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Abstract Prompt Gamma Imaging (PGI) is a promising technique for range verification in Particle Therapy. This technique was already tested in clinical environment with a knife-edge-collimator camera for proton treatments but remains relatively unexplored for Carbon Ion Radiation Therapy (CIRT). Previous FLUKA simulations suggested that PG profile shifts could be detected in CIRT with a precision of $$\sim$$ 4 mm ( $$2 \sigma$$ ) for a particle statistic equal to $$5 \cdot 10^{7}$$ C-ions using a 10 × 10 cm2 camera. An experimental campaign was carried out at CNAO (Pavia, Italy) to verify these results, using a knife-edge-collimator camera prototype based on a 5 × 5 cm2 pixelated LYSO crystal. PG profiles were measured irradiating a plastic phantom with a C-ion pencil beam at clinical energies and intensities, also moving the detector to extend the FOV to 13 × 5 cm2. The prototype detected Bragg-peak shifts with $$\sim$$ 4 mm precision for a statistic of $$\sim 4 \cdot 10^{8}$$ C-ions ( $$3 \cdot 10^{8}$$ for the extended FOV), slightly larger than expected. Nevertheless, the detector demonstrated significant potential for verifying the precision in dose delivery following a treatment fraction, which remains fundamental in the clinical environment. For the first time to our knowledge, range verification based on PGI was applied to a C-ion beam at clinical energy and intensities.

Abstract Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1–3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1–3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0–2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1–2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.

Abstract Human space exploration poses inherent risks to astronauts’ health, leading to molecular changes that can significantly impact their well-being. These alterations encompass genomic instability, mitochondrial dysfunction, increased inflammation, homeostatic dysregulation, and various epigenomic changes. Remarkably, these changes bear similarities to those observed during the aging process on Earth. However, our understanding of the connection between these molecular shifts and disease development in space remains limited. Frailty syndrome, a clinical syndrome associated with biological aging, has not been comprehensively investigated during spaceflight. To bridge this knowledge gap, we leveraged murine data obtained from NASA’s GeneLab, along with astronaut data gathered from the JAXA and Inspiration4 missions. Our objective was to assess the presence of biological markers and pathways related to frailty, aging, and sarcopenia within the spaceflight context. Through our analysis, we identified notable changes in gene expression patterns that may be indicative of the development of a frailty-like condition during space missions. These findings suggest that the parallels between spaceflight and the aging process may extend to encompass frailty as well. Consequently, further investigations exploring the utility of a frailty index in monitoring astronaut health appear to be warranted.

Abstract Mounting ambitions and capabilities for public and private, non-government sector crewed space exploration bring with them an increasingly diverse set of space travelers, raising new and nontrivial ethical, legal, and medical policy and practice concerns which are still relatively underexplored. In this piece, we lay out several pressing issues related to ethical considerations for selecting space travelers and conducting human subject research on them, especially in the context of non-governmental and commercial/private space operations.

Abstract Lipids are key constituents of the barrier function in the human stratum corneum (SC), which is the outermost layer of the epidermis and amenable to non-invasive sampling by tape stripping. The three major lipid classes in the SC, i.e., ceramides, fatty acids, and cholesterol, present equimolar concentration. Liquid chromatography coupled with mass spectrometry (LCMS) is elective in profiling lipids in the SC in both positive and negative ion modes. Nevertheless, the latter one allows for the simultaneous detection of the three major epidermal components of the SC. Determination of ceramides in the SC poses analytical challenges due to their wide range of structures and concentrations especially in the case of limited sample amounts. Ammonium formate is a commonly used modifier added to the mobile phase to assist ionization. However, it introduces uncertainty in the identification of ceramides when operating in negative ion mode, even with high resolution MS. We tested the advantages of using fluoride in the lipid profiling of SC and unambiguous identification of ceramides subclasses. The use of fluoride enhanced the ionization of ceramides, regardless the specific substructure, solved misidentification issues, and was successfully applied to the simultaneous detection of all three lipid classes in the human SC.

