and weight retention 5 years post-intervention; and to establish whether modifiable maternal behaviours were associated with these outcomes.Design: Randomised control trial of low glycaemic index (GI) diet in pregnancy with longitudinal follow up to 5 years post-intervention.Setting: Dublin, Ireland (2007-2016).Population: In all, 403 women of 759 (53.1%) were followed up at 5 years. A total of 370 (intervention n = 188; control n = 182) were included in this analysis.Methods: Fasting glucose was measured at 13 and 28 weeks' gestation and HbA1c (mmol/mol) at 5-year follow up. Weight retention (kg) from early pregnancy to 5 years post-intervention was calculated. Dietary intakes, anthropometry, and lifestyle factors were measured in pregnancy and 5 years post-intervention. Multiple linear regression models, controlling for confounders, were used for analysis.Outcome: Maternal diet, HbA1c, and weight retention at 5 years post-intervention.Results: There was no difference between the intervention and control at 5 years post-intervention for any long-term maternal outcomes measured. HbA1c at 5 years post-intervention was associated with early-pregnancy fasting glucose (B 1.70, 95% CI 0.36-3.04) and parity ≥3 (B 1.04, 95% CI 0.09-1.99). Weight retention was associated with change in well-being from pregnancy to 5 years (B -0.06, 95% CI -0.11 to -0.02), gestational weight gain (B 0.19, 95% CI 0.00-0.38), and GI (B 0.26, 95% CI 0.06-0.46) at 5 years.Conclusions: The ROLO low-GI dietary intervention in pregnancy had no impact on maternal dietary intakes, HbA1c or body composition 5 years post-intervention. Maternal factors and lifestyle behaviours in pregnancy have long-term effects on glucose metabolism and weight retention up to 5 years later.Tweetable Abstract: Pregnancy factors are associated with maternal glucose metabolism and weight retention 5 years later-findings from the ROLO Study. [ABSTRACT FROM AUTHOR]

Abstract Background Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which has been shown to increase the susceptibility of various bacteria to antimicrobials and demonstrated to have broad antimicrobial activity. This study describes transcriptome alterations in S. aureus strain COL grown with diclofenac and characterizes the effects of this NSAID on antibiotic susceptibility in laboratory, clinical and diclofenac reduced-susceptibility (DcRS) S. aureus strains. Methods Transcriptional alterations in response to growth with diclofenac were measured using S. aureus gene expression microarrays and quantitative real-time PCR. Antimicrobial susceptibility was determined by agar diffusion MICs and gradient plate analysis. Ciprofloxacin accumulation was measured by fluorescence spectrophotometry. Results Growth of S. aureus strain COL with 80 μg/ml (0.2 × MIC) of diclofenac resulted in the significant alteration by ≥2-fold of 458 genes. These represented genes encoding proteins for transport and binding, protein and DNA synthesis, and the cell envelope. Notable alterations included the strong down-regulation of antimicrobial efflux pumps including mepRAB and a putative emrAB/qacA-family pump. Diclofenac up-regulated sigB (σB), encoding an alternative sigma factor which has been shown to be important for antimicrobial resistance. Staphylococcus aureus microarray metadatabase (SAMMD) analysis further revealed that 46% of genes differentially-expressed with diclofenac are also σB-regulated. Diclofenac altered S. aureus susceptibility to multiple antibiotics in a strain-dependent manner. Susceptibility increased for ciprofloxacin, ofloxacin and norfloxacin, decreased for oxacillin and vancomycin, and did not change for tetracycline or chloramphenicol. Mutation to DcRS did not affect susceptibility to the above antibiotics. Reduced ciprofloxacin MICs with diclofenac in strain BB255, were not associated with increased drug accumulation. Conclusions The results of this study suggest that diclofenac influences antibiotic susceptibility in S. aureus, in part, by altering the expression of regulatory and structural genes associated with cell wall biosynthesis/turnover and transport.

