Myc-regulated miRNAs modulate p53 expression and impact animal survival under nutrient deprivation.

The conserved transcription factor Myc regulates cell growth, proliferation and apoptosis, and its deregulation has been associated with human pathologies. Although specific miRNAs have been identified as fundamental components of the Myc tumorigenic program, how Myc regulates miRNA biogenesis remains controversial. Here we showed that Myc functions as an important regulator of miRNA biogenesis in Drosophila by influencing both miRNA gene expression and processing. Through the analysis of ChIP-Seq datasets, we discovered that nearly 56% of Drosophila miRNA genes show dMyc binding, exhibiting either the canonical or non-canonical E-box sequences within the peak region. Consistently, reduction of dMyc levels resulted in widespread downregulation of miRNAs gene expression. dMyc also modulates miRNA processing and activity by controlling Drosha and AGO1 levels through direct transcriptional regulation. By using in vivo miRNA activity sensors we demonstrated that dMyc promotes miRNA-mediated silencing in different tissues, including the wing primordium and the fat body. We also showed that dMyc-dependent expression of miR-305 in the fat body modulates Dmp53 levels depending on nutrient availability, having a profound impact on the ability of the organism to respond to nutrient stress. Indeed, dMyc depletion in the fat body resulted in extended survival to nutrient deprivation which was reverted by expression of either miR-305 or a dominant negative version of Dmp53. Our study reveals a previously unrecognized function of dMyc as an important regulator of miRNA biogenesis and suggests that Myc-dependent expression of specific miRNAs may have important tissue-specific functions.

FOXO-mediated repression of Dicer1 regulates metabolism, stress resistance, and longevity in Drosophila.

The adipose tissue plays a crucial role in metabolism and physiology, affecting animal lifespan and susceptibility to disease. In this study, we present evidence that adipose Dicer1 (Dcr-1), a conserved type III endoribonuclease involved in miRNA processing, plays a crucial role in the regulation of metabolism, stress resistance, and longevity. Our results indicate that the expression of Dcr-1 in murine 3T3L1 adipocytes is responsive to changes in nutrient levels and is subject to tight regulation in the Drosophila fat body, analogous to human adipose and hepatic tissues, under various stress and physiological conditions such as starvation, oxidative stress, and aging. The specific depletion of Dcr-1 in the Drosophila fat body leads to changes in lipid metabolism, enhanced resistance to oxidative and nutritional stress, and is associated with a significant increase in lifespan. Moreover, we provide mechanistic evidence showing that the JNK-activated transcription factor FOXO binds to conserved DNA-binding sites in the dcr-1 promoter, directly repressing its expression in response to nutrient deprivation. Our findings emphasize the importance of FOXO in controlling nutrient responses in the fat body by suppressing Dcr-1 expression. This mechanism coupling nutrient status with miRNA biogenesis represents a novel and previously unappreciated function of the JNK-FOXO axis in physiological responses at the organismal level.

Different response of proanthocyanidins from Vitis vinifera cv. Monastrell depending on time of elicitor application.

BACKGROUND: Proanthocyanidins (PAs) are phenolic compounds present in skins and seeds of wine grapes and have great implications for plant physiology and wine quality. There are several strategies to increase PA concentration, such as application of elicitors methyl jasmonate (MeJ) and benzothiadiazole (BTH), compounds that can stimulate defence responses like phenolic compound biosynthesis in wine grapes, which have been applied mainly at veraison (beginning of ripening). We recently evaluated the application of MeJ and BTH on Vitis vinifera cv. Monastrell grapes during veraison and mid-ripening (3 weeks after veraison). Grapes treated at mid-ripening showed higher anthocyanin concentrations than those at veraison. In this trial, over two seasons, we evaluated whether time of application (veraison or mid-ripening) of MeJ and BTH on 'Monastrell' grapes is a determining factor in the biosynthesis and composition of PAs in grapes and their subsequent release into wines. RESULTS: Application of elicitors at different ripening times produced significant differences in the PAs of 'Monastrell' grapes, since those treated at mid-ripening recorded a higher PAs concentration in skin and seeds, and then in the wines produced, compared to grapes treated at veraison. CONCLUSION: Results suggest that despite different environmental conditions endured in each of the two seasons evaluated, application of elicitors at mid-ripening of Monastrell grapes could be used to harvest grapes with higher PA concentration, increasing the functional value of the wines, without altering their organoleptic quality. © 2022 Society of Chemical Industry.