Summary: Iroquois transcription factor gene IRX3 is highly expressed in 20–30% of acute myeloid leukemia (AML) and contributes to the pathognomonic differentiation block. Intron 8 FTO sequences ∼220kB downstream of IRX3 exhibit histone acetylation, DNA methylation, and contacts with the IRX3 promoter, which correlate with IRX3 expression. Deletion of these intronic elements confirms a role in positively regulating IRX3. RNAseq revealed long non-coding (lnc) transcripts arising from this locus. FTO-lncAML knockdown (KD) induced differentiation of AML cells, loss of clonogenic activity, and reduced FTO intron 8:IRX3 promoter contacts. While both FTO-lncAML KD and IRX3 KD induced differentiation, FTO-lncAML but not IRX3 KD led to HOXA downregulation suggesting transcript activity in trans. FTO-lncAMLhigh AML samples expressed higher levels of HOXA and lower levels of differentiation genes. Thus, a regulatory module in FTO intron 8 consisting of clustered enhancer elements and a long non-coding RNA is active in human AML, impeding myeloid differentiation.

Summary: Sea urchins can detect light and move in relation to luminous stimuli despite lacking eyes. They presumably detect light through photoreceptor cells distributed on their body surface. However, there is currently no mechanistic explanation of how these animals can process light to detect visual stimuli and produce oriented movement. Here, we present a model of decentralized vision in echinoderms that includes all known processing stages, from photoreceptor cells to radial nerve neurons to neurons contained in the oral nerve ring encircling the mouth of the animals. In the model, light stimuli captured by photoreceptor cells produce neural activity in the radial nerve neurons. In turn, neural activity in the radial nerves is integrated in the oral nerve ring to produce a profile of neural activity reaching spatially across several ambulacra. This neural activity is readout to produce a model of movement. The model captures previously published data on the behavior of sea urchin Diadema africanum probed with a variety of physical stimuli. The specific pattern of neural connections used in the model makes testable predictions on the properties of single neurons and aggregate neural behavior in Diadema africanum and other echinoderms, offering a potential understanding of the mechanism of visual orientation in these animals.

When two waves interact within a rock sample, the interaction strength depends strongly on the sample’s microstructural properties, including the orientation of the sample layering. The study that established this dependence on layering speculated that the differences were caused by cracks aligned with the layers in the sample. To test this, we applied a uniaxial load to similar samples of Crab Orchard Sandstone and measured the nonlinear interaction as a function of the applied load and layer orientation. We show that the dependence of the nonlinear signal changes on applied load is exponential, with a characteristic load of 11.4–12.5 MPa that is independent of sample orientation and probe wavetype (P or S); this value agrees with results from the literature, but does not support the cracks hypothesis.

Sustainable wildlife management is necessary to guarantee the viability of source populations; but it is rarely practiced in the tropics. The yellow anaconda (Eunectes notaeus) has long been harvested for its leather. Since 2002 its harvest has operated under a management program in northeastern Argentina, which relies on adaptive management practices, that limit the minimum body length permitted for harvesting, the number of active hunters and the length of hunting seasons. Here we investigated the effects of yellow anaconda harvest on its demography based on 2002-2019 data and show that exploitation levels are sustainable. The gradual reduction in annual hunting effort, due to a decrease in the number of hunters and hunting season duration, reduced the total number of anacondas harvested. Conversely, captures per unit effort increased across the study period. The body size of anacondas was not influenced by the harvesting, and more females than males were caught. We also found that a decrease in mean temperature positively influenced anaconda harvest and the capture of giant individuals. Because sustainable use is a powerful tool for conservation, and anacondas are widespread in South America, these discoveries are highly applicable to other species and regions.

