Biological and Urea Treatments Reduce the Primary Inoculum of Red Leaf Blotch of Almond Caused by Polystigma amygdalinum.

Red leaf blotch (RLB), caused by Polystigma amygdalinum, is considered the most prevalent foliar disease in both traditional and new intensive almond-growing areas in Spain. Since the disease is monocyclic, its control must be based on the reduction of the only source of inoculum-the leaves infected in the previous season and fallen to the ground in autumn. Thus, this study aimed to determine the effect of two microorganisms and urea on RLB inoculum reduction by evaluating different application modes to fallen leaves in field conditions. Leaves of almond cv. Guara showing symptoms of RLB were collected in autumn, placed into nylon mesh bags, and treated by dipping or spraying with conidial suspensions of Myrothecium inundatum or the nonpathogenic strain Fusarium oxysporum FO12. The bags were exposed on the ground or buried in an experimental almond field for 6 months in each experimental year. Bags treated with crystalline urea solution at 46% N or not treated were included as controls. The primary inoculum (number of ascospores per gram of leaf) and the development of fruiting bodies (maturity stages of perithecia) were monitored in the fallen leaves for each experimental treatment combination. M. inundatum significantly reduced the primary inoculum in comparison with the nontreated control or F. oxysporum FO12, showing a similar effect to that observed for urea in the 2 experimental years. The type of application (spraying or dipping) did not show any significant effect, whereas the inoculum was significantly reduced in buried leaves in comparison with leaves maintained on the ground for all the treatments tested. This study represents the first report evaluating management strategies against RLB based on the reduction of the primary inoculum of P. amygdalinum.

A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is characterized by a primary mechanical injury and a secondary injury associated with neuroinflammation, blood-brain barrier (BBB) disruption and neurodegeneration. We have developed a novel cannabidiol aminoquinone derivative, VCE-004.8, which is a dual PPARγ/CB2 agonist that also activates the hypoxia inducible factor (HIF) pathway. VCE-004.8 shows potent antifibrotic, anti-inflammatory and neuroprotective activities and it is now in Phase II clinical trials for systemic sclerosis and multiple sclerosis. Herein, we investigated the mechanism of action of VCE-004.8 in the HIF pathway and explored its efficacy in a preclinical model of TBI. METHODS: Using a phosphoproteomic approach, we investigated the effects of VCE-004.8 on prolyl hydroxylase domain-containing protein 2 (PHD2) posttranslational modifications. The potential role of PP2A/B55α in HIF activation was analyzed using siRNA for B55α. To evaluate the angiogenic response to the treatment with VCE-004.8 we performed a Matrigel plug in vivo assay. Transendothelial electrical resistance (TEER) as well as vascular cell adhesion molecule 1 (VCAM), and zonula occludens 1 (ZO-1) tight junction protein expression were studied in brain microvascular endothelial cells. The efficacy of VCE-004.8 in vivo was evaluated in a controlled cortical impact (CCI) murine model of TBI. RESULTS: Herein we provide evidence that VCE-004.8 inhibits PHD2 Ser125 phosphorylation and activates HIF through a PP2A/B55α pathway. VCE-004.8 induces angiogenesis in vivo increasing the formation of functional vessel (CD31/α-SMA) and prevents in vitro blood-brain barrier (BBB) disruption ameliorating the loss of ZO-1 expression under proinflammatory conditions. In CCI model VCE-004.8 treatment ameliorates early motor deficits after TBI and attenuates cerebral edema preserving BBB integrity. Histopathological analysis revealed that VCE-004.8 treatment induces neovascularization in pericontusional area and prevented immune cell infiltration to the brain parenchyma. In addition, VCE-004.8 attenuates neuroinflammation and reduces neuronal death and apoptosis in the damaged area. CONCLUSIONS: This study provides new insight about the mechanism of action of VCE-004.8 regulating the PP2A/B55α/PHD2/HIF pathway. Furthermore, we show the potential efficacy for TBI treatment by preventing BBB disruption, enhancing angiogenesis, and ameliorating neuroinflammation and neurodegeneration after brain injury.

Projecting the long-term societal value of a disease-modifying treatment for Alzheimer's disease in the United States.