Modeling multifunctionality of genes with secondary gene co-expression networks in human brain provides novel disease insights.

MOTIVATION: Co-expression networks are a powerful gene expression analysis method to study how genes co-express together in clusters with functional coherence that usually resemble specific cell type behavior for the genes involved. They can be applied to bulk-tissue gene expression profiling and assign function, and usually cell type specificity, to a high percentage of the gene pool used to construct the network. One of the limitations of this method is that each gene is predicted to play a role in a specific set of coherent functions in a single cell type (i.e. at most we get a single for each gene). We present here GMSCA (Gene Multifunctionality Secondary Co-expression Analysis), a software tool that exploits the co-expression paradigm to increase the number of functions and cell types ascribed to a gene in bulk-tissue co-expression networks. RESULTS: We applied GMSCA to 27 co-expression networks derived from bulk-tissue gene expression profiling of a variety of brain tissues. Neurons and glial cells (microglia, astrocytes and oligodendrocytes) were considered the main cell types. Applying this approach, we increase the overall number of predicted triplets by 46.73%. Moreover, GMSCA predicts that the SNCA gene, traditionally associated to work mainly in neurons, also plays a relevant function in oligodendrocytes. AVAILABILITYAND IMPLEMENTATION: The tool is available at GitHub, https://github.com/drlaguna/GMSCA as open-source software. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Deep connections: Divergence histories with gene flow in mesophotic Agaricia corals.

Largely understudied, mesophotic coral ecosystems lie below shallow reefs (at >30 m depth) and comprise ecologically distinct communities. Brooding reproductive modes appear to predominate among mesophotic-specialist corals and may limit genetic connectivity among populations. Using reduced representation genomic sequencing, we assessed spatial population genetic structure at 50 m depth in an ecologically important mesophotic-specialist species Agaricia grahamae, among locations in the Southern Caribbean. We also tested for hybridisation with the closely related (but depth-generalist) species Agaricia lamarcki, within their sympatric depth zone (50 m). In contrast to our expectations, no spatial genetic structure was detected between the reefs of Curaçao and Bonaire (~40 km apart) within A. grahamae. However, cryptic taxa were discovered within both taxonomic species, with those in A. lamarcki (incompletely) partitioned by depth and those in A. grahamae occurring sympatrically (at the same depth). Hybrid analyses and demographic modelling identified contemporary and historical gene flow among cryptic taxa, both within and between A. grahamae and A. lamarcki. These results (1) indicate that spatial connectivity and subsequent replenishment may be possible between islands of moderate geographic distances for A. grahamae, an ecologically important mesophotic species, (2) that cryptic taxa occur in the mesophotic zone and environmental selection along shallow to mesophotic depth gradients may drive divergence in depth-generalists such as A. lamarcki, and (3) highlight that gene flow links taxa within this relativity diverse Caribbean genus.

Ubiquitin-related processes and innate immunity in C. elegans.

Innate immunity is an evolutionary ancient defence strategy that serves to eliminate infectious agents while maintaining host health. It involves a complex network of sensors, signaling proteins and immune effectors that detect the danger, then relay and execute the immune programme. Post-translational modifications relying on conserved ubiquitin and ubiquitin-like proteins are an integral part of the system. Studies using invertebrate models of infection, such as the nematode Caenorhabditis elegans, have greatly contributed to our understanding of how ubiquitin-related processes act in immune sensing, regulate immune signaling pathways, and participate to host defence responses. This review highlights the interest of working with a genetically tractable model organism and illustrates how C. elegans has been used to identify ubiquitin-dependent immune mechanisms, discover novel ubiquitin-based resistance strategies that mediate pathogen clearance, and unravel the role of ubiquitin-related processes in tolerance, preserving host fitness during pathogen attack. Special emphasis is placed on processes that are conserved in mammals.