Sustainable wildlife management is necessary to guarantee the viability of source populations; but it is rarely practiced in the tropics. The yellow anaconda (Eunectes notaeus) has long been harvested for its leather. Since 2002 its harvest has operated under a management program in northeastern Argentina, which relies on adaptive management practices, that limit the minimum body length permitted for harvesting, the number of active hunters and the length of hunting seasons. Here we investigated the effects of yellow anaconda harvest on its demography based on 2002–2019 data and show that exploitation levels are sustainable. The gradual reduction in annual hunting effort, due to a decrease in the number of hunters and hunting season duration, reduced the total number of anacondas harvested. Conversely, captures per unit effort increased across the study period. The body size of anacondas was not influenced by the harvesting, and more females than males were caught. We also found that a decrease in mean temperature positively influenced anaconda harvest and the capture of giant individuals. Because sustainable use is a powerful tool for conservation, and anacondas are widespread in South America, these discoveries are highly applicable to other species and regions.

Abstract Bed bugs (Cimex lectularius) have proliferated globally and have become one of the most challenging pests to control indoors. They are nocturnal and use multiple sensory cues to detect and orient towards their human hosts. After feeding, usually on a sleeping human, they return to a shelter on or around the sleeping surface, but not directly on the host. We hypothesized that although human skin odors attract hungry bed bugs, human skin compounds may also prevent arrestment on hosts. We used arrestment assays to test human skin swabs, extracts from human skin swabs, and pure compounds identified from human skin swabs. When given a choice, bed bugs preferred to arrest on substrates not previously conditioned by humans. These responses were consistent among laboratory-reared and apartment-collected bed bugs. The compounds responsible for this behavior were found to be extractable in hexane, and bed bugs responded to such extracts in a dose-dependent manner. Bioassay-guided fractionation paired with thin-layer chromatography, GC–MS, and LC–MS analyses suggested that triglycerides (TAGs), common compounds found on human skin, were preventing arrestment on shelters. Bed bugs universally avoided sheltering in TAG-treated shelters, which was independent of the number of carbons or the number of double bonds in the TAG. These results provide strong evidence that the complex of human skin compounds serve as multifunctional semiochemicals for bed bugs, with some odorants attracting host-seeking stages, and others (TAGs and possibly other compounds) preventing bed bug arrestment. Host chemistry, environmental conditions and the physiological state of bed bugs likely influence the dual nature behavioral responses of bed bugs to human skin compounds.

Abstract Lipidomics is advantageous in the study of sebum perturbations occurring in acne. An extended evaluation of the sebum lipid profiles in acne-prone sebaceous areas is lacking in dark skin. Yet, there is a void space in understanding how the building blocks of sebum lipids, i.e. individual fatty acids (FAs), are intertwined with acne-prone skin. We aimed to determine the sebum lipidome in facial areas of adolescents with and without acne in Nigeria. A cross-sectional analytical study was conducted in 60 adolescents/young adults divided in 30 acne patients (15F, 15M) and 30 age and sex-matched controls. Sebum samples obtained from foreheads and cheeks were analysed separately by gas chromatography–mass spectrometry (GCMS) and thin layer chromatography (HPTLC). Distributions of sebum components were investigated with multivariate ANOVA-simultaneous component analysis (ASCA). Sebum incretion in acne was paralleled by significantly higher abundance of triglycerides, wax esters, and squalene together with monounsaturated FAs (MUFAs), and straight chain saturated FAs (SFAs), especially those with odd-carbon chain, i.e. C13:0, C15:0, and C17:0. Profiling weight/weight percentage of individual components revealed that, in acne, the free FAs (FFAs) array was shifted towards higher relative abundance of the SFAs C15:0, C16:0, and C17:0 and lower percentage of the anteiso-branched FFAs with 12, 14, 16, and 18 carbons. In acne patients, MUFAs and PUFAs were quantitatively increased and decreased on foreheads and cheeks, respectively. Relative abundance of fatty alcohols was decreased in acne independent on the site. The results indicated that acne associates with site-specific derangement of the pathways regulating the balance among odd straight-chain and branched-chain SFAs, MUFAs, which included sapienate (C16:1n-10), PUFAs, and squalene.

