Application of the speed-duration relationship to normalize the intensity of high-intensity interval training

The tolerable duration of continuous high-intensity exercise is determined by the hyperbolic Speed-tolerable duration (S-tLIM) relationship. However, application of the S-tLIM relationship to normalize the intensity of High-Intensity Interval Training (HIIT) has yet to be considered, with this the aim of present study. Subjects completed a ramp-incremental test, and series of 4 constant-speed tests to determine the S-tLIM relationship. A sub-group of subjects (n = 8) then repeated 4 min bouts of exercise at the speeds predicted to induce intolerance at 4 min (WR4), 6 min (WR6) and 8 min (WR8), interspersed with bouts of 4 min recovery, to the point of exercise intolerance (fixed WR HIIT) on different days, with the aim of establishing the work rate that could be sustained for 960 s (i.e. 4×4 min). A sub-group of subjects (n = 6) also completed 4 bouts of exercise interspersed with 4 min recovery, with each bout continued to the point of exercise intolerance (maximal HIIT) to determine the appropriate protocol for maximizing the amount of high-intensity work that can be completed during 4×4 min HIIT. For fixed WR HIIT tLIM of HIIT sessions was 399±81 s for WR4, 892±181 s for WR6 and 1517±346 s for WR8, with total exercise durations all significantly different from each other (P<0.050). For maximal HIIT, there was no difference in tLIM of each of the 4 bouts (Bout 1: 229±27 s; Bout 2: 262±37 s; Bout 3: 235±49 s; Bout 4: 235±53 s; P>0.050). However, there was significantly less high-intensity work completed during bouts 2 (153.5±40. 9 m), 3 (136.9±38.9 m), and 4 (136.7±39.3 m), compared with bout 1 (264.9±58.7 m; P>0.050). These data establish that WR6 provides the appropriate work rate to normalize the intensity of HIIT between subjects. Maximal HIIT provides a protocol which allows the relative contribution of the work rate profile to physiological adaptations to be considered during alternative intensity-matched HIIT protocols

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

A direct physical interaction between Nanog and Sox2 regulates embryonic stem cell self-renewal

Embryonic stem (ES) cell self-renewal efficiency is determined by the Nanog protein level. However, the protein partners of Nanog that function to direct self-renewal are unclear. Here, we identify a Nanog interactome of over 130 proteins including transcription factors, chromatin modifying complexes, phosphorylation and ubiquitination enzymes, basal transcriptional machinery members, and RNA processing factors. Sox2 was identified as a robust interacting partner of Nanog. The purified Nanog–Sox2 complex identified a DNA recognition sequence present in multiple overlapping Nanog/Sox2 ChIP-Seq data sets. The Nanog tryptophan repeat region is necessary and sufficient for interaction with Sox2, with tryptophan residues required. In Sox2, tyrosine to alanine mutations within a triple-repeat motif (S X T/S Y) abrogates the Nanog–Sox2 interaction, alters expression of genes associated with the Nanog-Sox2 cognate sequence, and reduces the ability of Sox2 to rescue ES cell differentiation induced by endogenous Sox2 deletion. Substitution of the tyrosines with phenylalanine rescues both the Sox2–Nanog interaction and efficient self-renewal. These results suggest that aromatic stacking of Nanog tryptophans and Sox2 tyrosines mediates an interaction central to ES cell self-renewal

Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by impaired clearance of pulmonary bacteria. OBJECTIVES: The effect of COPD on alveolar macrophage (AM) microbicidal responses was investigated. METHODS: Alveolar macrophages (AMs) were obtained from bronchoalveolar lavage from healthy donors or COPD patients and challenged with opsonized serotype 14 Streptococcus pneumoniae. Cells were assessed for apoptosis, bactericidal activity and mitochondrial reactive oxygen species (mROS) production. A transgenic mouse line, in which the CD68 promoter ensures macrophage specific expression of human Mcl-1 (CD68.hMcl-1), was used to model the molecular aspects of COPD. MEASUREMENTS AND MAIN RESULTS: COPD AM had elevated levels of Mcl-1, an anti-apoptotic Bcl-2 family member, with selective reduction of delayed intracellular bacterial killing. CD68.hMcl-1 AM phenocopied the microbicidal defect since transgenic mice demonstrated impaired clearance of pulmonary bacteria and increased neutrophilic inflammation. Murine bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages (MDM) generated mitochondrial reactive oxygen species (mROS) in response to pneumococci, which co-localized with bacteria and phagolysosomes to enhance bacterial killing. The Mcl-1 transgene increased oxygen consumption rates and mROS expression in mock-infected BMDM but reduced caspase-dependent mROS production after pneumococcal challenge. COPD AM also increased basal mROS expression, but failed to increase production after pneumococcal challenge, in keeping with reduced intracellular bacterial killing. The defect in COPD AM intracellular killing was associated with a reduced ratio of mROS /superoxide dismutase 2. CONCLUSIONS: Upregulation of Mcl-1 and chronic adaption to oxidative stress alters mitochondrial metabolism and microbicidal function, reducing the delayed phase of intracellular bacterial clearance in COPD

Mobile laminar air flow screen for additional operating room ventilation: reduction of intraoperative bacterial contamination during total knee arthroplasty

