Combining single-cell tracking and omics improves blood stem cell fate regulator identification.

Molecular programs initiating cell fate divergence (CFD) are difficult to identify. Current approaches usually compare cells long after CFD initiation, therefore missing molecular changes at its start. Ideally, single cells that differ in their CFD molecular program but are otherwise identical are compared early in CFD. This is possible in diverging sister cells, which were identical until their mother's division and thus differ mainly in CFD properties. In asymmetrically dividing cells, divergent daughter fates are prospectively committed during division, and diverging sisters can thus be identified at the start of CFD. Using asymmetrically dividing blood stem cells, we developed a pipeline (ie, trackSeq) for imaging, tracking, isolating, and transcriptome sequencing of single cells. Their identities, kinship, and histories are maintained throughout, massively improving molecular noise filtering and candidate identification. In addition to many identified blood stem CFD regulators, we offer here this pipeline for use in CFDs other than asymmetric division.

Evaluation of succulent plants Echeveria elegans as a biomonitor of heavy metals and radionuclides.

This work evaluates the use of Echeveria elegans as a biomonitor of metals and radionuclides, using semi-urban soils as a study area. The study area is exposed to various trace elements of concern for various social groups in nearby localities. The quantification of metals and radionuclides was performed by X-ray fluorescence spectrometry and gamma spectrometry, respectively. Cumulative frequency distribution curves, descriptive statistics, and multivariate analysis were used to estimate the local geochemical baseline and identify geochemical and anthropogenic patterns of metals and radionuclides from topsoil and E. elegans. The evaluation of contaminants and the contribution of possible exposure routes (topsoil and atmospheric deposition) was performed with the enrichment factor (EF) and the relative concentration factor (CFR). The results suggest that the plant does not present significant physical stress due to the environmental conditions to which it was exposed. Likewise, it can bioaccumulate heavy metals from natural and anthropogenic sources. The quantification of radionuclides in the plant is below the detection limits, indicating a low bioavailability and transfer factor. The CFR and EF results showed that the plant accumulates metals from the topsoil and atmospheric deposition. The bioaccumulation mechanism would be related to the functioning of Crassulaceae Acid Metabolism (CAM). In topsoil, the organic acids of the plant would modify the solubility of the metals present in an insoluble form in the soil, acting as ligands and, subsequently, following the transport route of these metabolites. In atmospheric deposition, the metals deposited in the leaves would be incorporated into the plant through the opening of the stomata because of the capture of CO2 (at night, day, or during environmental stress) by the CAM. Overall, the evidence showed that the succulent can be used as a biomonitor of heavy metals. However, additional studies are required to determine its usefulness as a radionuclide biomonitor.

Active and passive microrheology with large tracers in hard colloids.

The dynamics of a tracer particle in a bath of quasi-hard colloidal spheres is studied by Langevin dynamics simulations and mode coupling theory (MCT); the tracer radius is varied from equal to up to seven times larger than the bath particles radius. In the simulations, two cases are considered: freely diffusing tracer (passive microrheology) and tracer pulled with a constant force (active microrheology). Both cases are connected by linear response theory for all tracer sizes. It links both the stationary and transient regimes of the pulled tracer (for low forces) with the equilibrium correlation functions; the velocity of the pulled tracer and its displacement are obtained from the velocity auto-correlation function and the mean squared displacement, respectively. The MCT calculations give insight into the physical mechanisms: At short times, the tracer rattles in its cage of neighbours, with the frequency increasing linearly with the tracer radius asymptotically. The long-time tracer diffusion coefficient from passive microrheology, which agrees with the inverse friction coefficient from the active case, arises from the transport of transverse momentum around the tracer. It can be described with the Brinkman equation for the transverse flow field obtained in extension of MCT, but cannot be recovered from the MCT kernel coupling to densities only. The dynamics of the bath particles is also studied; for the unforced tracer the dynamics is unaffected. When the tracer is pulled, the velocity field in the bath follows the prediction of the Brinkman model, but different from the case of a Newtonian fluid.

Mild water stress-induced priming enhance tolerance to Rosellinia necatrix in susceptible avocado rootstocks.