Abstract This study aimed to assess cassava root and stem yield at different spacings and four transplanting seasons of seedlings produced by an adaptation of the rapid multiplication method. The experimental design was a randomized block design with three replications in a factorial (4 × 5) arranged in strips. Treatments consisted of the combinations of growing seasons (November 9 and 24 and December 3 and 26) and spacings (0.6 × 0.6, 0.8 × 0.8, 0.8 × 0.6, 1.0 × 0.6, and 1.0 × 0.8 m). The percentage of survival, main stem branching height, number of branches, base, middle, and upper diameter, mean diameter, stem length, number of buds per stem and hectare, root length and diameter, root fresh matter per plant and hectare, and number of roots per plant were measured at harvest. Seedling transplanting performed up to November 24 favored the expression of stem and root yield. The spacing of 1.0 × 0.6 m was the most suitable for stem yield traits.

Abstract Patients requiring diagnostic testing for coronavirus disease 2019 (COVID-19) are routinely assessed by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) amplification of Sars-CoV-2 virus RNA extracted from oro/nasopharyngeal swabs. Despite the good specificity of the assays certified for SARS-CoV-2 molecular detection, and a theoretical sensitivity of few viral gene copies per reaction, a relatively high rate of false negatives continues to be reported. This is an important challenge in the management of patients on hospital admission and for correct monitoring of the infectivity after the acute phase. In the present report, we show that the use of digital PCR, a high sensitivity method to detect low amplicon numbers, allowed us to correctly detecting infection in swab material in a significant number of false negatives. We show that the implementation of digital PCR methods in the diagnostic assessment of COVID-19 could resolve, at least in part, this timely issue.

The short timescale of the solar flare reconnection process has long proved to be a puzzle. Recent studies suggest the importance of the formation of plasmoids in the reconnecting current sheet, with quantifying the aspect ratio of the width to length of the current sheet in terms of a negative power $ \alpha $ of the Lundquist number, that is, $ {S}^{-\alpha } $ , being key to understanding the onset of plasmoids formation. In this paper, we make the first application of theoretical scalings for this aspect ratio to observed flares to evaluate how plasmoid formation may connect with observations. For three different flares that show plasmoids we find a range of $ \alpha $ values of $ \alpha =0.26 $ to $ 0.31 $ . The values in this small range implies that plasmoids may be forming before the theoretically predicted critical aspect ratio ( $ \alpha =1/3 $ ) has been reached, potentially presenting a challenge for the theoretical models.

Background: Acetabular microfractures for cartilage lesions have been shown to be a safe procedure able to improve patient reported outcomes (PROs). Nevertheless, the return to sport activity rate represents a crucial outcome to be investigated in these young athletic patients. Methods: Patients undergoing acetabular microfracture for full chondral acetabular lesions were compared to a 1:1 matched-pair by age and gender control group undergoing hip arthroscopy without microfractures. Clinical assessment was performed with PROs and participation in sports in terms of type and level of activities was evaluated preoperatively and at 2-years follow-up. Results: A total of 62 patients with an average age of 35.1 ± 8.1 (microfracture group) and 36.4 ± 6.3 (control group) were included. In both groups, the average values of PROs significantly increased from preoperatively to the last follow-up. There was no significant difference between the two groups in the number of patients playing at the amateur and elite level preoperatively and at the last follow-up. Conclusions: Microfractures for the management of full-thickness acetabular chondral defect provides good clinical results at a minimum follow-up of two years, which are not inferior to a matched-pair control group. Patients undergoing this procedure are likely able to return at the same level of sport before surgery.

Compressible magnetohydrodynamic (MHD) turbulence is a common feature of astrophysical systems such as the solar atmosphere and interstellar medium. Such systems are rife with shock waves that can redistribute and dissipate energy. For an MHD system, three broad categories of shocks exist (slow, fast, and intermediate); however, the occurrence rates of each shock type are not known for turbulent systems. Here, we present a method for detecting and classifying the full range of MHD shocks applied to the Orszag–Tang vortex. Our results show that the system is dominated by fast and slow shocks, with far less-frequent intermediate shocks appearing most readily near magnetic reconnection sites. We present a potential mechanism that could lead to the formation of intermediate shocks in MHD systems, and study the coherency and abundances of shocks in compressible MHD turbulence.