INTRODUCTION: We estimate societal value of a disease-modifying Alzheimer's disease (AD) treatment that reduces progression by 30% in early stages. METHODS: Using the International Society for Pharmacoeconomics and Outcomes Research value flower as framework, we estimate gross societal value, that is, not including treatment cost, from avoided medical and social care costs, productivity and quality-adjusted life-years (QALY) gains for patients and caregivers, adjusting for severity of disease, value of financial insurance, and value of insurance for currently unafflicted adults with a Markov model. RESULTS: Predicted societal value from 2021 until 2041 is $2.62 trillion for the overall afflicted US population and $986 billion for the 2021 prevalent cohort or $134,418 per person, with valuation of patients' QALY gains (63%) and avoided nursing-home costs (20%) as largest components. Delays in access because of health system capacity constraints could reduce realized value between 52% and 69%. The value of insurance for the unafflicted is $4.52 trillion or $18,399 on average per person. DISCUSSION: With a total of $5.5 trillion, the projected gross societal value of a hypothetical AD treatment is substantial, which may help to put the cost of treatment into perspective.

Betulinic acid hydroxamate prevents colonic inflammation and fibrosis in murine models of inflammatory bowel disease.

Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) and is defined as an excessive accumulation of scar tissue in the intestinal wall. Intestinal fibrosis occurs in both forms of IBD: ulcerative colitis and Crohn's disease. Small-molecule inhibitors targeting hypoxia-inducing factor (HIF) prolyl-hydroxylases are promising for the development of novel antifibrotic therapies in IBD. Herein, we evaluated the therapeutic efficacy of hydroxamate of betulinic acid (BHA), a hypoxia mimetic derivative of betulinic acid, against IBD in vitro and in vivo. We showed that BAH (5-20 µM) dose-dependently enhanced collagen gel contraction and activated the HIF pathway in NIH-3T3 fibroblasts; BAH treatment also prevented the loss of trans-epithelial electrical resistance induced by proinflammatory cytokines in Caco-2 cells. In two different murine models (TNBS- and DSS-induced IBD) that cause colon fibrosis, oral administration of BAH (20, 50 mg/kg·d, for 17 days) prevented colon inflammation and fibrosis, as detected using immunohistochemistry and qPCR assays. BAH-treated animals showed a significant reduction of fibrotic markers (Tnc, Col1a2, Col3a1, Timp-1, α-SMA) and inflammatory markers (F4/80+, CD3+, Il-1ß, Ccl3) in colon tissue, as well as an improvement in epithelial barrier integrity and wound healing. BHA displayed promising oral bioavailability, no significant activity against a panel of 68 potential pharmacological targets and was devoid of genotoxicity and cardiotoxicity. Taken together, our results provide evidence that oral administration of BAH can alleviate colon inflammation and colitis-associated fibrosis, identifying the enhancement of colon barrier integrity as a possible mechanism of action, and providing a solid rationale for additional clinical studies.

Inflammatory conditions promote a switch of oligosaccharyltransferase (OST) catalytic subunit isoform expression.

Oligosaccharyltransferase (OST) complex catalyzes the N-glycosylation of nascent polypeptides in the endoplasmic reticulum. Glycoproteins are critical for normal cell-cell interactions, especially during an immune response. Abnormal glycosylation is an insignia of several inflammatory diseases. However, the mechanisms that regulate the differential N-glycosylation are not fully understood. The OST complex can be assembled with one out of two catalytic subunits, STT3A or STT3B, which have different enzymatic properties. In this work, we investigated the expression of STT3A and STT3B in several mouse models such as a crossbreeding of normal and abortion-prone mice and an intestinal inflammation model. These animals were either exposed or not to acoustic stress (acute or chronic). The expression of the isoforms was analysed by immunohistochemistry and protein immunoblot. Finally, we investigated the gene regulatory elements employing public databases. Results demonstrated that inflammation alters the balance between the expression of both isoforms in the affected tissues. In homoeostatic conditions, STT3A expression predominates over STT3B, especially in epithelial cells. This relation is reversed as a consequence of inflammation. An increase in STT3B activity was associated to the generation of mannose-rich N-glycans. Accordingly, this type of N-glycans were found to decorate diverse inflamed tissues. The STT3A and STT3B genes are differentially regulated, which could account for the differences in the expression levels observed here. Our results support the idea that these isoforms could play different roles in cellular physiology. This study opens the possibility of studying the STT3A/STT3B expression ratio as a biomarker in acute inflammation or chronic diseases.