Eiger/TNFα-mediated Dilp8 and ROS production coordinate intra-organ growth in Drosophila.

Coordinated intra- and inter-organ growth during animal development is essential to ensure a correctly proportioned individual. The Drosophila wing has been a valuable model system to reveal the existence of a stress response mechanism involved in the coordination of growth between adjacent cell populations and to identify a role of the fly orthologue of p53 (Dmp53) in this process. Here we identify the molecular mechanisms used by Dmp53 to regulate growth and proliferation in a non-autonomous manner. First, Dmp53-mediated transcriptional induction of Eiger, the fly orthologue of TNFα ligand, leads to the cell-autonomous activation of JNK. Second, two distinct signaling events downstream of the Eiger/JNK axis are induced in order to independently regulate tissue size and cell number in adjacent cell populations. Whereas expression of the hormone dILP8 acts systemically to reduce growth rates and tissue size of adjacent cell populations, the production of Reactive Oxygen Species-downstream of Eiger/JNK and as a consequence of apoptosis induction-acts in a non-cell-autonomous manner to reduce proliferation rates. Our results unravel how local and systemic signals act concertedly within a tissue to coordinate growth and proliferation, thereby generating well-proportioned organs and functionally integrated adults.

Application of Elicitors in Two Ripening Periods of Vitis vinifera L. cv Monastrell: Influence on Anthocyanin Concentration of Grapes and Wines.

In recent years, it has been demonstrated that the application of elicitors such as methyl-jasmonate (MeJ) and benzothiadiazole (BTH) to wine grapes can increase their phenolic and aromatic compounds if they are treated at the beginning of ripening (veraison). However, the veraison period is short, and it is not always possible to apply the treatments in a few days. Therefore, it would be of great interest to optimize the moment of elicitor application or extend the treatment period. The aim of this paper was to analyze during two consecutive years (2016-2017) the foliar application of MeJ, BTH, and a combination of both, during two different ripening periods of Monastrell grapes (veraison and mid-ripening), and determine the more appropriate moment to increase the concentration of anthocyanins. To carry out this aim, analysis of anthocyanins by HPLC in grapes and wines was mainly performed. The most suitable period for the application of MeJ, BTH, and MeJ + BTH was at mid-ripening, since the grapes showed a greater accumulation of anthocyanins at harvest. However, the MeJ + BTH treatment applied during veraison also obtained similar results, which would allow extending the application period if necessary. However, the increase in the anthocyanin content of grapes was not reflected in all the wines, which may have been due to reinforcement of the skin cell wall as a result of the application of elicitors. Further analysis is needed to improve the maceration process of the Monastrell grapes and the extraction of the anthocyanins that were increased by the treatments applied in the vineyard.

Enhancing hygroscopic stability of agave fructans capsules obtained by electrospraying.

In this work, different whey protein (WP) ratios (5, 10, 20, 30, 40 and 50% w/w) were added as stabilizers to high degree of polymerization Agave fructans (HDPAF) capsules to decrease the hygroscopicity. Results showed that the WP and HDPAF in 1:520:80 ratio (20/80 w/w) decreased significantly the hygroscopicity of capsules from 12.19 to 8.34%. Additionally, this polymeric mixture was assessed for the encapsulation of sea grape (Coccoloba uvifera L.) leaf extract was achieved by via electrospray, using this biopolymers mixture. Scanning electron microscopy (SEM) images exhibited spherical particles with sizes from 655 to 7250 nm. The thermal stability of encapsulated extract was demonstrated by via thermogravimetric analysis. The in vitro release study in simulated stomach (0-180 min) and intestine conditions (0-300 min) showed the controlled release of the controlled release of the encapsulated extract. The encapsulated extract and its bioavailability in simulating the stomach (0-180 min) and small intestine (0-300 min) Therefore, HDPAF-WP is a viable option as an encapsulating matrix susceptible to be used in the food, pharmaceutical, and cosmetic industries.

Variations in Microbial Diversity and Metabolite Profiles of the Tropical Marine Sponge Xestospongia muta with Season and Depth.