For the measurement of flow-induced microrotations in flows utilizing the depolarization of phosphorescence anisotropy, suitable luminophores are crucial. The present work examines dyes of the xanthene family, namely Rhodamine B, Eosin Y and Erythrosine B. Both in solution and incorporated in particles, the dyes are examined regarding their luminescent lifetimes and their quantum yield. In an oxygen-rich environment at room temperature, all dyes exhibit lifetimes in the sub-microsecond range and a low intensity signal, making them suitable for sensing fast rotations with sensitive acquisition systems.

BackgroundCOVID-19 (COronaVIrus Disease 2019) is an infectious respiratory disease caused by the novel SARS-CoV-2 virus. Point of Care (POC) tests have been developed to detect specific antibodies, IgG and IgM, to SARS-CoV-2 virus in human whole blood. They need to be easily usable by the general population in order to alleviate the lockdown that many countries have initiated in response to the growing COVID-19 pandemic. A real-life study has been conducted in order to evaluate the performance of the COVID-PRESTO® POC test and the results were recently published. Even if this test showed very high sensitivity and specificity in a laboratory setting when used by trained professionals, it needs to be further evaluated for practicability when used by the general public in order to be approved by health authorities for in-home use.Methods143 participants were recruited between March 2020 and April 2020 among non-medical populations in central France (nuclear plant workers, individuals attending the Orleans University Hospital vaccination clinic and Orleans University Hospital non-medical staff). Instructions for use, with or without a tutorial video, were made available to the volunteers. Two separate objectives were pursued: evaluation of the capability of participants to obtain an interpretable result, and evaluation of the users' ability to read the results.Results88.4% of the test users judged the instructions for use leaflet to be clear and understandable. 99.3% of the users obtained a valid result and, according to the supervisors, 92.7% of the tests were properly performed by the users. Overall, 95% of the users gave positive feedback on the COVID PRESTO® as a potential self-test. Neither age nor education had an influence.ConclusionCOVID-PRESTO® was successfully used by an overwhelming majority of participants and its use was judged very satisfactory, therefore showing promising potential as a self-test to be used by the general population. This POC test can become an easy-to-use tool to help detect whether individuals are protected or not, particularly in the context of a second wave or a mass vaccination program.

Considering the Panigrahi and Chatterjee model (2017) for variable generalised Chaplygin gas, in this paper we found for this kind of exotic matter an analytic expression for the adiabatic compressibility βs. It was analyzed the behaviour of the adiabatic compressibility in the limit of high and low pressure. The derived equation for βs was used to deduce the value of the heat capacity at constant pressure Cp for variable generalised Chaplygin gas.

The angular power spectrum is a natural tool to analyse the observed galaxy number count fluctuations. In a standard analysis, the angular galaxy distribution is sliced into concentric redshift bins and all correlations of its harmonic coefficients between bin pairs are considered—a procedure referred to as ‘tomography’. However, the unparalleled quality of data from oncoming spectroscopic galaxy surveys for cosmology will render this method computationally unfeasible, given the increasing number of bins. Here, we put to test against synthetic data a novel method proposed in a previous study to save computational time. According to this method, the whole galaxy redshift distribution is subdivided into thick bins, neglecting the cross-bin correlations among them; each of the thick bin is, however, further subdivided into thinner bins, considering in this case all the cross-bin correlations. We create a simulated data set that we then analyse in a Bayesian framework. We confirm that the newly proposed method saves computational time and gives results that surpass those of the standard approach.

IntroductionCoronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy. The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome.MethodsThis observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW).ResultsOverall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2 200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n = 29, 22.3%), methylprednisolone (n = 45, 34.6%), or both (n = 56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW 0.48, 95%CI, 0.23-0.99; p = 0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW 0.41, 95%CI: 0.19-0.89, p = 0.025.ConclusionEarly adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.