Analysis of triglyceride synthesis unveils a green algal soluble diacylglycerol acyltransferase and provides clues to potential enzymatic components of the chloroplast pathway.

BACKGROUND: Microalgal triglyceride (TAG) synthesis has attracted considerable attention. Particular emphasis has been put towards characterizing the algal homologs of the canonical rate-limiting enzymes, diacylglycerol acyltransferase (DGAT) and phospholipid:diacylglycerol acyltransferase (PDAT). Less work has been done to analyze homologs from a phylogenetic perspective. In this work, we used HMMER iterative profiling and phylogenetic and functional analyses to determine the number and sequence characteristics of algal DGAT and PDAT, as well as related sequences that constitute their corresponding superfamilies. We included most algae with available genomes, as well as representative eukaryotic and prokaryotic species. RESULTS: Amongst our main findings, we identified a novel clade of DGAT1-like proteins exclusive to red algae and glaucophyta and a previously uncharacterized subclade of DGAT2 proteins with an unusual number of transmembrane segments. Our analysis also revealed the existence of a novel DGAT exclusive to green algae with moderate similarity to plant soluble DGAT3. The DGAT3 clade shares a most recent ancestor with a group of uncharacterized proteins from cyanobacteria. Subcellular targeting prediction suggests that most green algal DGAT3 proteins are imported to the chloroplast, evidencing that the green algal chloroplast might have a soluble pathway for the de novo synthesis of TAGs. Heterologous expression of C. reinhardtii DGAT3 produces an increase in the accumulation of TAG, as evidenced by thin layer chromatography. CONCLUSIONS: Our analysis contributes to advance in the knowledge of complex superfamilies involved in lipid metabolism and provides clues to possible enzymatic players of chloroplast TAG synthesis.

Usefulness of several biomarkers in the management of septic patients: C-reactive protein, procalcitonin, presepsin and mid-regional pro-adrenomedullin.

BACKGROUND: Our objective is to analyze whether the combination of C-reactive protein (CRP), procalcitonin (PCT), presepsin or SCD14-ST and mid-regional pro-adrenomedullin (MR-proADM) measured in the first 24 h from ICU admission allowing a better management of septic patients (diagnostic and prognostic) both in severe sepsis (SS) and septic shock (SSh). METHODS: Cohort study of 388 patients admitted in the ICU during 12 months of whom 142 were controls. Biomarkers were measured through immunoluminometric assays in samples of serum or plasma within the first 24 h after admission. Data were evaluated with non-parametric statistics bivariant, ROC curve analysis for diagnostic evaluation and multivariate analyses for survival analysis. RESULTS: In the analyzed cohort, 61.8% of patients were males, mean age: 63 years range (18-90) and 67.8% in controls mean age: 63 years, range (39-91). PCT showed the highest area under the curve (AUC) (0.989) as compared with the rest of biomarkers (p<0.01). PCT also enabled the difference between Gram-positive or Gram-negative bacteria to be determined. The AUCs for CRP (0.922) and presepsin (0.948) showed a similar diagnostic value. In cases of SSh, the AUC of presepsin experienced a noticeable increase (p<0.0001). MR-proADM showed a better prognostic value (p=0.00022) particularly in cases of SSh (p=0.00001) increasing along with the APACHE-II score. CONCLUSIONS: PCT, MR-proADM and presepsin are complementary markers that could be of great help in the management of septic patients when they are measured in the first 24 h after ICU admission.

The diversity of algal phospholipase D homologs revealed by biocomputational analysis.

