In Gram-negative bacteria, the introduction of disulfide bonds into folding proteins occurs in the periplasm and is catalyzed by donation of an energetically unstable disulfide from DsbA, which is ...subsequently re-oxidized through interaction with DsbB. Gram-positive bacteria lack a classic periplasm but nonetheless encode Dsb-like proteins. Staphylococcus aureus encodes just one Dsb protein, a DsbA, and no DsbB. Here we report the crystal structure of S. aureus DsbA (SaDsbA), which incorporates a thioredoxin fold with an inserted helical domain, like its Escherichia coli counterpart EcDsbA, but it lacks the characteristic hydrophobic patch and has a truncated binding groove near the active site. These findings suggest that SaDsbA has a different substrate specificity than EcDsbA. Thermodynamic studies indicate that the oxidized and reduced forms of SaDsbA are energetically equivalent, in contrast to the energetically unstable disulfide form of EcDsbA. Further, the partial complementation of EcDsbA by SaDsbA is independent of EcDsbB and biochemical assays show that SaDsbA does not interact with EcDsbB. The identical stabilities of oxidized and reduced SaDsbA may facilitate direct re-oxidation of the protein by extracellular oxidants, without the need for DsbB.
► We propose the intensity growth maps (IGM) to perform segmentation of one-year old data. ► The IGM captured intensity changes of 20–25% in immature WM regions. ► We generate adaptive tissue ...probability map of one-year old data using IGM. ► IGM-EM has a dice error ratio, GM: 9.75 and WM: 12.66. ► The results of IGM-EM show good performance in temporal and prefrontal lobe areas.
The degree of white matter (WM) myelination is rather inhomogeneous across the brain. White matter appears differently across the cortical lobes in MR images acquired during early postnatal development. Specifically at 1-year of age, the gray/white matter contrast of MR T1 and T2 weighted images in prefrontal and temporal lobes is reduced as compared to the rest of the brain, and thus, tissue segmentation results commonly show lower accuracy in these lobes. In this novel work, we propose the use of spatial intensity growth maps (IGM) for T1 and T2 weighted images to compensate for local appearance inhomogeneity. The IGM captures expected intensity changes from 1 to 2years of age, as appearance homogeneity is greatly improved by the age of 24months. The IGM was computed as the coefficient of a voxel-wise linear regression model between corresponding intensities at 1 and 2years. The proposed IGM method revealed low regression values of 1–10% in GM and CSF regions, as well as in WM regions at maturation stage of myelination at 1year. However, in the prefrontal and temporal lobes we observed regression values of 20–25%, indicating that the IGM appropriately captures the expected large intensity change in these lobes mainly due to myelination. The IGM is applied to cross-sectional MRI datasets of 1-year-old subjects via registration, correction and tissue segmentation of the IGM-corrected dataset. We validated our approach in a small leave-one-out study of images with known, manual ‘ground truth’ segmentations.
Purpose To evaluate the efficacy and safety of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in metastatic breast cancer (MBC). Experimental design Patients with measurable, progressive, or ...recurrent MBC whose primary tumor expressed >=1 ErbB receptor were randomized to the following CI-1033 regimens: 50 mg (arm A) or 150 mg (arm B) daily without rest period, or 450 mg/day x 14 days every 21 days (arm C). The primary endpoint was 1-year progression-free survival (PFS). Results Overall, 194 patients were treated. One-year PFS estimates were 3.8, 2.0, and 4.6%; median PFS was 61, 56, and 58 days; and investigator-assessed overall response rates were 1.5, 1.5, and 7.3%, in arms A, B, and C, respectively. Response duration was 110-419 days. In arm C, response (18.8 vs. 2.6%) and 1-year overall survival rates (86.7 vs. 47.5%) were greater in patients with HER2-positive versus HER2-negative tumors. The incidence of grade 3/4 adverse events (AEs) was dose-dependent, affecting 10.3, 48.6, and 80.4% of patients in arms A, B and C, respectively. The most common grade 3/4, treatment-related AEs were diarrhea, asthenia, and stomatitis. Arm C enrollment was prematurely discontinued due to a high frequency of grade 3/4 AEs. Conclusion Single-agent CI-1033 did not show clinically meaningful activity in heavily pretreated patients with MBC expressing >=1 ErbB receptor. Antitumor activity was observed in arm C patients with HER2-positive tumors. However, only the 50 mg dose was well tolerated, and the highest dose reached unacceptable levels of toxicity.