Abstract Background: Global patterns of gene expression of Escherichia coli K-12 during growth transitions have been deeply investigated, however, comparable studies of E. coli O157:H7 have not been explored, particularly with respect to factors regulating virulence genes and genomic islands specific to this pathogen. To examine the impact of growth phase on the dynamics of the transcriptome, O157:H7 Sakai strain was cultured in MOPS minimal media (0.1% glucose), RNA harvested at 10 time points from early exponential to full stationary phase, and relative gene expression was measured by co-hybridization on high-density DNA microarrays. Expression levels of 14 genes, including those encoding Shiga toxins and other virulence factors associated with the locus of enterocyte effacement (LEE), were confirmed by Q-PCR. Results: Analysis of variance (R/MAANOVA, Fs test) identified 442 (36%) of 1239 O157-specific ORFs and 2110 (59%) of 3647 backbone ORFs that changed in expression significantly over time. QT cluster analysis placed 2468 of the 2552 significant ORFs into 12 groups; each group representing a distinct expression pattern. ORFs from the largest cluster (n = 1078) decreased in expression from late exponential to early stationary phase: most of these ORFs are involved in functions associated with steady state growth. Also represented in this cluster are ORFs of the TAI island, encoding tellurite resistance and urease activity, which decreased ~4-fold. Most ORFs of the LEE pathogenicity island also decreased ~2-fold by early stationary phase. The ORFs encoding proteins secreted via the LEE encoded type III secretion system, such as tccP and espJ, also decreased in expression from exponential to stationary phase. Three of the clusters (n = 154) comprised genes that are transiently upregulated at the transition into stationary phase and included genes involved in nutrient scavenging. Upregulated genes with an increase in mRNA levels from late exponential to early stationary phase belonged to one cluster (n = 923) which includes genes involved in stress responses (e.g. gadAB, osmBC, and dps). These transcript levels remained relatively high for > 3 h in stationary phase. The Shiga toxin genes (stx1AB and stx2B) were significantly induced after transition into stationary phase. Conclusion: Expression of more than 300 O157-specific ORFs, many implicated in virulence of the O157 pathogen, was modulated in a growth dependent manner. These results provide a baseline transcriptional profile that can be compared to patterns of gene expression of this important foodborne pathogen under adverse environmental conditions.

The α-helix is the most commonly found natural secondary structure in proteins and is intrinsic to many protein-protein interactions involved in important biological functions. Novel peptides designed to mimic helices found in nature employ a variety of methods to control their structure. These approaches are significant due to potential applications in developing new therapeutic agents and materials. Over the years, many strategies have emerged to influence, initiate, and propagate helical content in short, synthetic peptides. Early innovations used the natural macrocycle tether of disulfide bond formation, metal-mediated or lactam group addition as a means to prompt helical formation. These examples have been applied to a host of peptides as inhibitors toward relevant diseases including cancer, viral and bacterial infection. In the most recent decades, hydrocarbon bridges to "staple" peptides across side chains or hydrogen bond surrogates in the backbone of peptides have been effective in producing biologically functional, helical peptidomimetics with non-natural elements, increased protease resistance and potency in vitro and in vivo. Modern methods expand and elaborate these, with applications of functional peptides from both synthetic and recombinant origins. Overall, efforts persist using these strategies to create peptides with great biological potential and a better understanding of the control of helical structure in protein folding.

Objective: To determine whether a dietary intervention in pregnancy had a lasting effect on maternal outcomes of diet, HbA1c and weight retention 5 years post-intervention; and to establish whether modifiable maternal behaviours were associated with these outcomes., Design: Randomised control trial of low glycaemic index (GI) diet in pregnancy with longitudinal follow up to 5 years post-intervention., Setting: Dublin, Ireland (2007-2016)., Population: In all, 403 women of 759 (53.1%) were followed up at 5 years. A total of 370 (intervention n = 188; control n = 182) were included in this analysis., Methods: Fasting glucose was measured at 13 and 28 weeks' gestation and HbA1c (mmol/mol) at 5-year follow up. Weight retention (kg) from early pregnancy to 5 years post-intervention was calculated. Dietary intakes, anthropometry, and lifestyle factors were measured in pregnancy and 5 years post-intervention. Multiple linear regression models, controlling for confounders, were used for analysis., Outcome: Maternal diet, HbA1c, and weight retention at 5 years post-intervention., Results: There was no difference between the intervention and control at 5 years post-intervention for any long-term maternal outcomes measured. HbA1c at 5 years post-intervention was associated with early-pregnancy fasting glucose (B 1.70, 95% CI 0.36-3.04) and parity ≥3 (B 1.04, 95% CI 0.09-1.99). Weight retention was associated with change in well-being from pregnancy to 5 years (B -0.06, 95% CI -0.11 to -0.02), gestational weight gain (B 0.19, 95% CI 0.00-0.38), and GI (B 0.26, 95% CI 0.06-0.46) at 5 years., Conclusions: The ROLO low-GI dietary intervention in pregnancy had no impact on maternal dietary intakes, HbA1c or body composition 5 years post-intervention. Maternal factors and lifestyle behaviours in pregnancy have long-term effects on glucose metabolism and weight retention up to 5 years later., Tweetable Abstract: Pregnancy factors are associated with maternal glucose metabolism and weight retention 5 years later-findings from the ROLO Study., (© 2018 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Multiple high-dose methamphetamine administrations cause long-lasting (>1 week) deficits in striatal dopaminergic neuronal function. This stimulant likewise causes rapid (within 1 h) and persistent (at least 48 h) decreases in activities of striatal: 1) dopamine transporters, as assessed in synaptosomes; and 2) vesicular monoamine transporter -2 (VMAT-2), as assessed in a non-membrane-associated (referred to herein as cytoplasmic) vesicular subcellular fraction. Importantly, not all brain areas are vulnerable to methamphetamine-induced long-lasting deficits. Similarly, the present study indicates that methamphetamine exerts differential acute effects on monoaminergic transporters according to brain region. In particular, results revealed that in the nucleus accumbens, methamphetamine rapidly, but reversibly (within 24 h), decreased plasmalemmal dopamine transporter function, without effect on plasmalemmal dopamine transporter immunoreactivity. Methamphetamine also rapidly and reversibly (within 48 h) decreased cytoplasmic VMAT-2 function in this region, with relatively little effect on cytoplasmic VMAT-2 immunoreactivity. In contrast, methamphetamine did not alter either dopamine transporter or VMAT-2 activity in the hypothalamus. Noteworthy, the nucleus accumbens and hypothalamus did not display the persistent long-lasting striatal dopamine depletions caused by the stimulant. Taken together, these data suggest that deficits in plasmalemmal and vesicular monoamine transporter activity lasting greater than 24-48 h may be linked to the long-lasting dopaminergic deficits caused by methamphetamine and appear to be region specific.

