Exploring the relationship between emotion regulation, inhibitory control, and eating psychopathology in a non-clinical sample.

OBJECTIVE: The present study aimed to explore the relationship between difficulties in emotion regulation and deficits in inhibitory control, and the role of these processes in eating psychopathology in a non-clinical sample. We also explored the specificity in which deficits in inhibitory control may underlie eating psychopathology, namely whether they can be conceptualised as context specific or more extensive in nature. METHOD: Participants were 107 healthy individuals recruited at a major Portuguese university, aged between 18 and 43 years-old (M = 21.23, SD = 4.79). Two computerised neuropsychological tasks (i.e., emotional go/no-go and food go/no-go tasks) were used to assess response inhibition in the presence of general versus context-specific stimuli. A set of self-report measures was used to assess variables of interest such as emotion regulation and eating psychopathology. RESULTS: Results indicated higher response inhibition deficits among participants with higher difficulties in emotion regulation comparing to those with lower difficulties in emotion regulation, particularly in the context of food-related stimuli. In addition, the relationship between difficulties in emotion regulation and eating psychopathology was moderated by inhibitory control deficits in both the context of food and pleasant stimuli. CONCLUSIONS: The present findings highlight inhibitory control as an important process underlying the relationship between difficulties in emotion regulation and eating psychopathology in non-clinical samples. Findings have important implications for clinical practice and the prevention of eating psychopathology in healthy individuals and individuals with eating disorders.

Bile acids profile and redox status in healthy infants.

BACKGROUND: At birth, human neonates are more likely to develop cholestasis and oxidative stress due to immaturity or other causes. We aimed to search for a potential association between bile acids profile, redox status, and type of diet in healthy infants. METHODS: A cross-sectional, exploratory study enrolled 2-month-old full-term infants (n = 32). We measured plasma bile acids (total and conjugated), and red blood cell (RBC) oxidative stress biomarkers. The type of diet (breastfeeding, mixed, formula) was used as an independent variable. RESULTS: Plasma total bile acids medium value was 14.80 µmol/L (IQR: 9.25-18.00). The plasma-conjugated chenodeoxycholic acid percentage (CDCA%) correlated significantly and negatively with RBCs membrane-bound hemoglobin percentage (MBH%) (r = -0.635, p < 0.01) and with RBC-oxidized glutathione (r = -0.403, p < 0.05) levels. RBC oxidative stress biomarkers (especially MBH%) were predictors of conjugated CDCA%, and this predictive ability was enhanced when adjusted for the type of diet (MBH, r = 0.452, p < 0.001). CONCLUSIONS: Our data suggest that the bile acid profile might play a role in the regulation of redox status (or vice versa) in early postnatal life. Eventually, the type of diet may have some impact on this process. IMPACT: The conjugated CDCA% in plasma is negatively correlated with biomarkers of RBC oxidative stress in healthy infants. Specific biomarkers of RBC oxidative stress (e.g. MBH, GSH, GSSG) may be promising predictors of conjugated CDCA% in plasma. The type of diet may influence the predictive ability of hit RBC oxidative stress biomarkers (e.g. MBH, GSH, GSSG). Our findings suggest a link between plasma bile acids profile and the RBC redox status in healthy infants, eventually modulated by the type of diet. The recognition of this link may contribute to the development of preventive and therapeutic strategies for neonatal cholestasis.

Cortical auditory evoked potentials in 1-month-old infants predict language outcomes at 12 months.

The neurophysiological assessment of infants in their first developmental year can provide important information about the functional changes of the brain and supports the study of behavioral and developmental characteristics. Infants' cortical auditory evoked potentials (CAEPs) reflect cortical maturation and appear to predict subsequent language abilities. This study aimed to identify CAEP components to two auditory stimulus intensities in 1-month-old infants and to understand how these are associated with social interactive and self-regulatory behaviors. In addition, it examined whether CAEPs predicted developmental outcomes when infants were assessed at 12 months of age. At 1 month, P2 and N2 components were present for both auditory stimulus intensities, with an increased P2 amplitude being observed for the higher-intensity stimuli. We also observed that an increased P2 amplitude in the lower intensity predicted receptive and expressive language competencies at 12 months. These results are consistent with previous findings indicating an association between auditory processing and developmental outcomes in infants. This study suggests that specific auditory neurophysiological markers are associated with developmental outcomes in the first developmental year.