Phospholipase D (PLD) participates in the formation of phosphatidic acid, a precursor in glycerolipid biosynthesis and a second messenger. PLDs are part of a superfamily of proteins that hydrolyze phosphodiesters and share a catalytic motif, HxKxxxxD, and hence a mechanism of action. Although HKD-PLDs have been thoroughly characterized in plants, animals and bacteria, very little is known about these enzymes in algae. To fill this gap in knowledge, we performed a biocomputational analysis by means of HMMER iterative profiling, using most eukaryotic algae genomes available. Phylogenetic analysis revealed that algae exhibit very few eukaryotic-type PLDs but possess, instead, many bacteria-like PLDs. Among algae eukaryotic-type PLDs, we identified C2-PLDs and PXPH-like PLDs. In addition, the dinoflagellate Alexandrium tamarense features several proteins phylogenetically related to oomycete PLDs. Our phylogenetic analysis also showed that algae bacteria-like PLDs (proteins with putative PLD activity) fall into five clades, three of which are novel lineages in eukaryotes, composed almost entirely of algae. Specifically, Clade II is almost exclusive to diatoms, whereas Clade I and IV are mainly represented by proteins from prasinophytes. The other two clades are composed of mitochondrial PLDs (Clade V or Mito-PLDs), previously found in mammals, and a subfamily of potentially secreted proteins (Clade III or SP-PLDs), which includes a homolog formerly characterized in rice. In addition, our phylogenetic analysis shows that algae have non-PLD members within the bacteria-like HKD superfamily with putative cardiolipin synthase and phosphatidylserine/phosphatidylglycerophosphate synthase activities. Altogether, our results show that eukaryotic algae possess a moderate number of PLDs that belong to very diverse phylogenetic groups.

Progesterone regulates the expression and activity of two mouse isoforms of the glycoprotein folding sensor UDP-Glc: glycoprotein glucosyltransferase (UGGT).

UDP-Glucose:glycoprotein glucosyltransferase (UGGT) is a central component of the endoplasmic reticulum (ER) glycoprotein-folding quality control system, which prevents the exit of partially folded species. UGGT activity can be regulated by the accumulation of misfolded proteins in the ER, a stimulus that triggers a complex signaling pathway known as unfolded protein response (UPR) which is closely associated with inflammation and disease. In this work, we investigated the effect of progesterone (P4) on the expression and activity of UGGT in a mouse hybridoma. We detected the expression of two UGGT isoforms, UGGT1 and UGGT2, and demonstrated that both isoforms are active in these cells. Interestingly, the expression of each isoform is regulated by high physiological P4 concentrations. This work provides the first evidence of a hormonal regulation of UGGT isoform expression and activity, which might influence the glycoprotein quality control mechanism. These findings could contribute to the study of pathologies triggered by the accumulation of misfolded proteins.

Renal involvement in adults with cystic fibrosis: study of 89 patients. / Afectación renal en adultos con fibrosis quística: estudio de 89 pacientes.

INTRODUCTION: We are assisting to an increase in survival rates among individuals with cystic fibrosis (CF). Until now, renal involvement was a minority issue, but with the rise in life expectancy, we will likely see an increase in its prevalence. Our main objective was to assess renal function in CF and study risk factors associated with its deterioration. METHODS: A cross-sectional, retrospective study was conducted, including adults with CF. Clinical, respiratory function, microbiological, blood and urine analysis, and major chronic treatments received were collected. RESULTS: Eighty nine patients with a mean age of 35±12 years were analyzed. Mean serum creatinine levels were 0.8±0.2mg/dL. 10.6% had a glomerular filtration rate less than 90mL/min/1.73m2. No patient showed albuminuria. In multivariate model, only age was an independent risk factor for reduced glomerular filtration (OR: 0.344; 95%CI: 0.004-0.017; P=.002). CONCLUSIONS: 11% of CF adults show decreased glomerular filtration, with age being the sole independent risk factor. Vigilance for this uncommon condition is crucial.

Neuroprotective effects of VCE-004.8 in a rat model of neonatal stroke.

BACKGROUND: Currently there is no effective treatment for neonatal stroke, an acute neurologic syndrome with sequelae, due to focal ischemic, thrombotic, or hemorrhagic event occurring in the perinatal period. VCE-004.8, an aminoquinone exhibiting activity on CB2 and PPARγ receptors, is neuroprotective in adult mice models of acute and chronic brain damaging conditions. We hereby aimed to study VCE-004.8 neuroprotection in a rat model of neonatal stroke. METHODS: 7-day-old (P7) Wistar rats of both sexes were submitted to Middle Cerebral Artery Occlusion (MCAO), receiving i.p. 30 min after vehicle (MCAO + VEH) or VCE-004.8 5 mg/kg (MCAO + VCE). Non-occluded rats served as controls (SHAM). MCAO consequences were assessed at P14 by MRI, histological (TUNEL staining), biochemical (lactate/n-acetyl aspartate ratio by 1H-NMR spectroscopy) and motor studies (grasp test), and at P37 assessing myelination (MBP signal), hemiparesis and hyperlocomotion. Effects of VCE-004.8 on excitotoxicity (glutamate/n-acetyl aspartate, 1H-NMR), oxidative stress (protein nitrosylation, Oxyblot) and neuroinflammation (Toll-like receptor 4 and TNFa expression, Western blot) were assessed at P14. Therapeutic window was assessed by delaying drug administration for 12 or 18 h. RESULTS: Post-MCAO administration of VCE-004.8 reduced the volume of infarct and histological and biochemical brain damage, reducing hyperlocomotion, restoring motor performance and preserving myelination, in a manner linked to the modulation of excitotoxicity, oxidative stress and neuroinflammation. VCE-004.8 was still effective being administered 12-18 h post-insult. CONCLUSIONS: These data suggest that this drug could be effective for the treatment of stroke in newborns.