BACKGROUND: White root rot (WRR) disease caused by Rosellinia necatrix is one of the most important threats affecting avocado orchards in temperate regions. The eradication of WRR is a difficult task and environmentally friendly control methods are needed to lessen its impact. Priming plants with a stressor (biotic or abiotic) can be a strategy to enhance plant defense/tolerance against future stress episodes but, despite the known underlying common mechanisms, few studies use abiotic-priming for improving tolerance to forthcoming biotic-stress and vice versa ('cross-factor priming'). To assess whether cross-factor priming can be a potential method for enhancing avocado tolerance to WRR disease, 'Dusa' avocado rootstocks, susceptible to R. necatrix, were subjected to two levels of water stress (mild-WS and severe-WS) and, after drought-recovery, inoculated with R. necatrix. Physiological response and expression of plant defense related genes after drought-priming as well as the disease progression were evaluated. RESULTS: Water-stressed avocado plants showed lower water potential and stomatal limitations of photosynthesis compared to control plants. In addition, NPQ and qN values increased, indicating the activation of energy dissipating mechanisms closely related to the relief of oxidative stress. This response was proportional to the severity of the water stress and was accompanied by the deregulation of pathogen defense-related genes in the roots. After re-watering, leaf photosynthesis and plant water status recovered rapidly in both treatments, but roots of mild-WS primed plants showed a higher number of overexpressed genes related with plant defense than severe-WS primed plants. Disease progression after inoculating primed plants with R. necatrix was significantly delayed in mild-WS primed plants. CONCLUSIONS: These findings demonstrate that mild-WS can induce a primed state in the WRR susceptible avocado rootstock 'Dusa' and reveal that 'cross-factor priming' with water stress (abiotic stressor) is effective for increasing avocado tolerance against R. necatrix (biotic stressor), underpinning that plant responses against biotic and abiotic stress rely on common mechanisms. Potential applications of these results may involve an enhancement of WRR tolerance of current avocado groves and optimization of water use via low frequency deficit irrigation strategies.

International survey on growth indices and impacting factors in children with food allergies.

BACKGROUND: Elimination diets required for the management of food allergies increase the risk for poor growth in children. Currently, no worldwide data exist on this topic and limited published data exist on the impact of atopic comorbidity, type of allergy and foods eliminated on growth. We therefore set out to perform a worldwide survey on growth and impacting factors in food allergic children. METHODS: A prospective growth survey was performed of children (aged 0-16 years) on an elimination diet with confirmed immunoglobulin (Ig)E and non-IgE mediated food allergies. Data collected included: weight-for-age, weight-for-height, height-for-age, head circumference, body mass index, type of food allergy and eliminated foods, allergic comorbidities and replacement milk/breast milk. Multivariable regression analysis was used to establish factors that affected growth. RESULTS: Data from 430 patients from twelve allergy centres were analysed: median age at diagnosis and data collection was 8 months and 23 months, respectively. Pooled data indicated that 6% were underweight, 9% were stunted, 5% were undernourished and 8% were overweight. Cow's milk elimination lead to a lower weight-for-height Z-scores than other food eliminations and mixed IgE and non-IgE mediated allergy had lower height-for-age Z-scores than IgE mediated allergy. Children with only non-IgE mediated allergies had lower weight-for-height and body mass index. Atopic comorbidities did not impact on growth. CONCLUSIONS: Stunting is more common in children with food allergies than low weight. Children particularly at risk of poor growth are those with non-IgE and mixed IgE and non-IgE mediated allergies, as well as those with cow's milk allergy.

Determining of risk areas due to exposure to heavy metals in the Toluca Valley using epiphytic mosses as a biomonitor.

The work aim is to identify the risk areas by exposure to Cr, Cu, Pb and Zn in the Metropolitan Zone of Toluca Valley (MZTV) using the mosses Fabriona cilaris and Leskea angustata as a biomonitors, geostatistical interpolation and multi-criteria evaluation by analytical hierarchy process. The results from the estimation of the enrichment factors (EF) showed that Pb is the heavy metal with the highest values, followed by the Zn, Cu and Cr. The EF obtained for all heavy metals show that there is a moderate to high anthropogenic enrichment. The above indicates that in the MZTV there are emission sources that contribute (significantly) in the amount of Cr, Cu, Pb and Zn accumulated in the biomonitor. Combustion processes, vehicle emissions, biomass burning, brick kiln emissions, agricultural and livestock activities, manufacturing industry and re-deposition by the action of the wind, were identified as the main heavy metals sources in the MZTV. Risk maps showed the high and medium risk areas are located in sites with poor urban vegetation coverage and close to highways and industrial parks. Low risk areas are located in sites with high urban vegetation coverage. The method used for identifying risk areas is a rapid and low-cost evaluation tool can allow local government environmental agencies to define public policies on air pollution control.

