A pilot study comparing the metabolic profiles of elite-level athletes from different sporting disciplines

Background: The outstanding performance of an elite athlete might be associated with changes in their blood metabolic profile. The aims of this study were to compare the blood metabolic profiles between moderate- and high-power and endurance elite athletes and to identify the potential metabolic pathways underlying these differences. Methods: Metabolic profiling of serum samples from 191 elite athletes from different sports disciplines (121 high- and 70 moderate-endurance athletes, including 44 high- and 144 moderate-power athletes), who participated in national or international sports events and tested negative for doping abuse at anti-doping laboratories, was performed using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Multivariate analysis was conducted using orthogonal partial least squares discriminant analysis. Differences in metabolic levels between high- and moderate-power and endurance sports were assessed by univariate linear models. Results: Out of 743 analyzed metabolites, gamma-glutamyl amino acids were significantly reduced in both high-power and high-endurance athletes compared to moderate counterparts, indicating active glutathione cycle. High-endurance athletes exhibited significant increases in the levels of several sex hormone steroids involved in testosterone and progesterone synthesis, but decreases in diacylglycerols and ecosanoids. High-power athletes had increased levels of phospholipids and xanthine metabolites compared to moderate-power counterparts. Conclusions: This pilot data provides evidence that high-power and high-endurance athletes exhibit a distinct metabolic profile that reflects steroid biosynthesis, fatty acid metabolism, oxidative stress, and energy-related metabolites. Replication studies are warranted to confirm differences in the metabolic profiles associated with athletes’ elite performance in independent data sets, aiming ultimately for deeper understanding of the underlying biochemical processes that could be utilized as biomarkers with potential therapeutic implications

A randomised trial into the effect of an isolated hip abductor strengthening programme and a functional motor control programme on knee kinematics and hip muscle strength

Background: Dynamic knee valgus and internal femoral rotation are proposed to be contributory risk factors for patellofemoral pain and anterior cruciate ligament injuries. Multimodal interventions including hip abductor strengthening or functional motor control programmes have a positive impact of pain, however their effect on knee kinematics and muscle strength is less clear. The aim of this study was to examine the effect of isolated hip abductor strengthening and a functional motor control exercise on knee kinematics and hip abductor strength. Methods: This prospective, randomised, repeated measures design included 29 asymptomatic volunteers presenting with increase knee valgus and femoral internal rotation. Participants completed either isolated hip abductor strengthening or a functional motor control exercise for 5 weeks. Knee kinematics were measured using inertial sensors during 2 functional activities and hip abductor strength measured using a load cell during isometric hip abduction. Results: There were no significant differences in dynamic knee valgus and internal rotation following the isolated hip abductor or functional motor control intervention, and no significant differences between the groups for knee angles. Despite this, the actual magnitude of reduction in valgus was 10° and 5° for the functional motor control group and strengthening group respectively. The actual magnitude of reduction in internal rotation was 9° and 18° for the functional motor control group and strengthening group respectively. Therefore there was a tendency towards clinically significant improvements in knee kinematics in both exercise groups. A statistically significant improvement in hip abductor strength was evident for the functional motor control group (27% increase; p = 0.008) and strengthening group (35% increase; p = 0.009) with no significant difference between the groups being identified (p = 0.475). Conclusions: Isolated hip strengthening and functional motor control exercises resulted in non-statistically significant changes in knee kinematics, however there was a clear trend towards clinically meaningful reductions in valgus and internal rotation. Both groups demonstrated similar significant gains in hip abductor strength suggesting\ud either approach could be used to strengthen the hip abductors

HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies

CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports malignancy. Owing to its activity against models of refractory human ovarian cancer, 1 was progressed into lead optimization. The reduction of P-glycoprotein efflux became a focus of early compound optimization; central ring halogen substitution was demonstrated by matched molecular pair analysis to be an effective strategy to mitigate this liability. Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian cancer and other malignancies

Low doses of caffeine reduce heart rate during submaximal cycle ergometry

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to examine the cardiovascular effects of two low-levels of caffeine ingestion in non habitual caffeine users at various submaximal and maximal exercise intensities.</p> <p>Methods</p> <p>Nine male subjects (19–25 yr; 83.3 ± 3.1 kg; 184 ± 2 cm), underwent three testing sessions administered in a randomized and double-blind fashion. During each session, subjects were provided 4 oz of water and a gelatin capsule containing a placebo, 1.5 mg/kg caffeine, or 3.0 mg/kg caffeine. After thirty minutes of rest, a warm-up (30 Watts for 2 min) the pedal rate of 60 rpm was maintained at a steady-state output of 60 watts for five minutes; increased to 120 watts for five minutes and to 180 watts for five minutes. After a 2 min rest the workload was 180 watts for one minute and increased by 30 watts every minute until exhaustion. Heart rate (HR) was measured during the last 15-seconds of each minute of submaximal exercise. Systolic blood pressure (BP) was measured at rest and during each of the three sub-maximal steady state power outputs. Minute ventilation (V_E), Tidal volume (V_T), Breathing frequency (Bf), Rating of perceived exertion (RPE), Respiratory exchange ratio (RER), and Oxygen consumption (VO₂) were measured at rest and during each minute of exercise.</p> <p>Results</p> <p>Caffeine at 1.5 and 3.0 mg/kg body weight significantly lowered (p < 0.05) HR during all three submaximal exercise intensities compared to placebo (range – 4 to 7 bpm lower) but not at rest or maximal exercise. BP was significantly higher (p < 0.05) at rest and after the 3 mg/kg caffeine vs placebo (116 ± 13 vs 123 ± 10 mm Hg). Neither dose of caffeine had any effect on BP during submaximal exercise. Caffeine had no effect on V_E, V_T, VO₂, RPE, maximal power output or time to exhaustion.</p> <p>Conclusion</p> <p>In non habitual caffeine users it appears that consuming a caffeine pill (1.5 & 3.0 mg/kg) at a dose comparable to 1–3 cups of coffee lowers heart rate during submaximal exercise but not at near maximal and maximal exercise. In addition, this caffeine dose also only appears to affect systolic blood pressure at rest but not during cycling exercise.</p