Impact of built, social, and economic environments on adolescent obesity and related health behaviors.

OBJECTIVE: This study aimed to estimate the effects of the built, social, and economic environments on adolescent obesity and related behaviors. METHODS: Exploiting quasi-exogenous variation in military families' geographic location, this study estimated intent-to-treat models of the association between the assigned installation's county environments and adolescents' (mean age 13.5 years) self-reported and model-corrected BMI, overweight or obesity status, and self-reported diet and exercise. Three indices for the built, social, and economic environments characterized county-level environments (higher value implies more advantageous environments) based on 19 indicators. Multivariate linear and logistic models were estimated on the full sample (N = 1111) and on subsamples with greater exposure based on time (n = 682) and off-installation residence (n = 604). RESULTS: Exposure to more advantageous built environments for more than 2 years was associated with lower probabilities of obesity (-0.18; 95% CI: -0.34 to -0.026) and overweight or obesity (-0.34; 95% CI: -0.56 to -0.12) and was associated with lower BMI z scores (-0.76; 95% CI: -1.45 to -0.02). Results for adolescents living off-installation were similar. More advantageous built environments were also associated with lower consumption of unhealthy foods, but not with physical activity. Social and economic environments were not associated with any outcomes. CONCLUSIONS: The built environment, but not social and economic environments, was a strong predictor of adolescents' BMI, overweight or obesity status, and eating behaviors.

Association of Place With Adolescent Obesity.

Importance: Despite strong evidence linking place and obesity risk, the extent to which this link is causal or reflects sorting into places is unclear. Objective: To examine the association of place with adolescents' obesity and explore potential causal pathways, such as shared environments and social contagion. Design, Setting, and Participants: This natural experiment study used the periodic reassignment of US military servicemembers to installations as a source of exogenous variation in exposure to difference places to estimate the association between place and obesity risk. The study analyzed data from the Military Teenagers Environments, Exercise, and Nutrition Study, a cohort of adolescents in military families recruited from 2013 through 2014 from 12 large military installations in the US and followed up until 2018. Individual fixed-effects models were estimated that examined whether adolescents' exposure to increasingly obesogenic places over time was associated with increases in body mass index (BMI) and probability of overweight or obesity. These data were analyzed from October 15, 2021, through March 10, 2023. Exposure: Adult obesity rate in military parent's assigned installation county was used as a summary measure of all place-specific obesogenic influences. Main Outcomes and Measures: Outcomes were BMI, overweight or obesity (BMI in the 85th percentile or higher), and obesity (BMI in the 95th percentile or higher). Time at installation residence and off installation residence were moderators capturing the degree of exposure to the county. County-level measures of food access, physical activity opportunities, and socioeconomic characteristics captured shared environments. Results: A cohort of 970 adolescents had a baseline mean age of 13.7 years and 512 were male (52.8%). A 5 percentage point-increase over time in the county obesity rate was associated with a 0.19 increase in adolescents' BMI (95% CI, 0.02-0.37) and a 0.02-unit increase in their probability of obesity (95% CI, 0-0.04). Shared environments did not explain these associations. These associations were stronger for adolescents with time at installation of 2 years or longer vs less than 2 years for BMI (0.359 vs. 0.046; P value for difference in association = .02) and for probability of overweight or obesity (0.058 vs. 0.007; P value for difference association = .02), and for adolescents who lived off installation vs on installation for BMI (0.414 vs. -0.025; P value for association = .01) and for probability of obesity (0.033 vs. -0.007; P value for association = .02). Conclusion and Relevance: In this study, the link between place and adolescents' obesity risk is not explained by selection or shared environments. The study findings suggest social contagion as a potential causal pathway.