[Mortality within 30 days of receiving systemic chemotherapy at a regional oncology unit]. / Mortalidad a 30 días posterior a la administración de quimioterapia sistémica en una unidad oncológica regional.

BACKGROUND: The use of systemic chemotherapy has survival and palliation benefits in oncological patients. Mortality at 30 days after the administration of systemic chemotherapy is considered as a quality and safety indicator of oncological patient care. The international mortality threshold is 5%, which is the figure used to compare institutions. AIM: To assess mortality at 30 days after the administration of ambulatory systemic chemotherapy in a regional referral center in adult cancer patients. MATERIAL AND METHODS: Retrospective observational study of patients receiving ambulatory systemic chemotherapy in the oncology service of a regional public hospital during 2018. The 30-day mortality rate was calculated. Demographic characteristics, baseline disease and the treatment received were recorded. RESULTS: During the study period, 690 patients received ambulatory systemic chemotherapy. Chemotherapy was palliative in 76% of patients and 53% received a first line treatment. Seventeen (2.5%) died within 30 days of treatment administration. Nine deaths (52.9%) were definitely related to treatment and sepsis was the most frequent cause. CONCLUSIONS: Our mortality rates are similar to international data. This type of audit reviews local outcomes and identifies factors contributing to mortality aiming to improve standards of care.

Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment.

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

Real-world effectiveness and safety of dapagliflozin therapy added to a GLP1 receptor agonist in patients with type 2 diabetes.

BACKGROUND AND AIM: To evaluate the effectiveness and safety of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, dapagliflozin, in patients with type 2 diabetes mellitus (T2DM) and background glucagon-like peptide-1 receptor agonist (GLP1-RA) therapy. METHODS AND RESULTS: This is a 12-month, real-world observational study, which assessed the effectiveness and safety of dapagliflozin in patients with T2DM and background GLP1-RA therapy. The main outcome measures were changes in A1C and weight at 6 and 12 months from baseline. Secondary outcomes were differences in A1C and weight reduction between this cohort and another group of patients with T2DM treated with dapagliflozin but without background GLP1-RA therapy. In total, 109 patients with GLP1-RA and 104 patients without GLP1-RA were included. Baseline mean A1C and weight in the GLP1-RA and non-GLP1-RA groups were 7.4% vs. 7.3% and 96.2 kg vs. 95.1 kg, respectively. A significant reduction in A1C was seen with dapagliflozin in both cohorts at 6 and 12 months (GLP1-RA: -0.51% and -0.34%, non-GLP1-RA: -0.69% and -0.62%, respectively, p < 0.0001 in all analyses). Weight was significantly reduced in both groups at 6 and 12 months (GLP1-RA: -2.3 kg and -2.4 kg, non-GLP1-RA: -3.9 kg and -4.8 kg, respectively, p < 0.0001 in all analyses). A1C reduction and weight loss were significantly lower in patients with GLP1-RA than in patients without GLP1-RAs. Drug discontinuation rates were similar in both cohorts. CONCLUSIONS: Dapagliflozin, when added in real life to patients with T2DM treated with GLP1-RAs, induced a further significant, albeit modest improvement in A1C and a further weight loss.

Cost-effectiveness of fondaparinux versus enoxaparin in non-ST-elevation acute coronary syndrome in Canada (OASIS-5).