Background Surgical site infections are important complications in orthopedic surgery. A mobile laminar air flow (LAF) screen could represent a useful addition to an operating room (OR) with conventional turbulent air ventilation (12.5 air changes/h), as it could decrease the bacterial count near the operating field. The purpose of this study was to evaluate LAF efficacy at reducing bacterial contamination in the surgical area during 34 total knee arthroplasties (TKAs). Materials and methods The additional unit was used in 17 operations; the LAF was positioned beside the operating table between two of the surgeons, with the air flow directed towards the surgical area (wound). The whole team wore conventional OR clothing and the correct hygiene procedures and rituals were used. Bacterial air contamination (CFU/m3) was evaluated in the wound area in 17 operations with the LAF unit and 17 without the LAF unit. Results The LAF unit reduced the mean bacterial count in the wound area from 23.5 CFU/m3 without the LAF to 3.5 CFU/m3 with the LAF (P<0.0001), which is below the suggested limit for anORwith ultraclean laminar ventilation. There were no significant differences in the mean bacterial count in the instrument table area: 28.6 CFU/m3 were recorded with the LAF (N = 6) unit and 30.8 CFU/m3 (N = 6) without the LAF unit (P = 0.631). During six operations with LAF and six without LAF, particle counts were performed and the number of 0.5 lm particles was analyzed. The particle counts decreased significantly when the LAF unit was used (P = 0.003). Conclusion When a mobile LAF unit was added to the standard OR ventilation, bacterial contamination of the wound area significantly decreased to below the accepted level for an ultraclean OR, preventing SSI infections

Roles for the coactivators CBP and p300 and the APC/C E3 ubiquitin ligase in E1A-dependent cell transformation

Adenovirus early region 1A (E1A) possesses potent transforming activity when expressed in concert with activated ras or E1B genes in in vitro tissue culture systems such as embryonic human retinal neuroepithelial cells or embryonic rodent epithelial and fibroblast cells. Early region 1A has thus been used extensively and very effectively as a tool to determine the molecular mechanisms that underlie the basis of cellular transformation. In this regard, roles for the E1A-binding proteins pRb, p107, p130, cyclic AMP response element-binding protein (CBP)/p300, p400, TRRAP and CtBP in cellular transformation have been established. However, the mechanisms by which E1A promotes transformation through interaction with these partner proteins are not fully delineated. In this review, we focus on recent advances in our understanding of CBP/p300 function, particularly with regard to its relationship to the anaphase-promoting complex/cyclosome E3 ubiquitin ligase, which has recently been shown to interact and affect the activity of CBP/p300 through interaction domains that are evolutionarily conserved in E1A

Ecological Thresholds in the Savanna Landscape: Developing a Protocol for Monitoring the Change in Composition and Utilisation of Large Trees

BACKGROUND: Acquiring greater understanding of the factors causing changes in vegetation structure -- particularly with the potential to cause regime shifts -- is important in adaptively managed conservation areas. Large trees (> or =5 m in height) play an important ecosystem function, and are associated with a stable ecological state in the African savanna. There is concern that large tree densities are declining in a number of protected areas, including the Kruger National Park, South Africa. In this paper the results of a field study designed to monitor change in a savanna system are presented and discussed. METHODOLOGY/PRINCIPAL FINDINGS: Developing the first phase of a monitoring protocol to measure the change in tree species composition, density and size distribution, whilst also identifying factors driving change. A central issue is the discrete spatial distribution of large trees in the landscape, making point sampling approaches relatively ineffective. Accordingly, fourteen 10 m wide transects were aligned perpendicular to large rivers (3.0-6.6 km in length) and eight transects were located at fixed-point photographic locations (1.0-1.6 km in length). Using accumulation curves, we established that the majority of tree species were sampled within 3 km. Furthermore, the key ecological drivers (e.g. fire, herbivory, drought and disease) which influence large tree use and impact were also recorded within 3 km. CONCLUSIONS/SIGNIFICANCE: The technique presented provides an effective method for monitoring changes in large tree abundance, size distribution and use by the main ecological drivers across the savanna landscape. However, the monitoring of rare tree species would require individual marking approaches due to their low densities and specific habitat requirements. Repeat sampling intervals would vary depending on the factor of concern and proposed management mitigation. Once a monitoring protocol has been identified and evaluated, the next stage is to integrate that protocol into a decision-making system, which highlights potential leading indicators of change. Frequent monitoring would be required to establish the rate and direction of change. This approach may be useful in generating monitoring protocols for other dynamic systems

Hepatopulmonary syndrome in patients with chronic liver disease: role of pulse oximetry

BACKGROUND: Hepatopulmonary syndrome (HPS) is a rare complication of liver diseases of different etiologies and may indicate a poor prognosis. Therefore, a simple non-invasive screening method to detect HPS would be highly desirable. In this study pulse oximetry was evaluated to identify patients with HPS. METHODS: In 316 consecutive patients with liver cirrhosis (n = 245), chronic hepatitis (n = 69) or non-cirrhotic portal hypertension (n = 2) arterial oxygen saturation (SaO(2)) was determined using a pulse oximeter. In patients with SaO(2 )≤92% in supine position and/or a decrease of ≥4% after change from supine to upright position further diagnostic procedures were performed, including contrast-enhanced echocardiography and perfusion lung scan. RESULTS: Seventeen patients (5.4%) had a pathological SaO(2). Four patients (1.3%) had HPS. HPS patients had a significant lower mean SaO(2 )in supine (89.7%, SD 5.4 vs. 96.0%, SD 2.3; p = 0.003) and upright position (84.3%, SD 5.0 vs. 96.0%, SD 2.4; p = 0.001) and had a lower mean PaO(2 )(56.2 mm Hg, SD 15.2 vs. 71.2 mm Hg, SD 20.2; p = 0.02) as compared to patients without HPS. The mean ΔSaO(2 )(difference between supine and upright position) was 5.50 (SD 7) in HPS patients compared to non-HPS patients who showed no change (p = 0.001). There was a strong correlation between shunt volume and the SaO(2 )values (R = -0.94). CONCLUSION: Arterial SaO(2 )determination in supine and upright position is a useful non-invasive screening test for HPS and correlates well with the intrapulmonary shunt volume