Xestospongia muta is among the most emblematic sponge species inhabiting coral reefs of the Caribbean Sea. Besides being the largest sponge species growing in the Caribbean, it is also known to produce secondary metabolites. This study aimed to assess the effect of depth and season on the symbiotic bacterial dynamics and major metabolite profiles of specimens of X. muta thriving in a tropical marine biome (Portobelo Bay, Panamá), which allow us to determine whether variability patterns are similar to those reported for subtropical latitudes. The bacterial assemblages were characterized using Illumina deep-sequencing and metabolomic profiles using UHPLC-DAD-ELSD from five depths (ranging 9-28 m) across two seasons (spring and autumn). Diverse symbiotic communities, representing 24 phyla with a predominance of Proteobacteria and Chloroflexi, were found. Although several thousands of OTUs were determined, most of them belong to the rare biosphere and only 23 to a core community. There was a significant difference between the structure of the microbial communities in respect to season (autumn to spring), with a further significant difference between depths only in autumn. This was partially mirrored in the metabolome profile, where the overall metabolite composition did not differ between seasons, but a significant depth gradient was observed in autumn. At the phyla level, Cyanobacteria, Firmicutes, Actinobacteria, and Spirochaete showed a mild-moderate correlation with the metabolome profile. The metabolomic profiles were mainly characterized by known brominated polyunsaturated fatty acids. This work presents findings about the composition and dynamics of the microbial assemblages of X. muta expanding and confirming current knowledge about its remarkable diversity and geographic variability as observed in this tropical marine biome.

Erythroxylum in Focus: An Interdisciplinary Review of an Overlooked Genus.

The genus Erythroxylum contains species used by indigenous people of South America long before the domestication of plants. Two species, E. coca and E. novogranatense, have been utilized for thousands of years specifically for their tropane alkaloid content. While abuse of the narcotic cocaine has impacted society on many levels, these species and their wild relatives contain untapped resources for the benefit of mankind in the form of foods, pharmaceuticals, phytotherapeutic products, and other high-value plant-derived metabolites. In this review, we describe the current state of knowledge of members within the genus and the recent advances in the realm of molecular biology and biochemistry.

Variables Associated With the Subjective Experience of Coercive Measures in Psychiatric Inpatients: A Systematic Review.

OBJECTIVE: This systematic review presents evidence regarding factors that may influence the patient's subjective experience of an episode of mechanical restraint, seclusion, or forced administration of medication. METHOD: Two authors searched CINAHL, PubMed, SCOPUS, Web of Science, and Psych-Info, considering published studies between 1 January 1992 and 1 February 2016. Based on the inclusion criteria and methodological quality, 34 studies were selected, reporting a total sample of 1,869 participants. RESULTS: The results showed that the provision of information, contact and interaction with staff, and adequate communication with professionals are factors that influence the subjective experience of these measures. Humane treatment, respect, and staff support are also associated with a better experience, and debriefing is an important procedure/technique to reduce the emotional impact of these measures. Likewise, the quality of the working and physical environment and some individual and treatment variables were related to the experience of these measures. There are different results in relation to the most frequently associated experiences and, despite some data that indicate positive experiences, the evidence shows such experiences to be predominantly negative and frequently with adverse consequences. It seems that patients find forced medication and seclusion to be more tolerable than mechanical restraint and combined measures. CONCLUSIONS: It appears that the role of the staff and the environmental conditions, which are potentially modifiable, affect the subjective experience of these measures. There was considerable heterogeneity among studies in terms of coercive measures experienced by participants and study designs.

Detecting accidental punctures and lacerations during cholecystectomy in large datasets: Two methods of analysis.