The mediating role of self-criticism, experiential avoidance and negative urgency on the relationship between ED-related symptoms and difficulties in emotion regulation.

OBJECTIVE: Difficulties in emotion regulation are thought to play a transdiagnostic role across eating disorders (ED). In the current study, we explored with a path analysis the mediating role of self-criticism, experiential avoidance and negative urgency on the relationship between ED-related symptoms and dimensions of difficulties in emotion regulation. METHOD: Participants were 103 female outpatients recruited at a Portuguese ED hospital unit, diagnosed with an ED, aged 14-60 years old (M = 28.0, SD = 10.5), body mass index (BMI) ranging from 11.72 to 39.44 (M = 20.1, SD = 5.4). RESULTS: The path analysis resulted in a model with an adequate fit to the data (SRMR = 0.05; RMSEA = 0.07 [0.00, 0.12], PCLOSE = 0.269; TLI = 0.97; IFI = 0.99; GFI = 0.95). A final model in which the relationship between ED-related symptoms and dimensions of difficulties in emotion regulation was mediated by self-criticism, experiential avoidance and negative urgency, accounted for a variance of 71% for strategies, 57% for non-acceptance, 62% for impulses, 56% for goals and 20% for clarity. CONCLUSION: Results suggest that self-criticism, experiential avoidance and negative urgency, combined, are relevant in the relationship between ED-related symptoms and difficulties in emotion regulation. ED treatment and emotion regulation skills may be enhanced through the inclusion of specific components that target self-criticism, experiential avoidance and negative urgency, as they become prominent during the therapeutic process.

Small Molecule Fisetin Modulates Alpha-Synuclein Aggregation.

Phenolic compounds are thought to be important to prevent neurodegenerative diseases (ND). Parkinson's Disease (PD) is a neurodegenerative disorder known for its typical motor features, the deposition of α-synuclein (αsyn)-positive inclusions in the brain, and for concomitant cellular pathologies that include oxidative stress and neuroinflammation. Neuroprotective activity of fisetin, a dietary flavonoid, was evaluated against main hallmarks of PD in relevant cellular models. At physiologically relevant concentrations, fisetin protected SH-SY5Y cells against oxidative stress overtaken by tert-butyl hydroperoxide (t-BHP) and against methyl-4-phenylpyridinuim (MPP+)-induced toxicity in dopaminergic neurons, the differentiated Lund human Mesencephalic (LUHMES) cells. In this cellular model, fisetin promotes the increase of the levels of dopamine transporter. Remarkably, fisetin reduced the percentage of cells containing αsyn inclusions as well as their size and subcellular localization in a yeast model of αsyn aggregation. Overall, our data show that fisetin exerts modulatory activities toward common cellular pathologies present in PD; remarkably, it modulates αsyn aggregation, supporting the idea that diets rich in this compound may prove beneficial.

Identification and Microbial Production of the Raspberry Phenol Salidroside that Is Active against Huntington's Disease.

Edible berries are considered to be among nature's treasure chests as they contain a large number of (poly)phenols with potentially health-promoting properties. However, as berries contain complex (poly)phenol mixtures, it is challenging to associate any interesting pharmacological activity with a single compound. Thus, identification of pharmacologically interesting phenols requires systematic analyses of berry extracts. Here, raspberry (Rubus idaeus, var Prestige) extracts were systematically analyzed to identify bioactive compounds against pathological processes of neurodegenerative diseases. Berry extracts were tested on different Saccharomyces cerevisiae strains expressing disease proteins associated with Alzheimer's, Parkinson's, or Huntington's disease, or amyotrophic lateral sclerosis. After identifying bioactivity against Huntington's disease, the extract was fractionated and the obtained fractions were tested in the yeast model, which revealed that salidroside, a glycosylated phenol, displayed significant bioactivity. Subsequently, a metabolic route to salidroside was reconstructed in S cerevisiae and Corynebacterium glutamicum The best-performing S cerevisiae strain was capable of producing 2.1 mm (640 mg L-1) salidroside from Glc in shake flasks, whereas an engineered C glutamicum strain could efficiently convert the precursor tyrosol to salidroside, accumulating up to 32 mm (9,700 mg L-1) salidroside in bioreactor cultivations (yield: 0.81 mol mol-1). Targeted yeast assays verified that salidroside produced by both organisms has the same positive effects as salidroside of natural origin.

Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open-label multiple-dose study.

This study evaluated the effect of age and renal impairment on pharmacokinetics of trimetazidine (TMZ) in healthy elderly and renally impaired subjects and assess safety and tolerability. In this open-label, multi-dose study, 73 subjects were divided into six treatment groups: (1) 55-65 years; (2) 66-75 years; (3) >75 years (dosing for groups 1-3 [healthy]: B.D. for 4 days), (4) mild renally impaired (dosed B.D. for 8 days); (5) moderate renally impaired (dosed O.D. for 8 days); and (6) severe renally impaired-no dialysis (dosed once every 48 h for 8 days). Blood and urine samples were collected and analyzed. The geometric least squares mean ratios for; Group 2 and 1 of AUC(0-τ)ss was 112.2 (90% CI; 92.0-136.8) and Cmax,ss was 109.9 (89.6-134.8), Group 3 and 1 of AUC(0-τ),ss was 140.5 (115.9-170.3) and Cmax,ss was 137.8 (112.9-168.2), Group 4 and 1 of AUC(0-τ),ss was 114.2 (90.3-144.4) and Cmax,ss was 120.8 (92.5-157.8), Group 5 and 1 of; AUC(0-τ),ss was 213.0 (153.1-296.3) and Cmax,ss was 123.3 (92.2-164.7) and Group 6 and 1 of AUC(0-τ),ss was 247.4 (197.8-309.6) and Cmax,ss was 95.6 (73.0-125.1). Significant increase in systemic exposure of TMZ was observed in subjects; over 75 year's age and renally impaired compared to healthy subjects. TMZ was safe and well-tolerated.

A drug utilization study to evaluate effectiveness of risk minimization measures for trimetazidine in France, Hungary, Romania and Spain.

WHAT IS KNOWN AND OBJECTIVE: The approved indication for trimetazidine (TMZ) was restricted to "add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies" in 2012 by the Committee for Medicinal Products for Human Use (CHMP). TMZ was no longer indicated for ophthalmology and otolaryngology (ENT) indications. This drug utilization study analysed actual utilization of TMZ before and after the restriction on its indications to evaluate the effectiveness of risk minimization measures (RMM). METHODS: This was a multi-national, cross-sectional, non-interventional drug utilization study using European databases: IMS Prescribing Insights (PI) for France and Spain, National Diagnostic Index (NDI) for Romania and National Prescription Audit (NPA) for Hungary. TMZ prescriptions issued by Ear-Nose-Throat (ENT) specialists, ophthalmologists, cardiologists and General Physicians (GPs)/others were analysed during the 24-month period before (reference period) and after RMM implementation (assessment period). RESULTS AND DISCUSSION: During the assessment period, most of the TMZ prescriptions for ENT and ophthalmology indications (un-authorized indications) were made by GPs/others followed by ENT specialists, ophthalmologists and cardiologists in most of the countries. The proportion of TMZ prescriptions for ENT or ophthalmological indications after the restrictions on indication was reduced in Hungary (by 0.4%) and Spain (by 11.8%), remained the same in Romania and increased in France (by 3.7%). WHAT IS NEW AND CONCLUSION: This study showed that a significant proportion of TMZ prescriptions was off-label for ENT or ophthalmological indications following the RMM implementation. More effective RMM strategies are required to reduce off-label prescriptions of TMZ.

Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity.

Synucleins belong to a family of intrinsically unstructured proteins that includes alpha-synuclein (aSyn), beta-synuclein (bSyn) and gamma-synuclein (gSyn). aSyn is the most studied member of the synuclein family due to its central role in genetic and sporadic forms of Parkinson's disease and other neurodegenerative disorders known as synucleionopathies. In contrast, bSyn and gSyn have been less studied, but recent reports also suggest that, unexpectedly, these proteins may also cause neurotoxicity. Here, we explored the yeast toolbox to investigate the cellular effects of bSyn and gSyn. We found that bSyn is toxic and forms cytosolic inclusions that are similar to those formed by aSyn. Moreover, we found that bSyn shares similar toxicity mechanisms with aSyn, including vesicular trafficking impairment and induction of oxidative stress. We demonstrate that co-expression of aSyn and bSyn exacerbates cytotoxicity, due to increased dosage of toxic synuclein forms, and that they are able to form heterodimers in both yeast and in human cells. In contrast, gSyn is not toxic and does not form inclusions in yeast cells. Altogether, our findings shed light into the question of whether bSyn can exert toxic effects and confirms the occurrence of aSyn/bSyn heterodimers, opening novel perspectives for the development of novel strategies for therapeutic intervention in synucleinopathies.

