The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of ...cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.
Parkinson’s disease (PD) is an incurable neurodegenerative disorder. Current therapeutic approaches are aimed to lessen the symptoms without slowing or halting the disease progression (Hammond, ...Constance et al., 2007). Models that allow to study the cellular and molecular mechanisms behind the neurological dysfunction are critical in developing new therapies. In vitro neuronal models have been used to recapitulate patient pathophysiology. However, it is crucial to choose the correct cell population to study the disease of interest. iPSC cellular models have the advantage of recapitulating the patient's own cellular background and for this reason they are considered the best model for generating disease-relevant neurons. Here we optimized a protocol to differentiate iPSC in mid-dopaminergic neurons (mDA, the cells affected by PD) and performed different assays to test the level of differentiation and neuronal phenotype.We tested samples from the 5 differentiation stages in our protocol and observed expression of both early and late classical dopaminergic neuronal markers such as SHH, FGF8, FOXA2, LMX1A, NURR1, TUBB and TH. To further characterize the maturation of our neuronal network upon differentiation of cells from neurospheres, we measured neuronal activity by using multi electrode array and calcium influx assay. Our data showed that the mean firing rate of iPSC-derived mDA increased from < 0.04 Hz at day 9, to 2.43 Hz by day 20. The number of spikes also increased from < 38 on day 5, to 2196 spikes on day 20, demonstrating action potentials are spontaneously being fired by the plated neurons. Finally, we observed that dysregulation of calcium influx in mature mDA neurons upon treatment with receptor agonists leads to cell death, as seen by the decrease in TH levels.Taken together the results we report here show we can efficiently differentiate human iPSCs in mature and active dopaminergic neurons and this model may be potentially used for further investigation of therapies against PD.
A new paradigm for data-driven, model-agnostic new physics searches at colliders is emerging, and aims to leverage recent breakthroughs in anomaly detection and machine learning. In order to develop ...and benchmark new anomaly detection methods within this framework, it is essential to have standard datasets. To this end, we have created the LHC Olympics 2020, a community challenge accompanied by a set of simulated collider events. Participants in these Olympics have developed their methods using an R&D dataset and then tested them on black boxes: datasets with an unknown anomaly (or not). Methods made use of modern machine learning tools and were based on unsupervised learning (autoencoders, generative adversarial networks, normalizing flows), weakly supervised learning, and semi-supervised learning. This paper will review the LHC Olympics 2020 challenge, including an overview of the competition, a description of methods deployed in the competition, lessons learned from the experience, and implications for data analyses with future datasets as well as future colliders.
Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (M. tuberculosis) followed by ...rapid progression to disease. Alveolar macrophages (AMs) are the first cells of the innate immune system that engage M. tuberculosis, but how HIV and antiretroviral therapy (ART) affect the anti-mycobacterial response of AMs is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AMs to M. tuberculosis, we obtained AMs by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as preexposure prophylaxis (PrEP) to prevent HIV infection. Following in vitro challenge with M. tuberculosis, AMs from each group displayed overlapping but distinct profiles of significantly up- and downregulated genes in response to M. tuberculosis. Comparatively, AMs isolated from both PLWH and PrEP subjects presented a substantially weaker transcriptional response. In addition, AMs from HC subjects challenged with M. tuberculosis responded with pronounced chromatin accessibility changes while AMs obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state. Collectively, these results revealed a stronger adverse effect of ART than HIV on the epigenetic landscape and transcriptional responsiveness of AMs.
Background
Asthmatic patients may benefit from exercise training, although the effects of a combined aerobic and resistance training program are still poorly investigated in children and adolescents.
...Objective
To analyze the effects of a combined exercise training (resistance and aerobic) program on aerobic fitness, lung function, asthma control and quality of life in a group of mild‐moderate asthmatic children with exercise symptoms.
Methods
This was a 12‐week randomized controlled trial including children and adolescents diagnosed with mild‐moderate asthma and presenting exercise‐induced symptoms. The intervention group (IG) performed the exercise training (resistance and aerobic) 3 days/week, for 60 minutes. The control group (CG) followed routine clinical orientations. The main outcomes were cardiorespiratory fitness, muscle strength, lung function, quality of life, asthma control, and functional tests after 3 months of the intervention.
Results
Fifty‐three patients (IG = 25 and CG = 28) with a mean age of 11.5 ± 2.6 years were included. No significant differences were found between groups regarding lung function, asthma control, quality of life, and functional tests. Ventilatory equivalent for oxygen consumption at ventilatory threshold (P = .025;
η
p
2 = 0.083), peak oxygen consumption (P = .008;
η
p
2 = 0.116) and test duration (P = .014;
η
p
2 = 0.1) presented greater improvements in the IG. In addition, improvements were observed in leg press (P < .001;
η
p
2 = 0.36), hamstring curl (P = .001;
η
p
2 = 0.217), high row (P = .003;
η
p
2 = .167), low row (P = .009;
η
p
2 = 0.128) and quadriceps leg extension (P = .015;
η
p
2 = 0.108) in the IG.
Conclusion
Combined exercise training (resistance and aerobic) improved cardiorespiratory fitness and muscle strength in children and adolescents with controlled asthma and exercise symptoms.
Introduction
Among the limited studies on physical exercise interventions in adults with cystic fibrosis (CF), few have specifically addressed the improvement of peripheral muscle strength and body ...fat‐free mass. The aim of this study was to examine the impacts of a remotely supervised, individualized 8‐week resistance training program of moderate to high intensity on strength and body composition in these subjects.