Despite emerging evidence that foot problems and inappropriate footwear increase the risk of falls, there is little evidence as to whether foot-related intervention strategies can be successfully ...implemented. The aim of this study was to evaluate adherence rates, barriers to adherence, and the predictors of adherence to a multifaceted podiatry intervention for the prevention of falls in older people.
The intervention group (n = 153, mean age 74.2 years) of a randomised trial that investigated the effectiveness of a multifaceted podiatry intervention to prevent falls was assessed for adherence to the three components of the intervention: (i) foot orthoses, (ii) footwear advice and footwear cost subsidy, and (iii) a home-based foot and ankle exercise program. Adherence to each component and the barriers to adherence were documented, and separate discriminant function analyses were undertaken to identify factors that were significantly and independently associated with adherence to the three intervention components.
Adherence to the three components of the intervention was as follows: foot orthoses (69%), footwear (54%) and home-based exercise (72%). Discriminant function analyses identified that being younger was the best predictor of orthoses use, higher physical health status and lower fear of falling were independent predictors of footwear adherence, and higher physical health status was the best predictor of exercise adherence. The predictive accuracy of these models was only modest, with 62 to 71% of participants correctly classified.
Adherence to a multifaceted podiatry intervention in this trial ranged from 54 to 72%. People with better physical health, less fear of falling and a younger age exhibited greater adherence, suggesting that strategies need to be developed to enhance adherence in frailer older people who are most at risk of falling.
Australian New Zealand Clinical Trials Registry ACTRN12608000065392.
This paper presents a summary of the key findings of the special issue of Atmosphere on Air Quality in New South Wales and discusses the implications of the work for policy makers and individuals. ...This special edition presents new air quality research in Australia undertaken by (or in association with) the Clean Air and Urban Landscapes hub, which is funded by the National Environmental Science Program on behalf of the Australian Government’s Department of the Environment and Energy. Air pollution in Australian cities is generally low, with typical concentrations of key pollutants at much lower levels than experienced in comparable cities in many other parts of the world. Australian cities do experience occasional exceedances in ozone and PM2.5 (above air pollution guidelines), as well as extreme pollution events, often as a result of bushfires, dust storms, or heatwaves. Even in the absence of extreme events, natural emissions play a significant role in influencing the Australian urban environment, due to the remoteness from large regional anthropogenic emission sources. By studying air quality in Australia, we can gain a greater understanding of the underlying atmospheric chemistry and health risks in less polluted atmospheric environments, and the health benefits of continued reduction in air pollution. These conditions may be representative of future air quality scenarios for parts of the Northern Hemisphere, as legislation and cleaner technologies reduce anthropogenic air pollution in European, American, and Asian cities. However, in many instances, current legislation regarding emissions in Australia is significantly more lax than in other developed countries, making Australia vulnerable to worsening air pollution in association with future population growth. The need to avoid complacency is highlighted by recent epidemiological research, reporting associations between air pollution and adverse health outcomes even at air pollutant concentrations that are lower than Australia’s national air quality standards. Improving air quality is expected to improve health outcomes at any pollution level, with specific benefits projected for reductions in long-term exposure to average PM2.5 concentrations.
Previous work has demonstrated the efficacy and safety of fesoterodine in older and younger subjects with overactive bladder (OAB) symptoms. The effect of long-term fesoterodine treatment in ...different age groups has not been assessed.
The aim was to determine the impact of age on the safety, tolerability and efficacy of long-term treatment with fesoterodine 8 mg in subjects with OAB syndrome.
This was a pooled analysis of two identically designed open-label extensions of 12-week, randomized, double-blind, placebo-controlled studies. The setting was urology and general practice offices. Subjects who participated in the 12-week, double-blind studies and opted to continue long-term, open-label treatment with fesoterodine were included. Subjects were initiated on fesoterodine 8 mg/day at open-label baseline. After 1 month, subjects could elect dose reduction to 4 mg/day and subsequent re-escalation to 8 mg; each was permitted once annually. Maximal duration of open-label treatment ranged from 24 to 36 months. Discontinuations, subject-reported treatment tolerance, and efficacy (3-day diaries) were assessed at open-label baseline and months 1, 4, 8, 12 and 24.