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

PURPOSE: In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. METHODS: A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries. RESULTS: Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris. CONCLUSIONS: RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

Phosphorylation modulates clearance of alpha-synuclein inclusions in a yeast model of Parkinson's disease.

Alpha-synuclein (aSyn) is the main component of proteinaceous inclusions known as Lewy bodies (LBs), the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Although aSyn is phosphorylated at low levels under physiological conditions, it is estimated that ∼ 90% of aSyn in LBs is phosphorylated at S129 (pS129). Nevertheless, the significance of pS129 in the biology of aSyn and in PD pathogenesis is still controversial. Here, we harnessed the power of budding yeast in order to assess the implications of phosphorylation on aSyn cytotoxicity, aggregation and sub-cellular distribution. We found that aSyn is phosphorylated on S129 by endogenous kinases. Interestingly, phosphorylation reduced aSyn toxicity and the percentage of cells with cytosolic inclusions, in comparison to cells expressing mutant forms of aSyn (S129A or S129G) that mimic the unphosphorylated form of aSyn. Using high-resolution 4D imaging and fluorescence recovery after photobleaching (FRAP) in live cells, we compared the dynamics of WT and S129A mutant aSyn. While WT aSyn inclusions were very homogeneous, inclusions formed by S129A aSyn were larger and showed FRAP heterogeneity. Upon blockade of aSyn expression, cells were able to clear the inclusions formed by WT aSyn. However, this process was much slower for the inclusions formed by S129A aSyn. Interestingly, whereas the accumulation of WT aSyn led to a marked induction of autophagy, cells expressing the S129A mutant failed to activate this protein quality control pathway. The finding that the phosphorylation state of aSyn on S129 can alter the ability of cells to clear aSyn inclusions provides important insight into the role that this posttranslational modification may have in the pathogenesis of PD and other synucleinopathies, opening novel avenues for investigating the molecular basis of these disorders and for the development of therapeutic strategies.

Protective Effect of a (Poly)phenol-Rich Extract Derived from Sweet Cherries Culls against Oxidative Cell Damage.

Oxidative stress is one of the key phenomena behind the most common types of chronic diseases. Therefore, the modulation of oxidative stress is an interesting target for acting either through prevention or as a therapeutic approach. In this work, a Portuguese variety of cherry (Saco Cherry) was processed in order to obtain a potent in vitro antioxidant phenolic-rich extract (Ch-PRE), which was further explored to evaluate its potential application as nutraceutical agent against cellular oxidative stress damage. Ch-PRE was mainly composed of anthocyanins, particularly cyanidin-3-rutinoside, cyanidin-3-glucoside, peonidin-3-glucoside and neochlorogenic acid, and exhibited a potent chemical antioxidant activity expressed by its oxygen radical absorbance capacity (ORAC) and hydroxyl radical averting capacity (HORAC) values. Ch-PRE also displayed effective intracellular radical scavenging properties in intestinal epithelial and neuronal cells challenged with oxidative stress but showed a different order of effectiveness regarding the modulation of endogenous antioxidant system. Ch-PRE could be an attractive candidate to formulate an agent for the prevention of oxidative stress-induced disorders such as intestinal inflammation disorders or with an appropriated delivery system for neurodegenerative diseases.

Intestinal Colonization by Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae in Infants.

