3,555 research outputs found

    Global patterns of diapycnal mixing from measurements of the turbulent dissipation rate

    Get PDF
    The authors present inferences of diapycnal diffusivity from a compilation of over 5200 microstructure profiles. As microstructure observations are sparse, these are supplemented with indirect measurements of mixing obtained from (i) Thorpe-scale overturns from moored profilers, a finescale parameterization applied to (ii) shipboard observations of upper-ocean shear, (iii) strain as measured by profiling floats, and (iv) shear and strain from full-depth lowered acoustic Doppler current profilers (LADCP) and CTD profiles. Vertical profiles of the turbulent dissipation rate are bottom enhanced over rough topography and abrupt, isolated ridges. The geography of depth-integrated dissipation rate shows spatial variability related to internal wave generation, suggesting one direct energy pathway to turbulence. The global-averaged diapycnal diffusivity below 1000-m depth is O(10?4) m2 s?1 and above 1000-m depth is O(10?5) m2 s?1. The compiled microstructure observations sample a wide range of internal wave power inputs and topographic roughness, providing a dataset with which to estimate a representative global-averaged dissipation rate and diffusivity. However, there is strong regional variability in the ratio between local internal wave generation and local dissipation. In some regions, the depth-integrated dissipation rate is comparable to the estimated power input into the local internal wave field. In a few cases, more internal wave power is dissipated than locally generated, suggesting remote internal wave sources. However, at most locations the total power lost through turbulent dissipation is less than the input into the local internal wave field. This suggests dissipation elsewhere, such as continental margins

    Assessing the impact of drinking water and sanitation on diarrhoeal disease in low- and middle-income settings: Systematic review and meta-regression

    Get PDF
    Objective: To assess the impact of inadequate water and sanitation on diarrhoeal disease in low- and middle-income settings. Methods: The search strategy used Cochrane Library, MEDLINE & PubMed, Global Health, Embase and BIOSIS supplemented by screening of reference lists from previously published systematic reviews, to identify studies reporting on interventions examining the effect of drinking water and sanitation improvements in low- and middle-income settings published between 1970 and May 2013. Studies including randomised controlled trials, quasi-randomised trials with control group, observational studies using matching techniques and observational studies with a control group where the intervention was well defined were eligible. Risk of bias was assessed using a modified Ottawa-Newcastle scale. Study results were combined using meta-analysis and meta-regression to derive overall and intervention-specific risk estimates. Results: Of 6819 records identified for drinking water, 61 studies met the inclusion criteria, and of 12 515 records identified for sanitation, 11 studies were included. Overall, improvements in drinking water and sanitation were associated with decreased risks of diarrhoea. Specific improvements, such as the use of water filters, provision of high-quality piped water and sewer connections, were associated with greater reductions in diarrhoea compared with other interventions. Conclusions: The results show that inadequate water and sanitation are associated with considerable risks of diarrhoeal disease and that there are notable differences in illness reduction according to the type of improved water and sanitation implemented

    Reply to Swartz et al.: Challenges and opportunities for identifying forced labor using satellite-based fishing vessel monitoring

    Get PDF
    We appreciate Swartz et al. (1) for highlighting several key considerations for interpreting our results (2). While we discuss many of these in our paper, we are grateful to further highlight our work’s strengths, limitations, and future opportunities. A major challenge with understanding fisheries labor abuses is a lack of data. Automatic identification system (AIS) is only used by a subset of the global fishing fleet. However, AIS is valuable for monitoring certain types of fishing vessels, especially those that are large (∼52 to 85% carry AIS) (3) and those fishing on the high seas (∼80% carry AIS) (4). Mandating AIS and unique identifiers on fishing vessels and publishing vessel registries would facilitate more inclusive AIS-based analyses (5)