A total of 890 subjects were treated (age <45 years, n = 140; 45-64 years, n = 444; 65-74 years, n = 208; ≥75 years, n = 98); 49% continued treatment for ≥ 24 months (age <45 years, 43%; 45-64 years, 54%; 65-74 years, 50%; ≥75 years, 37%). Seventy-seven percent of subjects remained on fesoterodine 8 mg throughout treatment; this rate was highest among subjects aged ≥75 years (age <45 years, 72%; 45-64 years, 77%; 65-74 years, 73%; ≥75 years, 87%). Approximately 80% of continuing subjects were receiving fesoterodine 8 mg at each visit after open-label baseline up to 36 months. No new or unexpected safety signals were observed in any age group. Most subjects reported 'good' or 'excellent' treatment tolerance throughout the study (age <45 years, ≥90%; 45-64 years, ≥93%; 65-74 years, ≥85%; ≥75 years, ≥86%). Dry mouth, the most commonly reported treatment-emergent adverse event, was lowest among subjects aged ≥75 years (age <45 years, 31%; 45-64 years, 30%; 65-74 years, 32%; ≥75 years, 26%). Rates of discontinuation due to dry mouth were low in all age groups. Significant improvements in all diary variables, including urgency urinary incontinence episodes per 24 hours, micturitions per 24 hours, urgency episodes per 24 hours, and mean voided volume per micturition, observed between double-blind baseline and open-label baseline were sustained or increased during open-label treatment in the overall population and all age groups.
Long-term fesoterodine (administered primarily as 8 mg) was well tolerated and associated with sustained improvements in OAB symptoms, irrespective of age.
Summary This study was undertaken to investigate whether or not substrate selection during exercise is altered with participation in Ramadan, and whether or not this alteration is influenced by ...exercise intensity. Eight men (21–41 years) exercised on an electronically braked cycle ergometer at three 10-min workloads (45, 60 and 75% VO2peak ): (1) the week before Ramadan; (2) the end of the first week of Ramadan and (3) the final week of Ramadan. Four subjects were unable to complete the final 10-min (75% VO2peak ) workload during Ramadan. During the two lower workloads, exercise RER significantly decreased during Ramadan ( p < 0.01) and there was a significant effect of Ramadan on the increase in RER with increased workload ( p = 0.041). Post hoc contrasts revealed only that RER during exercise at the end of the first week was significantly lower ( p < 0.01) than pre-Ramadan. Rate of lipid oxidation increased from 0.18 g min−1 ± 0.22 to 0.31 g min−1 ± 0.28 by the first week of Ramadan ( p < 0.01), the effect reversed by the final week (0.23 g min−1 ± 0.22) ( p = 0.02). Although body weight declined during Ramadan (from 71.1 kg ± 6.9 to 69.8 kg ± 7.3, p = 0.02), percentage body fat, measured via underwater weighing, did not change. In conclusion, daily fasting during Ramadan induces changes in substrate selection during submaximal exercise within 1 week, but these changes are moderated with continued daily fasting. However, changes in anthropometric variables reflect a net energy deficit during Ramadan which may have mediated the observed increased lipid oxidation during submaximal exercise.
Many rivers experience intermittent flows naturally or as a consequence of water abstraction. Climate change is likely to exacerbate flow variability such that dry spells may become more common. It ...is important to understand the ecological consequences of flow intermittency and habitat fragmentation in rivers, and to identify and protect habitat patches that provide refugia for aquatic biota. This paper explores environmental factors influencing dry season fish losses from isolated waterbodies in Cooper Creek, an unregulated arid-zone river in the Lake Eyre Basin, Australia. Multivariate ordination techniques and classification and regression trees (CART) were used to decompose species-environment relationships into a hierarchically structured data set, and to determine factors explaining changes in fish assemblage structure and species losses over a single dry season. Canonical correspondence analysis (CCA) explained 74% of fish assemblage change in terms of waterhole morphology (wetted perimeter, depth), habitat structure (bench development, off-take channels), waterhole quality (eroded banks, gross primary production), the size of surrounding floodplains and the relative isolation of waterholes. Classification trees for endemic and restricted species reaffirmed the importance of these waterhole and floodplain variables as drivers of fish losses. The CCA and CART models offer valuable tools for identification of refugia in Cooper Creek and, possibly, other dryland rivers.