BACKGROUND: Members of the Enterobacteriaceae family are common agents of nosocomial infections. Intestinal colonization by these microorganisms represents a major step in the development of systemic infection. Extended-spectrum b-lactamase-producing bacteria are usually associated with outbreaks, but endemic infections are common in intensive care units. OBJECTIVE: To determine the frequency of intestinal colonization with extended-spectrum b-lactamase-producing Enterobacteriaceae in newborns. PATIENTS AND METHODS: This was a descriptive cohort study. Newborns from two general hospitals (A and B) in Mexico City were included during a five-month period; those with a hospital stay > 7 days were selected. Fecal samples were obtained by rectal swab on day 7 and every week until discharge. Extended-spectrum b-lactamase production was confirmed in enterobacteria by the Etest. Clonal relatedness was established by pulsed-field gel electrophoresis. RESULTS: 102 newborns were included; 63/102 (61.7%) were colonized by extended-spectrum b-lactamase-producing Enterobacteriaceae on day 7, 17/21 (81%) on day 14, and 6/8 (75%) on day 21 of hospitalization. Klebsiella pneumoniae was recovered most frequently (75.4%). A predominant clone (95%) was found in hospital B, and a major clone (75%) in Hospital A. Other extended-spectrum b-lactamase-producing Enterobacteriaceae isolates were Enterobacter spp. (16%) and Escherichia coli (7.6%). CONCLUSIONS: High rates of colonization and horizontal transmission of extended-spectrum b-lactamase-producing Enterobacteriaceae were found in the newborn care units of two general hospitals. Clonal relatedness was identified. Lack of adherence to standard precautions and hand hygiene were determining factors.

Combining bird tracking data with high-resolution thermal mapping to identify microclimate refugia.

Elevated temperatures can have a range of fitness impacts, including high metabolic cost of thermoregulation, hence access to microclimate refugia may buffer individuals against exposure to high temperatures. However, studies examining the use of microclimate refugia, remain scarce. We combined high resolution microclimate modelling with GPS tracking data as a novel approach to identify the use and availability of cooler microclimate refugia (sites > 0.5 °C cooler than the surrounding landscape) at the scales experienced by individual animals. 77 little bustards (Tetrax tetrax) were tracked between 2009 and 2019. The 92,685 GPS locations obtained and their surrounding 500 m areas were characterised with hourly temperature and habitat information at 30 m × 30 m and used to determine microclimate refugia availability and use. We found that the semi-natural grassland landscapes used by little bustards have limited availability of cooler microclimate areas-fewer than 30% of the locations. The use of cooler microclimate sites by little bustards increased at higher ambient temperatures, suggesting that individuals actively utilise microclimate refugia in extreme heat conditions. Microclimate refugia availability and use were greater in areas with heterogeneous vegetation cover, and in coastal areas. This study identified the landscape characteristics that provide microclimate opportunities and shelter from extreme heat conditions. Little bustards made greater use of microclimate refugia with increasing temperatures, particularly during the breeding season, when individuals are highly site faithful. This information can help identify areas where populations might be particularly exposed to climate extremes due to a lack of microclimate refugia, and which habitat management measures may buffer populations from expected increased exposure to temperature extremes.

Temperature and microclimate refugia use influence migratory timings of a threatened grassland bird.

BACKGROUND: Seasonal changes in resource availability are known to influence the migratory behaviour of animals, including both timing and distance. While the influence of environmental cues on migratory behaviour has been widely studied at the population level, it has rarely been examined at the spatial scale at which individuals experience their environment. Here, we test the hypothesis that individuals exposed to similar large-scale environmental cues may vary in migratory behaviour in response to the different microclimate conditions they experience at fine scales. METHODS: We combine high-spatial and temporal resolution microclimate and habitat information with GPS tracking data for a partially migratory threatened grassland bird. Data from 47 little bustards (Tetrax tetrax; 67 breeding events) tracked between 2009 and 2019 was used to (i) evaluate individual consistency in migratory behaviour (timing and distance) and (ii) assess whether the local environmental characteristics experienced by individuals - and in particular their use of microclimate refugia - influence distance and timing of migration, from and to the breeding sites. RESULTS: Migratory distance was consistent for birds tracked over multiple years, while the timing of migration showed high variability among individuals. Departures from breeding areas spanned from May to August, with a few birds remaining in their breeding areas. Vegetation greenness (a proxy for food availability) was positively associated with the time birds spent in the breeding area. The best model also included a positive effect of microclimate refugia availability on breeding season length, although an interaction with temperature suggested that this effect did not occur at the highest relative temperatures. The return date to breeding grounds, although spanning from September to April, was not influenced by the environmental conditions or food availability. CONCLUSIONS: Food availability, measured by a vegetation greenness proxy, was associated with later migration at the end of the breeding season. Availability of cooler microclimate refugia may also allow for later departures from the breeding sites in all but the hottest conditions. Management measures that increase microclimate refugia availability and provide foraging resources can thus potentially increase the length of the breeding season for this species.