    Cytokine Response to Traditional and Cluster Sets in Resistance-trained Women

    Get PDF
    Resistance exercise that incorporates intra-set rest between repetition blocks (i.e., cluster sets [CS]) can produce a smaller metabolic stress and endocrine response than traditional sets (TS). PURPOSE: To examine the effect of CS on the acute cytokine response in resistance trained women. METHODS: 12 resistance-trained women (mean ± SE; 23.7 ± 1.1 years; 160.1 ± 1.5 cm; 62.5 ± 1.7 kg; 5 ± 1 years training) completed 3 sessions in the follicular phase. One-repetition maximum (1RM) back squat (BS) (98.7 ± 4.1 kg), and BS:body mass (1.6 ± 0.1) were determined in Session 1. For Session 2 (3 days post Session 1) and Session 3 (7 days post Session 2), subjects were randomly assigned to either 4 sets of 10 reps with 120 seconds (s) inter-set rest (TS) or 4 x (2 x 5 reps) with 30s intra-set rest and 90s inter-set rest (CS). All performed both protocols at 70% 1RM BS. Instructions were to perform every rep “as explosively as possible”. Blood was collected pre-exercise (PRE), immediately after sets 1, 2, 3, 4 (IP), and at 5 (+5), 15 (+15), 30 (+30), and 60 (+60) min post-exercise and analyzed for interleukin (IL)-1β, IL-2, IL-6, IL-8, IL 10, and IL-15. Data were analyzed using repeated measures ANOVAs (2 × 9). RESULTS: A significant main effect of time (p\u3c0.05) was found for IL-1β, IL-2, IL-8, IL-10, and IL-15. Concentration of IL-1β was smaller at +5 (3.9 ± 0.4 ng/mL), +15 (3.6 ± 0.4) +30 (3.5 ± 0.3), and +60 (3.7 ± 0.4) compared to IP (4.1 ± 0.4). IL-2 was greater after set 1 (10.8 ± 1.0 ng/mL), and set 2 (11.0 ± 1.2) compared to PRE (10.2 ± 1.0), and smaller at +30 (9.9 ± 1.0) compared to IP (11.0 ± 1.0). IL-8 was greater after set 1 (8.4 ± 0.6 ng/mL), set 2 (8.6 ± 0.7), and set 3 (8.5 ± 0.7) compared to PRE (8.0 ± 0.6). IL-10 was smaller at +30 (31.3 ± 7.4 ng/mL) compared to PRE (34.0 ± 7.4), and also smaller at +15 (32.6 ± 7.9) +30 (31.3 ± 7.4), and +60 (33.4 ± 8.6) compared to IP (38.0 ± 8.6). IL-15 was greater at IP (15.5 ± 4.0 ng/mL) compared to PRE (13.4 ± 3.5), and smaller at PRE (13.4 ± 3.5), +30 (11.9 ± 3.3), and +60 (11.6 ± 3.2) compared to IP (15.5 ± 4.0). No condition × time point effects were observed. CONCLUSION: Both TS and CS induced an acute cytokine response in resistance-trained women; incorporating intra-set rest (CS) did not appear to affect this cytokine response

    Permeation of macromolecules into the renal glomerular basement membrane and capture by the tubules

    Get PDF
    Human kidneys contain ∼2 x 106 glomeruli that produce ∼180 L per day of primary filtrate. Downstream tubules reabsorb most of the water, salt, and desirable low-molecular weight substances, leaving 1 to 2 L per day of urine containing undesirable waste products. Currently, most investigators think that the primary filtrate is low in protein because fluid exiting the glomerulus passes through slits spanned by a diaphragm that acts as a low-porosity molecular sieve. Our experiments challenge this view; they show that size-dependent permeation into the glomerular basement membrane and into a gel-like coat that covers the slits, together with saturable tubular reabsorption, determines which macromolecules reach the urine. The slit diaphragm is essential for capillary structure but may not directly determine glomerular size selectivity

    Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents via regulation of ERK signaling response genes

    Get PDF
    Dual specificity phosphatase 6 (DUSP6) is a protein phosphatase that deactivates extracellular-signal-regulated kinase (ERK). Since the ovarian cancer biomarker human epididymis protein 4 (HE4) interacts with the ERK pathway, we sought to determine the relationship between DUSP6 and HE4 and elucidate DUSP6’s role in epithelial ovarian cancer (EOC). Viability assays revealed a significant decrease in cell viability with pharmacological inhibition of DUSP6 using (E/Z)-BCI hydrochloride in ovarian cancer cells treated with carboplatin or paclitaxel, compared to treatment with either agent alone. Quantitative PCR was used to evaluate levels of ERK pathway response genes to BCI in combination with recombinant HE4 (rHE4), carboplatin, and paclitaxel. Expression of EGR1, a promoter of apoptosis, was higher in cells co-treated with BCI and paclitaxel or carboplatin than in cells treated with chemotherapeutic agents alone, while expression of the proto-oncogene c-JUN was decreased with co-treatment. The effect of BCI on the expression of these two genes opposed that of rHE4. Pathway focused quantitative PCR also revealed suppression of ERBB3 in cells co-treated with BCI plus carboplatin or paclitaxel. Finally, expression levels of DUSP6 in EOC tissue were evaluated by immunohistochemistry, revealing significantly increased levels of DUSP6 in serous EOC tissue compared to adjacent normal tissue. A positive correlation between HE4 and DUSP6 levels was determined by Spearman Rank correlation. In conclusion, DUSP6 inhibition sensitizes ovarian cancer cells to chemotherapeutic agents and alters gene expression of ERK response genes, suggesting that DUSP6 could plausibly function as a novel therapeutic target to reduce chemoresistance in EOC