BACKGROUND: After the Institute of Medicine (IOM) report To Err Is Human highlighted the impact of medical errors, the Agency for Healthcare Research and Quality (AHRQ) developed Patient-Safety Indicators (PSI) to improve quality by identifying potential inpatient safety problems. PSI-15 was created to study accidental punctures and lacerations (APL), but PSI-15 may underestimate APLs in populations of patients. This study compares PSI-15 with a more inclusive approach using a novel composite of secondary diagnostic and procedural codes. METHODS: We used Nationwide Inpatient Sample (NIS) data (2000-2012) from AHRQ's Healthcare Cost and Utilization Project (H-CUP). We analyzed PSI-15-positive and -negative cholecystectomies. Cross tabulations identified codes that were significantly more frequent among PSI-15-positive cases; these secondary diagnostic and procedural codes were selected as candidate members of a composite marker (CM) of APL. We chose cholecystectomy patients for study because this is one of the most common general operations, and the large size of NIS allows for meaningful analysis of infrequent occurrences such as APL rates. RESULTS: CM identified 1.13 times more APLs than did PSI-15. Patients with CM-detected APLs were significantly older and had worse mortality, comorbidities, lengths of stay, and charges than those detected with PSI-15. Further comparison of these two approaches revealed that time-series analysis for both APL markers revealed parallel trends, with inflections in 2007, and lowest APL rates in July. CONCLUSIONS: Although CM may yield more false positives, it appears more inclusive, identifying more clinically significant APLs, than PSI-15. Both measures presented similar trends over time, arguing against inflation in PSI-15 reporting. While arguably less specific, CM may increase sensitivity for detecting APL events during cholecystectomies. These results may inform the interpretation of other large population studies of APLs following abdominal operations.

Chikungunya Virus: History, Geographic Distribution, Clinical Picture, and Treatment.

Chikungunya fever (CHIKF) is a re-emerging mosquito-borne disease caused by a virus endemic to Africa and Asia. Due to the ease with which its vectors propagate, the virus has spread to India and Europe, and more recently it arrived to the Caribbean, eventually extending into North, Central, and South America. According to the World Health Organization (WHO), the most common clinical manifestations are abrupt fever, polyarthralgia, headache, maculopapular rash, myalgia, and nausea/vomiting. Severe joint pain and stiffness have been known to incapacitate some patients from a few days to several months after infection. Fatal cases are rare, but some individuals have been known to develop severe forms of the disease that include neurological and cardiac complications and severe cutaneous manifestations. Additionally, there have been reports of infected mothers miscarrying and newborns that were infected in utero being born with congenital illnesses. Advanced age and various comorbidities have been associated with severe or atypical forms of CHIKF. Currently there are no approved vaccines for the chikungunya virus (CHIKV), and treatment aims to alleviate patient symptoms. The re emergence of the CHIKV and its spread to new places around the globe encourage the development of new preventive, diagnostic, and treatment options.

A case of modular phenotypic plasticity in the depth gradient for the gorgonian coral Antillogorgia bipinnata (Cnidaria: Octocorallia).

BACKGROUND: Phenotypic plasticity, as a phenotypic response induced by the environment, has been proposed as a key factor in the evolutionary history of corals. A significant number of octocoral species show high phenotypic variation, exhibiting a strong overlap in intra- and inter-specific morphologic variation. This is the case of the gorgonian octocoral Antillogorgia bipinnata (Verrill 1864), which shows three polyphyletic morphotypes along a bathymetric gradient. This research tested the phenotypic plasticity of modular traits in A. bipinnata with a reciprocal transplant experiment involving 256 explants from two morphotypes in two locations and at two depths. Vertical and horizontal length and number of new branches were compared 13 weeks following transplant. The data were analysed with a linear mixed-effects model and a graphic approach by reaction norms. RESULTS: At the end of the experiment, 91.8% of explants survived. Lower vertical and horizontal growth rates and lower branch promotion were found for deep environments compared to shallow environments. The overall variation behaved similarly to the performance of native transplants. In particular, promotion of new branches showed variance mainly due to a phenotypic plastic effect. CONCLUSIONS: Globally, environmental and genotypic effects explain the variation of the assessed traits. Survival rates besides plastic responses suggest an intermediate scenario between adaptive plasticity and local adaptation that may drive a potential process of adaptive divergence along depth cline in A. bipinnata.

Investigation of the Best Approach for Assessing Human Exposure to Poly- and Perfluoroalkyl Substances through Indoor Air.