Water relations of evergreen and drought-deciduous trees along a seasonally dry tropical forest chronosequence

Seasonally dry tropical forests (SDTF) are characterized by pronounced seasonality in rainfall, and as a result trees in these forests must endure seasonal variation in soil water availability. Furthermore, SDTF on the northern Yucatan Peninsula, Mexico, have a legacy of disturbances, thereby creating a patchy mosaic of different seral stages undergoing secondary succession. We examined the water status of six canopy tree species, representing contrasting leaf phenology (evergreen vs. drought-deciduous) at three seral stages along a fire chronosequence in order to better understand strategies that trees use to overcome seasonal water limitations. The early-seral forest was characterized by high soil water evaporation and low soil moisture, and consequently early-seral trees exhibited lower midday bulk leaf water potentials (ΨL) relative to late-seral trees (−1.01 ± 0.14 and −0.54 ± 0.07 MPa, respectively). Although ΨL did not differ between evergreen and drought-deciduous trees, results from stable isotope analyses indicated different strategies to overcome seasonal water limitations. Differences were especially pronounced in the early-seral stage where evergreen trees had significantly lower xylem water δ18O values relative to drought-deciduous trees (−2.6 ± 0.5 and 0.3 ± 0.6‰, respectively), indicating evergreen species used deeper sources of water. In contrast, drought-deciduous trees showed greater enrichment of foliar 18O (∆18Ol) and 13C, suggesting lower stomatal conductance and greater water-use efficiency. Thus, the rapid development of deep roots appears to be an important strategy enabling evergreen species to overcome seasonal water limitation, whereas, in addition to losing a portion of their leaves, drought-deciduous trees minimize water loss from remaining leaves during the dry season

Integrated syphilis/HIV screening in China: a qualitative analysis

<p>Abstract</p> <p>Background</p> <p>The last decade has seen enormous advances in HIV treatment and care, but how to implement scaled up HIV testing, prevention, and treatment in low-income areas still presents a formidable public health challenge. South China faces expanding syphilis and sexually transmitted HIV epidemics, but health systems characteristics important for scaling up syphilis and HIV testing have not been defined.</p> <p>Methods</p> <p>A purposive sample to ensure public, private, and public-private hybrid STI clinic inclusion was selected in a South China city. Eight key informant interviews were conducted with the STI clinic manager, followed by eight focus group discussions with physicians. Data collection relied on a semi-structured format that included questions in each of the following domains: 1) clinical facilities; 2) laboratory capacity with a focus on syphilis/HIV diagnosis; 3) clinic personnel; 4) physical space with a focus on locations to disclose confidential results; 5) financial support.</p> <p>Results</p> <p>Public STI clinics had free syphilis testing/treatment and laboratory facilities to perform essential syphilis and HIV tests. However, despite serving a large number of STI patients, private STI clinics lacked nontreponemal syphilis testing, HIV testing, and had fewer connections to the public health infrastructure. Formally trained assistant physicians were 2.5 times as common as physicians at STI clinics. Only one of the 8 sites had onsite voluntary counseling and testing (VCT) services available.</p> <p>Conclusion</p> <p>These STI case studies reveal the potential for expanding integrated syphilis/HIV services at public STI clinics in China. More health services research is needed to guide scale-up of syphilis/HIV testing in China.</p

The unusual M-dwarf Warm Jupiter TOI-1899~b: Refinement of orbital and planetary parameters

TOI-1899~b is a rare exoplanet, a temperate Warm Jupiter orbiting an M-dwarf, first discovered by \citet{Canas2020_toi1899} from a TESS single-transit event. Using new radial velocities (RVs) from the precision RV spectrographs HPF and NEID, along with additional TESS photometry and ground-based transit follow-up, we are able to derive a much more precise orbital period of $P = 29.090312_{-0.000035}^{+0.000036}$~d, along with a radius of $R_p = 0.99\pm0.03$~\unit{R_{J}}. We have also improved the constraints on planet mass, $M_p = 0.67\pm{0.04}$~\unit{M_{J}}, and eccentricity, which is consistent with a circular orbit at 2$\sigma$ ($e = 0.044_{-0.027}^{+0.029}$). TOI-1899~b occupies a unique region of parameter space as the coolest known ($T_{eq} \approx$ 380~K) Jovian-sized transiting planet around an M-dwarf; we show that it has great potential to provide clues regarding the formation and migration mechanisms of these rare gas giants through transmission spectroscopy with JWST as well as studies of tidal evolution.Comment: 19 pages, 7 figures, 3 tables, submitted to AJ (comments welcome

Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar−/−) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia

Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. Results: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 Pmeta = 3.7 × 10-09). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1 15:01 P = 1.3 × 10-7 and DQB1 06:02 P = 6.1 × 10-8). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1 15:01 and DQB1 06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10-16)