    Evolutionary Toggling of Vpx/Vpr Specificity Results in Divergent Recognition of the Restriction Factor SAMHD1

    Get PDF
    SAMHD1 is a host restriction factor that blocks the ability of lentiviruses such as HIV-1 to undergo reverse transcription in myeloid cells and resting T-cells. This restriction is alleviated by expression of the lentiviral accessory proteins Vpx and Vpr (Vpx/Vpr), which target SAMHD1 for proteasome-mediated degradation. However, the precise determinants within SAMHD1 for recognition by Vpx/Vpr remain unclear. Here we show that evolution of Vpx/Vpr in primate lentiviruses has caused the interface between SAMHD1 and Vpx/Vpr to alter during primate lentiviral evolution. Using multiple HIV-2 and SIV Vpx proteins, we show that Vpx from the HIV-2 and SIVmac lineage, but not Vpx from the SIVmnd2 and SIVrcm lineage, require the C-terminus of SAMHD1 for interaction, ubiquitylation, and degradation. On the other hand, the N-terminus of SAMHD1 governs interactions with Vpx from SIVmnd2 and SIVrcm, but has little effect on Vpx from HIV-2 and SIVmac. Furthermore, we show here that this difference in SAMHD1 recognition is evolutionarily dynamic, with the importance of the N- and C-terminus for interaction of SAMHD1 with Vpx and Vpr toggling during lentiviral evolution. We present a model to explain how the head-to-tail conformation of SAMHD1 proteins favors toggling of the interaction sites by Vpx/Vpr during this virus-host arms race. Such drastic functional divergence within a lentiviral protein highlights a novel plasticity in the evolutionary dynamics of viral antagonists for restriction factors during lentiviral adaptation to its hosts. © 2013 Fregoso et al

    Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy

    Get PDF
    BACKGROUND: Both forms of facioscapulohumeral muscular dystrophy (FSHD) are associated with aberrant epigenetic regulation of the chromosome 4q35 D4Z4 macrosatellite. Chromatin changes due to large deletions of heterochromatin (FSHD1) or mutations in chromatin regulatory proteins (FSHD2) lead to relaxation of epigenetic repression and increased expression of the deleterious double homeobox 4 (DUX4) gene encoded within the distal D4Z4 repeat. However, many individuals with the genetic requirements for FSHD remain asymptomatic throughout their lives. Here we investigated family cohorts of FSHD1 individuals who were either affected (manifesting) or without any discernible weakness (nonmanifesting/asymptomatic) and their unaffected family members to determine if individual epigenetic status and stability of repression at the contracted 4q35 D4Z4 array in myocytes correlates with FSHD disease. RESULTS: Family cohorts were analyzed for DNA methylation on the distal pathogenic 4q35 D4Z4 repeat on permissive A-type subtelomeres. We found DNA hypomethylation in FSHD1-affected subjects, hypermethylation in healthy controls, and distinctly intermediate levels of methylation in nonmanifesting subjects. We next tested if these differences in DNA methylation had functional relevance by assaying DUX4-fl expression and the stability of epigenetic repression of DUX4-fl in myogenic cells. Treatment with drugs that alter epigenetic status revealed that healthy cells were refractory to treatment, maintaining stable repression of DUX4, while FSHD1-affected cells were highly responsive to treatment and thus epigenetically poised to express DUX4. Myocytes from nonmanifesting subjects had significantly higher levels of DNA methylation and were more resistant to DUX4 activation in response to epigenetic drug treatment than cells from FSHD1-affected first-degree relatives containing the same contraction, indicating that the epigenetic status of the contracted D4Z4 array is reflective of disease. CONCLUSIONS: The epigenetic status of the distal 4qA D4Z4 repeat correlates with FSHD disease; FSHD-affected subjects have hypomethylation, healthy unaffected subjects have hypermethylation, and nonmanifesting subjects have characteristically intermediate methylation. Thus, analysis of DNA methylation at the distal D4Z4 repeat could be used as a diagnostic indicator of developing clinical FSHD. In addition, the stability of epigenetic repression upstream of DUX4 expression is a key regulator of disease and a viable therapeutic target
    corecore