Repeated high-dose injections of methamphetamine (METH) rapidly decrease dopamine uptake by the vesicular monoamine transporter-2 (VMAT-2) associated with dopaminergic nerve terminals, as assessed in nonmembrane-associated vesicles purified from striata of treated rats. The purpose of this study was to determine whether METH similarly affects vesicular uptake in the hippocampus; a region innervated by both serotonergic and noradrenergic neurons and profoundly affected by METH treatment. Results revealed that repeated high-dose METH administrations rapidly (within 1 h) reduced hippocampal vesicular dopamine uptake, as assessed in vesicles purified from treated rats. This reduction was likely associated with serotonergic nerve terminals because METH did not further reduce vesicular monoamine uptake in para-chloroamphetamine-lesioned animals. Pretreatment with the serotonin transporter inhibitor fluoxetine blocked both this acute effect on VMAT-2 and the decrease in serotonin content observed 7 days after METH treatment. In contrast, there was no conclusive evidence that METH affected vesicular dopamine uptake in noradrenergic neurons or caused persistent noradrenergic deficits. These findings suggest a link between METH-induced alterations in serotonergic hippocampal vesicular uptake and the persistent hippocampal serotonergic deficits induced by the stimulant.

Cell survival during a severe heat stress can be enhanced when heat shock proteins are induced prior to the severe heat treatment. Induction can be accomplished either by heat or chemical treatments. The increase in survival at these severe elevated temperatures after pretreatment has been referred to as thermotolerance, which we now refer to as survival thermotolerance. It has also been shown previously that mild heat treatment allows splicing in cells subjected to a severe heat treatment, now referred to as splicing thermotolerance. The experiments shown here demonstrate that even though chemical induction of the heat shock proteins leads to survival thermotolerance, this same treatment does not induce splicing thermotolerance. These are the first results that demonstrate at least two distinct aspects of thermotolerance.

Electron microscopy of lentigines was performed to study the pigmentation abnormality in two children with LEOPARD syndrome. Giant melanosomes similar to those seen in café-au-lait spots of neurofibromatosis and nevus spilus were found in a lentigine from one of our cases. Our results show that "spherical granular melanosomes" described in neurofibromatosis, are lysosomal-like structures associated with the development of complex melanin granules. Our study also demonstrates that immature melanosomes are present in some keratinocytes of LEOPARD syndrome. This finding is in contrast to the prevailing concept that only mature melanosomes are transferred to keratinocytes. The occurrence of individual melanosomes of normal size and shape in keratinocytes of skin in whites with LEOPARD syndrome, suggests that neither the size of melanosomes, nor the racial differences are the factors determining the distribution of melanosomes in keratinocytes.

Five brothers of from 6 to 18 years of age experienced immunological or neoplastic disorders during an 8-year interval. 2 boys succumbed to glioblastoma multiforme, another to metastatic carcinoma, and the 2 surviving brothers had a histiocytic lymphoma and idiopathic thrombocytopenia purpura, respectively. The mother of the boys was healthy, but her twin sister died in utero of birth defects. We suggest that an intrinsic cellular defect inherited from their mother rendered the boys vulnerable to oncogenesis.