Epidermal homeostasis is maintained by the activity of stem cells. Here, the authors show that deficiency of the transcription factor JunB leads to altered Notch signaling in stem cells, resulting in a cell fate switch and de novo formation of aberrant sebaceous glands, altered epidermal differentiation and impaired barrier function.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BackgroundFew studies, based on a limited number of patients using non-uniform therapeutic protocols, have analyzed Methicillin-resistant Staphylococcus aureus (MRSA) eradication.MethodsIn a randomized multicenter trial conducted on patients with new-onset MRSA infection we evaluated the efficacy of an early eradication treatment (arm A) compared with an observational group (B). Arm A received oral rifampicin and trimethoprim/sulfamethoxazole (21 days). Patients' microbiological status, FEV1, BMI, pulmonary exacerbations and use of antibiotics were assessed.ResultsSixty-one patients were randomized. Twenty-nine (47.5%) patients were assigned to active arm A and 32 (52.5%) patients to observational arm B. Twenty-nine (47.5%) patients, 10 patients in arm A and 19 in arm B, dropped out of the study. At 6 months MRSA was eradicated in 12 (63.2%) out of 19 patients in arm A while spontaneous clearance was observed in 5 (38.5%) out of 13 patients in arm B. A per-protocol analysis showed a 24.7% difference in the proportion of MRSA clearance between the two groups (z = 1.37, P(Z>z) = 0.08). Twenty-seven patients, 15 (78.9%) out of 19 in arm A and 12 (92.3%) out of 13 in arm B, were able to perform spirometry. The mean (±SD) FEV1 change from baseline was 7.13% (±14.92) in arm A and -1.16% (±5.25) in arm B (p = 0.08). In the same period the BMI change (mean ±SD) from baseline was 0.54 (±1.33) kg/m2 in arm A and -0.38 (±1.56) kg/m2 in arm B (p = 0.08). At 6 months no statistically significant differences regarding the number of pulmonary exacerbations, days spent in hospital and use of antibiotics were observed between the two arms.ConclusionsAlthough the statistical power of the study is limited, we found a 24.7% higher clearance of MRSA in the active arm than in the observational arm at 6 months. Patients in the active arm A also had favorable FEV1 and BMI tendencies.

BACKGROUND:Interactions between diet, physical activity and genetic predisposition contribute to variable body mass changes observed in response to weight loss interventions. Circulating microRNAs (c-miRNAs) may act as 'biomarkers' that are associated with the rate of change in weight loss, and/or play a role in regulating the biological variation, in response to energy restriction. OBJECTIVE:To quantify targeted c-miRNAs with putative roles in energy metabolism and exercise adaptations following a 16 wk diet and exercise intervention in individuals with large (high responders; HiRes) versus small (low responders; LoRes) losses in body mass. METHODS:From 89 male and female overweight/obese participants who completed the intervention (energy restriction from diet, 250 kcal/d, and exercise, 250 kcal/d), subgroups of HiRes (>10% body mass loss, n = 22) and LoRes (

IntroductionThe culture in many team sports involves consumption of large amounts of alcohol after training/competition. The effect of such a practice on recovery processes underlying protein turnover in human skeletal muscle are unknown. We determined the effect of alcohol intake on rates of myofibrillar protein synthesis (MPS) following strenuous exercise with carbohydrate (CHO) or protein ingestion.MethodsIn a randomized cross-over design, 8 physically active males completed three experimental trials comprising resistance exercise (8×5 reps leg extension, 80% 1 repetition maximum) followed by continuous (30 min, 63% peak power output (PPO)) and high intensity interval (10×30 s, 110% PPO) cycling. Immediately, and 4 h post-exercise, subjects consumed either 500 mL of whey protein (25 g; PRO), alcohol (1.5 g·kg body mass⁻¹), 12±2 standard drinks) co-ingested with protein (ALC-PRO), or an energy-matched quantity of carbohydrate also with alcohol (25 g maltodextrin; ALC-CHO). Subjects also consumed a CHO meal (1.5 g CHO·kg body mass⁻¹) 2 h post-exercise. Muscle biopsies were taken at rest, 2 and 8 h post-exercise.ResultsBlood alcohol concentration was elevated above baseline with ALC-CHO and ALC-PRO throughout recovery (PConclusionWe provide novel data demonstrating that alcohol consumption reduces rates of MPS following a bout of concurrent exercise, even when co-ingested with protein. We conclude that alcohol ingestion suppresses the anabolic response in skeletal muscle and may therefore impair recovery and adaptation to training and/or subsequent performance.