BACKGROUND: Acute coronary syndrome (ACS) refers to a spectrum of life-threatening cardiac diseases usually due to coronary artery plaque rupture, subsequent thrombin generation plaque activation and thrombus formation. To date, no economic analyses have been published about the use of fondaparinux in NSTE-ACS patients in Canada. The purpose of our study is to estimate the lifetime cost-effectiveness of fondaparinux compared to enoxaparin for non-ST-elevation acute coronary syndrome (NSTE-ACS) patients in a Canadian hospital setting. METHODS: As an extension of a previous published economic analysis for US patients, an event-based decision analytic model was constructed using clinical and resource use data from OASIS-5, a randomized trial of 20,078 patients from 41 countries. A public payer perspective in the hospital setting was adopted. Resource use data from the trial were valued using Canadian costs. A cost regression model was developed to estimate the mean cost of managing the clinical events over the 180 day period. Annual costs of long-term care for ACS patients were added after 180 days until death. Long-term survival was incorporated using Canadian life tables with further adjustment for additional risks associated with NSTE-ACS. Quality-of-life (utility) decrements from published sources were applied to clinical events. Lifetime costs (2009 CAD$) and quality-adjusted life-years (QALYs), discounted annually at 5 %, were estimated for the typical patient in OASIS-5 (i.e., at mean covariate values). RESULTS: The trial data showed that fondaparinux is protective against all clinical events observed in the trial. The model showed that: over 180 days, fondaparinux dominates enoxaparin, producing similar estimates of QALYs gained and saving $439; over a patient's lifetime, fondaparinux yields an ICER of $4293/QALY. Based on PSA, the probabilities that fondaparinux dominates enoxaparin (less costly and more effective) and that is cost-effective at a $50,000 threshold were 42 % and 96 %, respectively. CONCLUSIONS: In the Canadian hospital setting, fondaparinux is cost-effective when compared to enoxaparin for the treatment of NSTE-ACS. This result holds both in the immediate post-event period and over the lifetimes of patients.

Imidazolium salts as antifungal agents: strong antibiofilm activity against multidrug-resistant Candida tropicalis isolates.

UNLABELLED: The in vitro activity of the imidazolium salt C16 MImCl against planktonic and biofilm cells of multidrug-resistant isolates of Candida tropicalis was evaluated, both in solution and applied on a commercial catheter surface. This was determined by inhibition and susceptibility assays of biofilm and planktonic cells. In both cases, C16 MImCl prevented in vitro biofilm formation of C. tropicalis strains, including multidrug-resistant ones. Outstanding performances were observed, even at extremely low concentrations. Furthermore, this is the first report of the antifungal lock property of C16 MImCl, using a tracheal catheter as the test specimen to mimic a clinical in vivo condition. As such, C16 MImCl has been identified as a promising antimicotic pharmaceutical candidate for the treatment of candidiasis infections. SIGNIFICANCE AND IMPACT OF THE STUDY: The imidazolium salt 1-n-hexadecyl-3-methylimidazolium chloride (C16 MImCl) strongly prevents, in concentrations as low as 0·028 µg ml(-1) , the biofilm formation of multidrug-resistant Candida tropicalis isolates, either in solution or applied on the surface of commercial catheters. This presents an effective antimicotic candidate and alternative for invasive clinical procedure toolset asepsis.

Differential expression of serine protease inhibitors 1 and 2 in Crassostrea corteziensis and C. virginica infected with Perkinsus marinus.

Proliferation of Perkinsus marinus (Dermo) in vitro is inhibited by the action of 2 serine protease inhibitors belonging to the I-84 family. We compared the levels of expression of serine protease inhibitors 1 and 2 (SPI-1 and SPI-2) in 2 oyster species (Crassostrea virginica and C. corteziensis) inoculated with the parasite P. marinus. C. virginica is well known to be susceptible to this parasite, whereas C. corteziensis is apparently more tolerant. Oysters were inoculated with trophozoites (1 × 106 trophozoites oyster-1) of P. marinus while control oysters were injected with saline solution. Oysters were maintained in a closed water system for 2 wk. The oysters were then sacrificed and parasite burden, histological damage, and gene expression were evaluated. The results showed that the challenged oysters presented a significant increase in parasite burden, which generated histological damage in digestive gland and gills. Quantitative PCR detected significant differences in SPI-1 and SPI-2 expression levels in the 2 oyster species, with C. corteziensis showing higher expression levels than C. virginica as a response to P. marinus inoculation. Our results provide valuable information for the understanding of the defense response in C. corteziensis and a possible explanation for its tolerance to the parasite.

Asymptomatic carotid stenosis and cognitive improvement using transcervical stenting with protective flow reversal technique.