Per- and polyfluoroalkyl substances (PFASs), including fluorotelomer alcohols (FTOHs), perfluoroalkyl sulfonamidoethanols (FOSEs), and perfluoroalkyl sulfonamides (FOSAs), were assessed in 61 residential indoor air and 15 personal air samples collected in Oslo area, Norway. FTOHs were detected in all samples, and the median concentrations in residential indoor air were 2970, 10400, and 3120 pg m-3 for 6:2, 8:2, and 10:2 FTOH, respectively. This is similar to or higher than previously reported in studies from the same geographical area and worldwide. FOSEs and FOSAs were detected in 49-70% and 7-13% of the residential indoor air samples, respectively. The median FTOH concentrations observed in personal air were 1970, 7170, and 1590 pg m-3 for 6:2, 8:2, and 10:2 FTOH, respectively, which is 30 to 50% lower than the median concentrations in residential indoor air. No FOSEs or FOSAs were detected above the method detection limit (MDL) in the personal air samples. Intakes of perfluorohexanoate (PFHxA), perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), and perfluorooctyl sulfonate (PFOS) through inhalation and biotransformation of PFAS precursors in air were estimated. Median intakes of 1.7, 0.17, 5.7, 0.57, 1.8, 0.18, and 2.3 pg kg bw-1 day-1 were obtained in residential indoor air, while 1.0, 0.10, 3.3, 0.33, 0.88, and 0.09 pg kg bw-1 day-1 were found in personal air for PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, and PFOS, respectively. The median PFOA intakes from residential indoor air (5.7 pg kg bw-1 day-1) and personal air (3.3 pg kg bw-1 day-1) were both around 5 orders of magnitude lower than the tolerable daily intake (TDI) reported by the European Food Safety Authority (EFSA).

The Antarctic Circumpolar Current as a diversification trigger for deep-sea octocorals.

BACKGROUND: Antarctica is surrounded by the Antarctic Circumpolar Current (ACC), the largest and strongest current in the world. Despite its potential importance for shaping biogeographical patterns, the distribution and connectivity of deep-sea populations across the ACC remain poorly understood. In this study we conducted the first assessment of phylogeographical patterns in deep-sea octocorals in the South Pacific and Southern Ocean, specifically a group of closely related bottlebrush octocorals (Primnoidae: Tokoprymno and Thourella), as a test case to study the effect of the ACC on the population structure of brooding species. We assessed the degree to which the ACC constitutes a barrier to gene flow between northern and southern populations and whether the onset of diversification of these corals coincides with the origin of the ACC (Oligocene-Miocene boundary). RESULTS: Based on DNA sequences of two nuclear genes from 80 individuals and a combination of phylogeographic model-testing approaches we found a phylogenetic break corresponding to the spatial occurrence of the ACC. We also found significant genetic structure among our four regional populations. However, we uncovered shared haplotypes among certain population pairs, suggesting long-distance, asymmetrical migration. Our divergence time analyses indicated that the separation of amphi-ACC populations took place during the Middle Miocene around 12.6 million years ago, i.e., after the formation of the ACC. CONCLUSION: We suggest that the ACC constitutes a semi-permeable barrier to these deep-sea octocorals capable of separating and structuring populations, while allowing short periods of gene flow. The fluctuations in latitudinal positioning of the ACC during the Miocene likely contributed to the diversification of these octocorals. Additionally, we provide evidence that the populations from each of our four sampling regions could actually constitute different species.

Sex Disparities in Ischemic Stroke Care: FL-PR CReSD Study (Florida-Puerto Rico Collaboration to Reduce Stroke Disparities).