In neuronal cells, actin remodeling plays a well known role in neurite extension but is also deeply involved in the organization of intracellular structures, such as the Golgi apparatus. However, it is still not very clear which mechanisms may regulate actin dynamics at the different sites. In this report we show that high levels of the TTC3 protein, encoded by one of the genes of the Down Syndrome Critical Region (DCR), prevent neurite extension and disrupt Golgi compactness in differentiating primary neurons. These effects largely depend on the capability of TTC3 to promote actin polymerization through signaling pathways involving RhoA, ROCK, CIT-N and PIIa. However, the functional relationships between these molecules differ significantly if considering the TTC3 activity on neurite extension or on Golgi organization. Finally, our results reveal an unexpected stage-dependent requirement for F-actin in Golgi organization at different stages of neuronal differentiation.

BACKGROUND: Neutrophils are involved in thrombus formation. We investigated whether specific features of neutrophil activation characterize patients with acute coronary syndromes (ACS) compared to stable angina and to systemic inflammatory diseases. METHODS AND FINDINGS: The myeloperoxidase (MPO) content of circulating neutrophils was determined by flow cytometry in 330 subjects: 69 consecutive patients with acute coronary syndromes (ACS), 69 with chronic stable angina (CSA), 50 with inflammation due to either non-infectious (acute bone fracture), infectious (sepsis) or autoimmune diseases (small and large vessel systemic vasculitis, rheumatoid arthritis). Four patients have also been studied before and after sterile acute injury of the myocardium (septal alcoholization). One hundred thirty-eight healthy donors were studied in parallel. Neutrophils with normal MPO content were 96% in controls, >92% in patients undergoing septal alcoholization, 91% in CSA patients, but only 35 and 30% in unstable angina and AMI (STEMI and NSTEMI) patients, compared to 80%, 75% and 2% of patients with giant cell arteritis, acute bone fracture and severe sepsis. In addition, in 32/33 STEMI and 9/21 NSTEMI patients respectively, 20% and 12% of neutrophils had complete MPO depletion during the first 4 hours after the onset of symptoms, a feature not observed in any other group of patients. MPO depletion was associated with platelet activation, indicated by P-selectin expression, activation and transactivation of leukocyte β2-integrins and formation of platelet neutrophil and -monocyte aggregates. The injection of activated platelets in mice produced transient, P-selectin dependent, complete MPO depletion in about 50% of neutrophils. CONCLUSIONS: ACS are characterized by intense neutrophil activation, like other systemic inflammatory syndromes. In the very early phase of acute myocardial infarction only a subpopulation of neutrophils is massively activated, possibly via platelet-P selectin interactions. This paroxysmal activation could contribute to occlusive thrombosis.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function that represents one of the most dramatic medical challenges for the aging population. Aβ peptides, generated by processing of the Amyloid Precursor Protein (APP), are thought to play a central role in the pathogenesis of AD. However, the network of physical and functional interactions that may affect their production and deposition is still poorly understood. The use of a bioinformatic approach based on human/mouse conserved coexpression allowed us to identify a group of genes that display an expression profile strongly correlated with APP. Among the most prominent candidates, we investigated whether the collagen chaperone HSP47 could be functionally correlated with APP. We found that HSP47 accumulates in amyloid deposits of two different mouse models and of some AD patients, is capable to physically interact with APP and can be relocalized by APP overexpression. Notably, we found that it is possible to reduce the levels of secreted Aβ peptides by reducing the expression of HSP47 or by interfering with its activity via chemical inhibitors. Our data unveil HSP47 as a new functional interactor of APP and imply it as a potential target for preventing the formation and/or growth amyloid plaques.