OBJECTIVES: The relationship between carotid artery stenosis and cognitive function in individuals without a history of stroke is not clear. The possible pathomechanisms of cognitive impairment include silent embolization and hypoperfusion. In this study the aim was to assess cognitive changes after transcervical carotid artery stenting with proximal cerebral protection by flow reversal in patients with asymptomatic carotid stenosis, a novel technique that has been proved to decrease the number intraoperative emboli. METHODS: 25 consecutive patients were assessed, of which 22 were men (88%) mean age of 74 years with severe asymptomatic carotid stenosis who underwent revascularization by carotid artery stenting (CAS) with flow reversal. Patients were evaluated 1 day before and 6 months after the procedure using a standardized neuropsychological battery. Test scores were adjusted according to age, sex, education level and were standardized (0-100). The mean of all the cognitive function scores yielded the global cognitive score (GCS). RESULTS: There were no neurological complications during the procedure or during hospitalization in any patient. No deaths or cardiac complications occurred in any patient. The pre-procedure neuropsychological study showed cognitive impairment in: information processing speed in 15 patients (62.5%), visuospatial function in 14 (56.0%), memory in 18 (72.0%), executive functions in 14 (56.0%), language in three (12.0%), attention in 10 (40.0%), and global cognitive performance in eight (32.0%). Comparison of these scores with those obtained 6-month post-procedure showed significant improvement in GCS in all patients (p = .002), with a particularly marked gain in information processing speed (p = .018). Although significant improvement was not found for the remaining cognitive functions assessed, some gain was documented, and there was no deterioration. CONCLUSIONS: Revascularization by transcervical CAS with flow reversal for cerebral protection results in improved neurocognitive performance in asymptomatic elderly patients with severe carotid artery stenosis.

Extraintestinal manifestations in children with gastrointestinal food allergy.

OBJECTIVES: The presence of extraintestinal manifestations (EIM) in children with gastrointestinal (GI) food allergy (GIFA) is greatly debated. In the present study we assessed the prevalence of EIM in children with GIFA and investigated whether their presence is helpful in the allergy-focused history-taking process. METHODS: The medical records of all children with a proven diagnosis of GIFA were reviewed along with those of children diagnosed as having inflammatory bowel disease (IBD) as controls. Data regarding age at onset, age at diagnosis, atopic family history, atopic comorbidities, GI symptoms, and EIM were recorded. RESULTS: Data from 436 children with GIFA and 74 children with IBD were included in the analysis. EIM were documented in 368 children with GIFA, including fatigue (53.0%), allergic shiners (49.1%), mouth ulcers (39.0%), joint pain/hypermobility (35.8%), poor sleep (34.4%), night sweats (34.4%), headache (22.7%), and bed-wetting (17.7%). The proportion of patients with EIM was higher in the GIFA group compared with that in the IBD group (368/436 [84.4%] vs 40/74 [54.1%]; P < 0.001). Segregating the GIFA group into children with and without atopic comorbidities, both atopic (276/30; 89.9%) and nonatopic (93/130; 71.5%) children showed higher proportion of EIM than children with IBD ([40/74; 54.1%], P < 0.01 and <0.05, respectively). CONCLUSIONS: GIFA are commonly associated with a wide range of EIM, which appear to represent important and specific clinical features of this group of conditions. Their recognition in taking an allergy-focused history may play an important role for both diagnosis and management.

Malnutrition in children with food allergies in the UK.

BACKGROUND: The mainstay of dietary management of food allergies remains the elimination diet. However, the removal of major food groups may predispose children to an inadequate nutrient intake. We therefore set out to establish growth status in food allergic children receiving dietetic input in the UK. METHODS: Dietitians were approached via the Food Allergy and Intolerance Specialist Group from the British Dietetic Association and asked to submit anthropometrical data for children with food allergies. Data collected related to the systems involved and number of foods excluded. Malnutrition was defined according to World Health Organization standards. RESULTS: Data from 13 different centres yielded 97 patients (51 male and 46 female) of which 66 excluded ≤2 foods and 31 excluded ≥3 foods. Data indicated that 8.5% had a weight for age ≤ -2 Z-score and, conversely, 8.5% were ≥2 Z-score. For height for age, 11.1% were ≤ -2 Z-score and, for weight for height, 3.7% were ≤ -2 Z-score and 7.5% ≥2 Z-score. Type of allergy, system involved and specific food elimination did not impact on the level of malnutrition. However, the elimination of ≥3 foods significantly impacted on weight for age (P = 0.044). CONCLUSIONS: The present study demonstrates that children with food allergies are more underweight than the general UK population, which appears to be linked to the number of foods excluded. However, the impact of the disease process itself should not be disregarded. Additionally, obesity can also occur in this population despite dietary elimination.