Corrigendum: Severe and enduring' stage in anorexia nervosa: comparing eating attitudes, impairment and associated psychopathology.

[This corrects the article DOI: 10.3389/fnut.2022.867401.].

Eating disorders during lockdown: the transcultural influence on eating and mood disturbances in Ibero-Brazilian population.

BACKGROUND: COVID-19 pandemic has implied exceptional restrictive measures to contain its widespread, with adverse consequences on mental health, especially for those people with a background of mental illness, such as eating disorders (EDs). In this population, the influence of socio-cultural aspects on mental health has been still underexplored. Then, the main aim of this study was to assess changes in eating and general psychopathology in people with EDs during lockdown regarding the ED subtype, age, and provenance, and considering socio-cultural aspects (e.g., socioeconomical factors such as work and financial losses, social support, restrictive measures, or health accessibility, among others). METHODS: The clinical sample was composed of 264 female participants with EDs (74 anorexia nervosa (AN), 44 bulimia nervosa (BN), 81 binge eating disorder (BED), and 65 other specified feeding and eating disorder (OSFED)), with a mean age of 33.49 years old (SD = 12.54), from specialized ED units in Brazil, Portugal, and Spain. The participants were evaluated using the COVID-19 Isolation Eating Scale (CIES). RESULTS: A global impairment in mood symptoms and emotion regulation was reported in all the ED subtypes, groups of age, and countries. Spanish and Portuguese individuals seemed more resilient than Brazilian ones (p < .05), who reported a more adverse socio-cultural context (i.e., physical health, socio-familial, occupational, and economic status) (p < .001). A global trend to eating symptoms worsening during lockdown was observed, regardless of the ED subtype, group of age, and country, but without reaching statistical significance. However, the AN and BED groups described the highest worsening of the eating habits during lockdown. Moreover, individuals with BED significantly increased their weight and body mass index, similarly to BN, and in contrast to the AN and OSFED groups. Finally, we failed to find significant differences between groups of age although the younger group described a significant worsening of the eating symptoms during lockdown. CONCLUSIONS: This study reports a psychopathological impairment in patients with EDs during lockdown, being socio-cultural aspects potential modulatory factors. Individualized approaches to detect special vulnerable groups and long-term follow-ups are still needed.

Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.

Parkinson's Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.

Severe and Enduring' Stage in Anorexia Nervosa: Comparing Eating Attitudes, Impairment and Associated Psychopathology.

This study aimed to assess differences in eating attitudes, impairment, and related psychopathology at treatment presentation for patients with "Non-severe and enduring Anorexia Nervosa" (illness duration of <7 years) and patients with "severe and enduring Anorexia Nervosa" (illness duration of 7 years or more). One hundred and thirty-nine patients diagnosed with Anorexia Nervosa participated in this study. Participants were interviewed with the Eating Disorder Examination (EDE) and asked to complete several questionnaires at the end of the first treatment appointment. We also explored differences at treatment presentation by considering alternative criteria to define groups, namely a composite of illness duration and clinical impairment (≥16 CIA total score). No differences were found when comparing participants based on illness duration. However, when participants were classified into a different classification scheme: "Non-severe and enduring Anorexia Nervosa" (illness duration <7 years and a CIA total score <16) vs. "severe and enduring Anorexia Nervosa" (illness duration ≥7 years and CIA total score ≥16), significant differences were found in terms of eating pathology, depressive symptomatology, psychological distress, and emotion dysregulation. Further research is needed to better understand the role of illness duration and clinical impairment in informing the course of AN.

Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action.

Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) and mutant MEK12 models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK1/2 and a panel of MEK1/2 mutant cell lines. Using a structure-based approach, the optimization addressed the liabilities by systematic analysis of molecular matched pairs (MMPs) and ligand conformation. Addition of only three heavy atoms to early tool compound 6 removed Cyp3A4 liabilities and increased the cellular potency by 100-fold, while reducing log P by 5 units. Profiling of MAP855, compound 30, in pharmacokinetic-pharmacodynamic and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK1/2 inhibitors. Compound 30 is a novel highly potent and selective MEK1/2 kinase inhibitor with equipotent inhibition of WT and mutant MEK1/2, whose drug-like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy.