Protein trafficking through the endosomal system prepares intracellular parasites for a home invasion

Toxoplasma (toxoplasmosis) and Plasmodium (malaria) use unique secretory organelles for migration, cell invasion, manipulation of host cell functions, and cell egress. In particular, the apical secretory micronemes and rhoptries of apicomplexan parasites are essential for successful host infection. New findings reveal that the contents of these organelles, which are transported through the endoplasmic reticulum (ER) and Golgi, also require the parasite endosome-like system to access their respective organelles. In this review, we discuss recent findings that demonstrate that these parasites reduced their endosomal system and modified classical regulators of this pathway for the biogenesis of apical organelles

The feasibility of an exercise intervention in males at risk of oesophageal adenocarcinoma: a randomized controlled trial

Objective: To investigate the feasibility and safety of a 24-week exercise intervention, compared to control, in males with Barrett's oesophagus, and to estimate the effect of the intervention, compared to control, on risk factors associated with oesophageal adenocarcinoma development. Methods: A randomized controlled trial of an exercise intervention (60 minutes moderate-intensity aerobic and resistance exercise five days/week over 24 weeks; one supervised and four unsupervised sessions) versus attention control (45 minutes stretching five days/week over 24 weeks; one supervised and four unsupervised sessions) in inactive, overweight/obese (25.0-34.9 kg/m2) males with Barrett's oesophagus, aged 18-70 years. Primary outcomes were obesity-associated hormones relevant to oesophageal adenocarcinoma risk (circulating concentrations of leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, C-reactive protein, and insulin resistance HOMA). Secondary outcomes included waist circumference, body composition, fitness, strength and gastro-oesophageal reflux symptoms. Outcomes were measured at baseline and 24-weeks. Intervention effects were analysed using generalised linear models, adjusting for baseline value. Results: Recruitment was difficult in this population with a total of 33 participants recruited (target sample size: n = 80); 97% retention at 24-weeks. Adherence to the exercise protocol was moderate. No serious adverse events were reported. A statistically significant intervention effect (exercise minus control) was observed for waist circumference (-4.5 95%CI -7.5, -1.4 cm; p < 0.01). Effects on primary outcomes were not statistically significant. Conclusion: This small, exploratory trial provides important information to inform future trial development including recruitment rates and estimates of effect sizes on outcomes related to oesophageal adenocarcinoma risk. Future trials should investigate a combined dietary and exercise intervention to achieve greater weight loss in this population and relax inclusion criteria to maximize recruitment. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000401257. © 2015 Winzer et al

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Abstract Background Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied. Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns. Results Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Despite low SNV rates in their genomic neighbourhood, anchor points emerge as sites of evolutionary innovation, showing enrichment for structural variant (SV) breakpoints and a peak of SNVs at focal CTCF sites within the anchor points. Both CTCF-bound and non-CTCF anchor points harbour an excess of SV breakpoints in multiple tumour types and are prone to double-strand breaks in cell lines. Common fragile sites, which are hotspots for genome instability, also show elevated numbers of intersecting loop anchor points. Recurrently disrupted anchor points are enriched for genes with functions in cell cycle transitions and regions associated with predisposition to cancer. We also discover a novel class of CTCF-bound anchor points which overlap meiotic recombination hotspots and are enriched for the core PRDM9 binding motif, suggesting that the anchor points have been foci for diversity generated during recent human evolution. Conclusions We suggest that the unusual chromatin environment at loop anchor points underlies the elevated rates of variation observed, marking them as sites of regulatory importance but also genomic fragility

Superior cardiac mechanics without structural adaptations in pre-adolescent soccer players.

AIMS: This study aimed to evaluate left ventricular structure, function and mechanics, in highly-trained, pre-adolescent soccer players compared with age- and sex-matched controls. DESIGN: The study design was a prospective, cross-sectional comparison of left ventricular structure, function and mechanics. METHODS: Twenty-two male soccer players from two professional youth soccer academies (age: 12.0 ± 0.3 years) and 22 recreationally active controls (age: 11.7 ± 0.3 years) were recruited. Two-dimensional conventional and speckle tracking echocardiography were used to quantify left ventricular structure, function and peak/temporal values for left ventricular strain and twist, respectively. RESULTS: End-diastolic volume index was larger in soccer players (51 ± 8 mm/(m2)1.5vs. 45 ± 6 mm/(m2)1.5; p = 0.007) and concentricity was lower in soccer players (4.3 ± 0.7 g/(mL)0.667vs. 4.9 ± 1.0 g/(mL)0.667; p = 0.017), without differences in mean wall thickness between groups (6.0 ± 0.4 mm vs. 6.1 ± 0.5 mm; p = 0.754). Peak circumferential strain at the base (-22.2% ± 2.5% vs. -20.5% ± 2.5%; p = 0.029) and papillary muscle levels (-20.1% ± 1.5% vs. -18.3% ± 2.5%; p = 0.007) were greater in soccer players. Peak left ventricular twist was larger in soccer players (16.92° ± 7.55° vs. 12.34° ± 4.99°; p = 0.035) and longitudinal early diastolic strain rate was greater in soccer players (2.22 ± 0.40 s-1vs. 2.02 ± 0.46 s-1; p = 0.025). CONCLUSIONS: Highly-trained soccer players demonstrated augmented cardiac mechanics with greater circumferential strains, twist and faster diastolic lengthening in the absence of differences in wall thickness between soccer players and controls

The influence of training status on right ventricular morphology and segmental strain in elite pre-adolescent soccer players.

Cardiac modifications to training are a product of the genetic pre-disposition for adaptation and the repetitive haemodynamic loads that are placed on the myocardium. Elite pre-adolescent athletes are exposed to high-intensity training at a young age with little understanding of the physiological and clinical consequences. It is unclear how right ventricular (RV) structure and function may respond to this type of stimulus. The aim of this study was to compare RV structure and strain across the cardiac cycle and within individual segments in elite soccer players (SP) and controls (CON). METHODS: Twenty-two highly trained, male pre-adolescent SP and 22 age-and sex-matched recreationally active individuals CON were investigated using 2D echocardiography, including myocardial speckle tracking to assess basal, mid-wall, apical and global longitudinal strain and strain rate during systole (SRS) and diastole (SRE and SRA). RESULTS: greater RV cavity size was identified in the SP compared to CON (RVD1 SP: 32.3 ± 3.1 vs. CON: 29.6 ± 2.8 (mm/m2)0.5; p = 0.005). No inter-group differences were noted for peak global RV strain (SP: - 28.6 ± 4.9 vs CON: - 30.3 ± 4.0%, p = 0.11). Lower mid-wall strain was demonstrated in the SP compared to CON (SP: - 27.9 ± 5.8 vs. CON: - 32.2 ± 4.4%, p = 0.007). CONCLUSION: Soccer training has the potential to increase RV size in pre-adolescent players. The unique segmental analyses used in this study have identified inter-group differences that were masked by global strain evaluations. The clinical and physiological implications of these findings warrant further investigation

The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms

Left Ventricular Responses during Exercise in Highly Trained Youth Athletes: Echocardiographic Insights on Function and Adaptation

There is an increase in the prevalence of elite youth sports academies, whose sole aim is to develop future elite athletes. This involves the exposure of the child and adolescent athlete to high-volume training during a period of volatile growth. The large amount of data in this area has been garnered from the resting echocardiographic left ventricular (LV) evaluation of the youth athlete; while this can provide some insight on the functional adaptations to training, it is unable to elucidate a comprehensive overview of the function of the youth athletes’ LV during exercise. Consequently, there is a need to interrogate the LV responses in-exercise. This review outlines the feasibility and functional insight of capturing global indices of LV function (Stroke Index-SVIndex and Cardiac Index-QIndex), systolic and diastolic markers, and cardiac strain during submaximal and maximal exercise. Larger SVI and QI were noted in these highly trained young athletes compared to recreationally active peers during submaximal and maximal exercise. The mechanistic insights suggest that there are minimal functional systolic adaptions during exercise compared to their recreationally active peers. Diastolic function was superior during exercise in these young athletes, and this appears to be underpinned by enhanced determinants of pre-load

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The effect of long-term soccer training on left ventricular structure and function in elite male youth soccer players.

Aims Cardiac adaptations in elite, male adolescent youth soccer players have been demonstrated in relation to training status. The time course of these adaptations and the delineation of the influence of volatile growth phases from the training effect on these adaptations remain unclear. Consequently, the aims of the study were to evaluate the impact of 3 years of elite-level soccer training on changes in left ventricular (LV) structure and function in a group of highly trained elite youth male soccer players (SP) as they transitioned through the pre-to-adolescent phase of their growth. Methods Twenty-two male youth SP from the highest Level of English Premier League Academy U-12 teams were evaluated once a year for three soccer seasons as the players progressed from the U-12 to U-14 teams. Fifteen recreationally active control participants (CON) were also evaluated over the same 3-year period. Two-dimensional transthoracic echocardiography was used to quantify LV structure and function. Results After adjusting for the influence of growth and maturation, training-induced increases in Years 2 and 3 were noted for: LV end diastolic volume (LVEDV; p = 0.02) and LV end systolic volume (LVESV; p = 0.02) in the SP compared to CON. Training-induced decrements were noted for LV ejection fraction (LVEF; p = 0.006) and TDI-S′ (p < 0.001). Conclusions An increase in training volume (Years 2 and 3) were aligned with LV volumetric adaptations and decrements in systolic function in the SP that were independent from the influence of rapid somatic growth. Decrements in systolic function were suggestive of a functional reserve for exercise

Left ventricular morphological and functional predictors of V̇O2peak: A 3-year observational study

The aim of the study was to identify central determinants of V̇O2peak using a 3-year longitudinal evaluation of left ventricular (LV) morphological and functional (global, tissue-Doppler and strain) outcome measures obtained at rest and during both submaximal and maximal exercise in a group of highly trained male youth soccer players (SP) and recreationally active male participants (CON). Once a year for 3 years, measurements were obtained in both the SP and CON groups (12.0 ± 0.3 and 11.7 ± 0.2 years of age, respectively, at the onset of the study). Cardiac ultrasound measures were used to identify LV morphological indices at rest and functional parameters during submaximal and maximal exercise. Training status (P < 0.0001) emerged as the only significant independent predictor of V̇O2peak, when considering LV morphological variables. At maximal exercise, early diastolic filling (E) was a significant (P = 0.001) predictor of V̇O2peak, irrespective of the influence of training status. Training status emerged as the significant predictor of V̇O2peak across all models that were developed in this study. Minimal LV structural and functional adaptations at both rest and exercise influence V̇O2peak, beyond the impact of training status alone. The broader implication of these findings is that the influence of LV cardiac adaptations on V̇O2peak over time is mediated by the stimulus of training; this association occurs independently from the impact of growth and maturation on V̇O2peak