Quaternary origin and genetic divergence of the endemic cactus Mammillaria pectinifera in a changing landscape in the Tehuacán Valley, Mexico.

The endemic Mexican cactus, Mammillaria pectinifera, shows low dispersal capabilities and isolated populations within the highly dissected landscape of Tehuacán Valley. These characteristics can restrict gene flow and act upon the genetic divergence and speciation in arid plants. We conducted a phylogeographic study to determine if the origin, current distribution, and genetic structure of M. pectinifera were driven by Quaternary geomorphic processes. Sequences of the plastids psbA-trnH and trnT-trnL obtained from 66 individuals from seven populations were used to estimate genetic diversity. Population differentiation was assessed by an analysis of molecular variance. We applied a stepwise phylogenetic calibration test to determine whether species origin and genetic divergence among haplotypes were temporally concordant with recognizable episodes of geomorphic evolution. The combination of plastid markers yielded six haplotypes, with high levels of haplotype diversity (h = 0.622) and low nucleotide diversity (π = 0.00085). The populations were found to be genetically structured (F(ST) = 0.682; P < 0.00001), indicating that geographic isolation and limited dispersal were the primary causes of genetic population differentiation. The estimated origin and divergence time among haplotypes were 0.017-2.39 and 0.019-1.237 mya, respectively, which correlates with Pleistocene tectonics and erosion events, supporting a hypothesis of geomorphically-driven geographical isolation. Based on a Bayesian skyline plot, these populations showed long term demographic stability, indicating that persistence in confined habitats has been the main response of this species to landscape changes. We conclude that the origin and haplotype divergence of M. pectinifera were a response to local Quaternary geomorphic evolution.

Energy conversion theorems for some linear steady states.

One of the main issues that real energy converters present, when they produce effective work, is the inevitable entropy production. Within the context of nonequilibrium thermodynamics, entropy production tends to energetically degrade human-made or living systems. On the other hand, it is not useful to think about designing an energy converter that works in the so-called minimum entropy production regime since the effective power output and efficiency are zero. In this paper we establish some energy conversion theorems similar to Prigogine's theorem with constrained forces. The purpose of these theorems is to reveal trade-offs between design and the so-called operation modes for (2×2)-linear isothermal energy converters. The objective functions that give rise to those thermodynamic constraints show stability. A two-mesh electric circuit was built as an example to demonstrate the theorems' validity. Likewise, we reveal a type of energetic hierarchy for power output, efficiency, and dissipation function when the circuit is tuned to any of the operating regimes studied here. These are maximum power output (MPO), maximum efficient power (MPη), maximum omega function (MΩ), maximum ecological function (MEF), maximum efficiency (Mη), and minimum dissipation function (mdf).

No association between peripheral serotonin-gene-related DNA methylation and brain serotonin neurotransmission in the healthy and depressed state.

BACKGROUND: Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. RESULTS: We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. CONCLUSIONS: We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.

Dysfunction of proprioceptive sensory synapses is a pathogenic event and therapeutic target in mice and humans with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that SMA patients exhibit impaired proprioception, and their proprioceptive sensory synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex (H-reflex). We further show that loss of excitatory afferent synapses and altered potassium channel expression in SMA motor neurons are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory SMA patients and mouse models treated with SMN-inducing drugs correlate with increased function of sensory-motor circuits that can be accurately captured by the H-reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the H-reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.

Carnot, Stirling, and Ericsson stochastic heat engines: Efficiency at maximum power.

This work uses the low-dissipation strategy to obtain efficiency at maximum power from a stochastic heat engine performing Carnot-, Stirling- and Ericsson-like cycles at finite time. The heat engine consists of a colloidal particle trapped by optical tweezers, in contact with two thermal baths at different temperatures, namely hot (T_{h}) and cold (T_{c}). The particle dynamics is characterized by a Langevin equation with time-dependent control parameters bounded to a harmonic potential trap. In a low-dissipation approach, the equilibrium properties of the system are required, which in our case, can be calculated through a statelike equation for the mean value 〈x^{2}〉_{eq} coming from a macroscopic expression associated with the Langevin equation.