VCE-005.1, an hypoxia mimetic betulinic acid derivative, induces angiogenesis and shows efficacy in a murine model of traumatic brain injury.

One of the main global causes of mortality and morbidity is traumatic brain injury (TBI). Neuroinflammation and brain-blood barrier (BBB) disruption play a pivotal role in the pathogenesis of acute and chronic TBI onset. The activation of the hypoxia pathway is a promising approach for CNS neurodegenerative diseases, including TBI. Herein, we have studied the efficacy of VCE-005.1, a betulinic acid hydroxamate, against acute neuroinflammation in vitro and on a TBI mouse model. The effect of VCE-005.1 on the HIF pathway in endothelial vascular cells was assessed by western blot, gene expression, in vitro angiogenesis, confocal analysis and MTT assays. In vivo angiogenesis was evaluated through a Matrigel plug model and a mouse model of TBI induced by a controlled cortical impact (CCI) was used to assess VCE-005.1 efficacy. VCE-005.1 stabilized HIF-1α through a mechanism that involved AMPK and stimulated the expression of HIF-dependent genes. VCE-005.1 protected vascular endothelial cells under prooxidant and pro-inflammatory conditions by enhancing TJ protein expression and induced angiogenesis both in vitro and in vivo. Furthermore, in CCI model, VCE-005.1 greatly improved locomotor coordination, increased neovascularization and preserved BBB integrity that paralleled with a large reduction of peripheral immune cells infiltration, recovering AMPK expression and reducing apoptosis in neuronal cells. Taken together, our results demonstrate that VCE-005.1 is a multitarget compound that shows anti-inflammatory and neuroprotective effects mainly by preventing BBB disruption and has the potential to be further developed pharmacologically in TBI and maybe other neurological conditions that concur with neuroinflammation and BBB disruption.

Neuroprotective Efficacy of Betulinic Acid Hydroxamate, a B55α/PP2A Activator, in Acute Hypoxia-Ischemia-Induced Brain Damage in Newborn Rats.

There is an increasing evidence of the neuroprotective effects of hypoxia inducing factor prolyl-hydroxylase inhibitors (HIF-PHDi) after hypoxic-ischemic (HI) brain damage (HIBD). We studied the neuroprotective effects of betulinic hydroxamate (BAH), a novel B55α/PP2A activator that dephosphorylates and inhibits PHD2 activity, in a rat model of neonatal HIBD. Seven-day-old (P7) Wistar rats were exposed to hypoxia after left carotid artery electrocoagulation and then received vehicle (HI + VEH) or BAH 3 mg/kg i.p. 30 min post-insult. Brain damage was assessed by magnetic resonance imaging (MRI) and neurobehavioral studies testing motor and cognitive performance at P14 and P37, as well as immunohistochemical studies (TUNEL and myelin basic protein (MBP) signal) at P37. Mechanisms of damage were assessed at P14 determining excitotoxicity (glutamate/N-acetylaspartate ratio by H+-magnetic resonance spectroscopy), oxidative stress (protein nitrosylation by Oxyblot), and inflammation (cytokine and chemokine concentration). BAH reduced brain damage volume and cell death, preventing the development of motor and working memory deficits. BAH showed a robust protective effect on myelination, restoring MBP expression at P37. BAH modulated excitotoxicity, oxidative stress, and inflammation. Most neuroprotective effects were still present despite BAH administration was delayed for 12 h, whereas beneficial effects on motor strength at P14 and on cell death and myelination at P37 were preserved even when BAH administration was delayed for 24 h. In conclusion, BAH appears as an effective neuroprotective treatment for neonatal HIBD in a manner associated with the modulation of excitotoxicity, oxidative stress, and inflammation, showing a broad therapeutic window.

Burnout, Resilience and Self-Esteem in School Teaching University Students.