Methods
This was a randomized controlled trial performed in adults with CF. The exercise group (EX) performed three 1‐h resistance training sessions per week over 8 weeks. The control group (CON) followed the physical activity recommendations of their physician. The main outcomes were muscle strength and body composition, with secondary measures including pulmonary function and quality of life. Two‐way repeated measures analysis was used.
Results
In 23 participants (age 32.13 ± 7.72 years), the intervention showed a significant beneficial effect on leg press strength, with a large effect size, both in absolute (p = 0.011; ηp2$$ {\eta}_{\mathrm{p}}^2 $$ = 0.281) and relative (p = 0.007; ηp2$$ {\eta}_{\mathrm{p}}^2 $$ = 0.310) terms. Large intervention effects were observed on total fat mass (p < 0.001; ηp2$$ {\eta}_{\mathrm{p}}^2 $$ = 0.415), body adiposity index (p < 0.001; ηp2$$ {\eta}_{\mathrm{p}}^2 $$ = 0.436), and fat mass index (p < 0.001; ηp2$$ {\eta}_{\mathrm{p}}^2 $$ = 0.445), all showing reduction in the EX group. In addition, significant large size effects were detected on total fat‐free mass (p = 0.046; ηp2$$ {\eta}_{\mathrm{p}}^2 $$ = 0.177), trunk fat‐free mass (p = 0.039; ηp2$$ {\eta}_{\mathrm{p}}^2 $$ = 0.188), and fat‐free mass index (p = 0.048; ηp2$$ {\eta}_{\mathrm{p}}^2 $$ = 0.174), all favoring exercise. No significant effects were observed on pulmonary function and quality of life.
Conclusions
An 8‐week remotely supervised resistance training program, with moderate to high intensity, effectively improved lower limb muscle strength and body composition.
Introduction
Exercise intolerance is common in chronic airway diseases (CAD), but its mechanisms are still poorly understood. The aim of this study was to evaluate exercise capacity and its ...association with lung function, ventilatory limitation, and ventilatory efficiency in children and adolescents with cystic fibrosis (CF) and asthma when compared to healthy controls.
Methods
Cross‐sectional study including patients with mild‐to‐moderate asthma, CF and healthy children and adolescents. Anthropometric data, lung function (spirometry) and exercise capacity (cardiopulmonary exercise testing) were evaluated. Primary outcomes were peak oxygen consumption (VO2peak), forced expiratory volume in 1 s (FEV1), breathing reserve (BR), ventilatory equivalent for oxygen consumption (VE/VO2) and for carbon dioxide production (VE/VCO2), both at the ventilatory threshold (VT1) and peak exercise.
Results
Mean age of 147 patients included was 11.8 ± 3.0 years. There were differences between asthmatics and CF children when compared to their healthy peers for anthropometric and lung function measurements. Asthmatics showed lower VO2peak when compared to both healthy and CF subjects, although no differences were found between healthy and CF patients. A lower BR was found when CF patients were compared to both healthy and asthmatic. Both CF and asthmatic patients presented higher values for VE/VO2 and VE/VCO2 at VT1 when compared to healthy individuals. For both VE/VO2 and VE/VCO2 at peak exercise CF patients presented higher values when compared to their healthy peers.
Conclusion
Patients with CF achieved good exercise capacity despite low ventilatory efficiency, low BR, and reduced lung function. However, asthmatics reported reduced cardiorespiratory capacity and normal ventilatory efficiency at peak exercise. These results demonstrate differences in the mechanisms of ventilatory limitation to maximum exercise testing in children and adolescents with CAD.
We investigated the bioavailability of the calcium salt (HMB-Ca) and the free acid (HMB-FA) forms of β-hydroxy-β-methylbutyrate (HMB). Sixteen young individuals received the following treatments on ...three different occasions in a counterbalanced crossover fashion: (1) HMB-FA in clear capsules; (2) HMB-Ca in gelatine capsules; (3) HMB-Ca dissolved in water. All treatments provided 1 g of HMB. Blood samples were taken before and on multiple time points following ingestion. The following parameters were calculated: peak plasma (Cmax), time to peak (Tmax), slope of HMB appearance in blood, area under the curve (AUC), half-life time (
t
1/2
) and relative bioavailability (HMB-Ca in water set as reference). All treatments led to rapid and large increases in plasma HMB. HMB-Ca in capsules and in water showed similar plasma HMB values across time (
p
= 0.438). HMB-FA resulted in lower concentrations vs
.
the other treatments (both
p
< 0.001). AUC (HMB-Ca in capsules: 50,078 ± 10,507; HMB-Ca in water: 47,871 ± 10,783; HMB-FA: 29,130 ± 12,946 µmol L
−1
× 720 min), Cmax (HMB-Ca in capsules: 229.2 ± 65.9; HMB-Ca in water: 249.7 ± 49.7; HMB-FA: 139.1 ± 67.2 µmol L
−1
) and relative bioavailability (HMB-Ca in capsules: 104.8 ± 14.9%; HMB-FA: 61.5 ± 17.0%) were lower in HMB-FA vs. HMB-Ca (all
p
< 0.001). HMB-Ca in water resulted in the fastest Tmax (43 ± 22 min) compared to HMB-Ca in capsules (79 ± 40 min) and HMB-FA (78 ± 21 min) (all
p
< 0.05), while
t
1/2
was similar between treatments. To conclude, HMB-Ca exhibited superior bioavailability compared to HMB-FA, with HMB-Ca in water showing faster absorption. Elimination kinetics were similar across all forms, suggesting that the pharmaceutical form of HMB affects the absorption rates, but not its distribution or elimination.
PDF