BACKGROUND AND PURPOSE: Sex-specific disparities in stroke care including thrombolytic therapy and early hospital admission are reported. In a large registry of Florida and Puerto Rico hospitals participating in the Get With The Guidelines-Stroke program, we sought to determine sex-specific differences in ischemic stroke performance metrics and overall thrombolytic treatment. METHODS: Around 51 317 (49% women) patients were included from 73 sites from 2010 to 2014. Multivariable logistic regression with generalized estimating equations evaluated sex-specific differences in the prespecified Get With The Guidelines-Stroke metrics for defect-free care in ischemic stroke, adjusting for age, race-ethnicity, insurance status, hospital characteristics, individual risk factors, and the presenting stroke severity. RESULTS: As compared with men, women were older (73±15 versus 69±14 years; P<0.0001), more hypertensive (67% versus 63%, P<0.0001), and had more atrial fibrillation (19% versus 16%; P<0.0001). Defect-free care was slightly lower in women than in men (odds ratio, 0.96; 95% confidence interval, 0.93-1.00). Temporal trends in defect-free care improved substantially and similarly for men and women, with a 29% absolute improvement in women (P<0.0001) and 28% in men (P<0.0001), with P value of 0.13 for time-by-sex interaction. Women were less likely to receive thrombolysis (odds ratio, 0.92; 95% confidence interval, 0.86-0.99; P=0.02) and less likely to have a door-to-needle time <1 hour (odds ratio, 0.83; 95% confidence interval, 0.71-0.97; P=0.02) as compared with men. CONCLUSIONS: Women received comparable stroke care to men in this registry as measured by prespecified Get With The Guidelines metrics. However, women less likely received thrombolysis and had door-to-needle time <1 hour, an observation that calls for the implementation of interventions to reduce sex disparity in these measures.

Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice: Dysregulation of PGC1α and Mitochondrial Homeostasis.

OBJECTIVE: Neuropilin-1 (NRP-1) is a multidomain membrane receptor involved in angiogenesis and development of neuronal circuits, however, the role of NRP-1 in cardiovascular pathophysiology remains elusive. APPROACH AND RESULTS: In this study, we first observed that deletion of NRP-1 induced peroxisome proliferator-activated receptor γ coactivator 1α in cardiomyocytes and vascular smooth muscle cells, which was accompanied by dysregulated cardiac mitochondrial accumulation and induction of cardiac hypertrophy- and stress-related markers. To investigate the role of NRP-1 in vivo, we generated mice lacking Nrp-1 in cardiomyocytes and vascular smooth muscle cells (SM22-α-Nrp-1 KO), which exhibited decreased survival rates, developed cardiomyopathy, and aggravated ischemia-induced heart failure. Mechanistically, we found that NRP-1 specifically controls peroxisome proliferator-activated receptor γ coactivator 1 α and peroxisome proliferator-activated receptor γ in cardiomyocytes through crosstalk with Notch1 and Smad2 signaling pathways, respectively. Moreover, SM22-α-Nrp-1 KO mice exhibited impaired physical activities and altered metabolite levels in serum, liver, and adipose tissues, as demonstrated by global metabolic profiling analysis. CONCLUSIONS: Our findings provide new insights into the cardioprotective role of NRP-1 and its influence on global metabolism.

Effectiveness of a Multimodal Intervention Program for Restraint Prevention in an Acute Spanish Psychiatric Ward.

BACKGROUND: International recommendations have called to implement strategies to reduce the use of coercion in psychiatric settings. However, in Spain there is a lack of research about intervention programs to reduce mechanical restraint in acute psychiatric units. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a multimodal intervention program based on the principles of six core strategies to reduce the frequency of use of mechanical restraint in an acute psychiatric ward. DESIGN: The design was a retrospective analysis of the frequency and duration of episodes of mechanical restraint prior to the intervention program (2012) and during the intervention program (2013) in one acute psychiatric ward. The intervention was governed by four strategies: (1) leadership and organizational changes, (2) registration and monitoring of risk patients, (3) staff training, and (4) involving patients in the treatment program. RESULTS: There was a significant difference between the mean number of monthly episodes of mechanical restraint per 1,000 patient days, pre-intervention (18.54 ± 8.78) compared with postintervention (8.53 ± 7.00; p = .005). We found the probability that mechanical restraint would occur in a hospital admission decreased after performing the intervention (odds ratio = .587; confidence interval = 0.411-0.838; p = .003) after adjusting for confounding variables. The total percentage of restrained patients fell from 15.07% to 9.74%. CONCLUSIONS: The main implication of the study is to support the effectiveness of specific intervention programs based on different measures to reduce mechanical restraint and without contemplating all the strategies that are considered effective.