Burnout syndrome seems to involve fatigue that is characterised by loss of motivation, lack of energy, and some apathy as a consequence of continued exposure to stress in demanding performance circumstances. BACKGROUND: The goal of the present study is to analyse the relationship between burnout in university students with a degree in Teaching and some variables that may be associated with it such as self-esteem, resilience or age. METHODS: A total of 1547 graduate students enrolled in the career of Teaching in the Faculty of Educational Sciences of the University of Granada, Spain, participated in the study. Of them, 337 (21.8%) were men, 1195 (77.3%) were women, 14 (0.9%) indicated other gender options, and 1 (0%) did not respond to this item. The mean age of the participants was 20.52. RESULTS: The results show that low levels of self-esteem and resilience, are the variables that best predict the increase in burnout in students of Teaching. CONCLUSIONS: Findings are discussed regarding applied implications and the need for future research. Intervention initiatives focused on enhancing personal strengths such as resilience or self-esteem can help students to cope with the stress associated with demanding educational situations and thus reduce the presence of burnout.

Do Sheriff-Coroners Underreport Officer-Involved Homicides?

Introduction: In the United States, each state sets its own standards for its death investigation system. These may require independent medical examiners and coroners or allow for the sheriff to assume the role of coroner. Motivated by the well-established fact that counts of officer-involved homicides in official data sets grossly undercount the number of these incidents, we examine the possibility that different death investigation systems may lead to different death classification outcomes. Methods: To examine the potential differences in officer-involved homicide underreporting by presence of sheriff-coroner and violent death type (gunshot, intentional use of force, pursuit, or other vehicle accident), we compare ratios of incidents from both the Federal Bureau of Investigation's Supplementary Homicide Reports and the restricted Multiple-Cause of Death files from the National Vital Statistics System to the Fatal Encounters data across coroner contexts in California between 2000 and 2018; we quantify differences descriptively and examine bivariate tests of means. Results: We find significantly greater underreporting of officer-involved deaths in sheriff-coroner counties in both official data sets for all incidents compared with non-sheriff-coroner counties, independently of the period considered. These underreporting differences in the National Vital Statistics System are robust to restricting to gunshot and intentional use of force deaths, the type of incident expected to be less prone to misclassification in that data set. Conclusions: Officer-involved death underreporting in sheriff-coroner counties necessitates further scrutiny. Disparities in officer-involved death reporting suggest political pressure may play a role in classifying deaths.

Cannabidiol markedly alleviates skin and liver fibrosis.

Cannabidiol (CBD) has been suggested as a potential therapy for inflammatory and fibrotic diseases. Cannabidiol was demonstrated to reduce alcohol-induced liver inflammation and steatosis but its specific activity on the fibrotic process was not investigated. Herein, the antifibrotic effects of cannabidiol in the skin were analysed in vitro using NIH-3T3 fibroblasts and human dermal fibroblasts and in vivo using the bleomycin-induced model of skin fibrosis. In a second model, non-alcoholic liver fibrosis was induced in mice by CCl4 exposure. Cannabidiol was administered daily, intraperitoneally in mice challenged with bleomycin and orally in CCl4 mice, and skin and liver fibrosis and inflammation were assessed by immunochemistry. Cannabidiol inhibited collagen gene transcription and synthesis and prevented TGFß-and IL-4 induced fibroblast migration. In the bleomycin model, cannabidiol prevented skin fibrosis and collagen accumulation around skin blood vessels, and in the CCl4 model cannabidiol significantly attenuated liver fibrosis measured by picrosirius red and Tenascin C staining and reduced T cell and macrophage infiltration. Altogether, our data further support the rationale of the medicinal use of this cannabinoid, as well as cannabis preparations containing it, in the management of fibrotic diseases including Systemic Sclerosis and Non-Alcoholic Fatty Liver Disease.

Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats.

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity of the hypoxia-inducing factor prolyl-hydroxylase type 2. IVH was induced in 1-day-old (P1) Wistar rats by the left periventricular injection of Clostridial collagenase. Then, pups received i.p. vehicle or BAH 3 mg/kg single dose. At P6, P14 and P45, brain damage (area of damage, neurobehavioral deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: corpus callosum atrophy and myelin basic protein signal reduction) and inflammation (TLR4, NF-κB and TNFα expression), excitotoxicity (Glutamate/N-acetylspartate) and oxidative stress (protein nitrosylation) were evaluated. BAH treatment did not reduce the volume of brain damage, but it did reduce perilesional tissue damage, preventing an IVH-induced increase in Lac/NAA. BAH restored neurobehavioral performance at P45 preventing WMI. BAH prevented an IVH-induced increase in inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, BAH reduced IVH-induced brain damage and prevented its long-term functional consequences, preserving normal myelination in a manner related to the modulation of inflammation, excitotoxicity and oxidative stress.