Perivascular spaces (PVS) and cerebrospinal fluid (CSF) are essential components of the glymphatic system, regulating brain homeostasis and clearing neural waste throughout the lifespan. Enlarged PVS ...have been implicated in neurological disorders and sleep problems in adults, and excessive CSF volume has been reported in infants who develop autism. Enlarged PVS have not been sufficiently studied longitudinally in infancy or in relation to autism outcomes or CSF volume.
To examine whether enlarged PVS are more prevalent in infants who develop autism compared with controls and whether they are associated with trajectories of extra-axial CSF volume (EA-CSF) and sleep problems in later childhood.
This prospective, longitudinal cohort study used data from the Infant Brain Imaging Study. Magnetic resonance images were acquired at ages 6, 12, and 24 months (2007-2017), with sleep questionnaires performed between ages 7 and 12 years (starting in 2018). Data were collected at 4 sites in North Carolina, Missouri, Pennsylvania, and Washington. Data were analyzed from March 2021 through August 2022.
PVS (ie, fluid-filled channels that surround blood vessels in the brain) that are enlarged (ie, visible on magnetic resonance imaging).
Outcomes of interest were enlarged PVS and EA-CSF volume from 6 to 24 months, autism diagnosis at 24 months, sleep problems between ages 7 and 12 years.
A total of 311 infants (197 63.3% male) were included: 47 infants at high familial likelihood for autism (ie, having an older sibling with autism) who were diagnosed with autism at age 24 months, 180 high likelihood infants not diagnosed with autism, and 84 low likelihood control infants not diagnosed with autism. Sleep measures at school-age were available for 109 participants. Of infants who developed autism, 21 (44.7%) had enlarged PVS at 24 months compared with 48 infants (26.7%) in the high likelihood but no autism diagnosis group (P = .02) and 22 infants in the control group (26.2%) (P = .03). Across all groups, enlarged PVS at 24 months was associated with greater EA-CSF volume from ages 6 to 24 months (β = 4.64; 95% CI, 0.58-8.72; P = .002) and more frequent night wakings at school-age (F = 7.76; η2 = 0.08; P = .006).
These findings suggest that enlarged PVS emerged between ages 12 and 24 months in infants who developed autism. These results add to a growing body of evidence that, along with excessive CSF volume and sleep dysfunction, the glymphatic system could be dysregulated in infants who develop autism.
This study demonstrated that 1,3-dinitrobenzene-induced (1,3-DNB) oxidative stress led to the oxidative carbonlyation of specific protein targets in DI TNC1 cells. 1,3-DNB-induced mitochondrial ...dysfunction, as indicated by loss of tetramethyl rhodamine methyl ester (TMRM) fluorescence, was initially observed at 5h and coincided with peak reactive oxygen species (ROS) production. ROS production was inhibited in cells pre-treated with the mitochondrial permeability transition (MPT) inhibitor, bonkrekic acid (BkA). Pre-incubation with the antioxidant deferoxamine inhibited loss of TMRM fluorescence until 24h after initial exposure to 1,3-DNB. Two-dimensional polyacrylamide gel electrophoresis (2D PAGE) and subsequent Oxyblot analysis were used to determine if 1,3-DNB exposure led to the formation of protein carbonyls. Exposing DI TNC1 cells to 1,3-DNB led to marked protein carbonylation 45min following initial exposure. Pre-treatment with deferoxamine or Trolox reduced the intensity of protein carbonylation in DI TNC1 cells exposed to 1mM 1,3-DNB. Tandem MS/MS performed on protein samples isolated from 1,3-DNB-treated cells revealed that specific proteins within the mitochondria, endoplasmic reticulum (ER), and cytosol are targets of protein carbonylation. The results presented in this study are the first to suggest that the molecular mechanism of 1,3-DNB neurotoxicity may occur through selective carbonylation of protein targets found within specific intracellular compartments of susceptible cells.
PDF
