Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-ß signaling.

TGF-ß receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-ß signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulation of differentiation genes in mouse mesendoderm precursors. FOXH1 is prebound to target sites in these loci and recruits SMAD3 independently of TGF-ß signals, whereas SMAD2 remains predominantly cytoplasmic in the basal state and set to bind SMAD4 and join SMAD3:FOXH1 at target promoters in response to Nodal TGF-ß signals. The results support a model in which signal-independent binding of SMAD3 and FOXH1 prime mesendoderm differentiation gene promoters for activation, and signal-driven SMAD2:SMAD4 binds to promoters that are preloaded with SMAD3:FOXH1 to activate transcription.

The Ighmbp2D564N mouse model is the first SMARD1 model to demonstrate respiratory defects.

Spinal muscular atrophy with respiratory distress type I (SMARD1) is a neurodegenerative disease defined by respiratory distress, muscle atrophy and sensory and autonomic nervous system defects. SMARD1 is a result of mutations within the IGHMBP2 gene. We have generated six Ighmbp2 mouse models based on patient-derived mutations that result in SMARD1 and/or Charcot-Marie Tooth Type 2 (CMT2S). Here we describe the characterization of one of these models, Ighmbp2D564N (human D565N). The Ighmbp2D564N/D564N mouse model mimics important aspects of the SMARD1 disease phenotype, including motor neuron degeneration and muscle atrophy. Ighmbp2D564N/D564N is the first SMARD1 mouse model to demonstrate respiratory defects based on quantified plethysmography analyses. SMARD1 disease phenotypes, including the respiratory defects, are significantly diminished by intracerebroventricular (ICV) injection of ssAAV9-IGHMBP2 and the extent of phenotypic restoration is dose-dependent. Collectively, this model provides important biological insight into SMARD1 disease development.

Variation in global network properties across risk factors for adolescent internalizing symptoms: evidence of cumulative effects on structure and connectivity.

BACKGROUND: Identifying adolescents at risk of internalizing problems is a key priority. However, studies have tended to consider such problems in simple ways using diagnoses, or item summaries. Network theory and methods instead allow for more complex interaction between symptoms. Two key hypotheses predict differences in global network properties for those at risk: altered structure and increased connectivity. METHODS: The current study evaluated these hypotheses for nine risk factors (e.g. income deprivation and low parent/carer support) individually and cumulatively in a large sample of 12-15 year-olds (N = 34 564). Recursive partitioning and bootstrapped networks were used to evaluate structural and connectivity differences. RESULTS: The pattern of network interactions was shown to be significantly different via recursive partitioning for all comparisons across risk-present/absent groups and levels of cumulative risk, except for income deprivation. However, the magnitude of differences appeared small. Most individual risk factors also showed relatively small effects for connectivity. Exceptions were noted for gender and sexual minority risk groups, as well as low parent/carer support, where larger effects were evident. A strong linear trend was observed between increasing cumulative risk exposure and connectivity. CONCLUSIONS: A robust approach to considering the effect of risk exposure on global network properties was demonstrated. Results are consistent with the ideas that pathological states are associated with higher connectivity, and that the number of risks, regardless of their nature, is important. Gender/sexual minority status and low parent/carer support had the biggest individual impacts on connectivity, suggesting these are particularly important for identification and prevention.

Do Patterns of Adolescent Participation in Arts, Culture and Entertainment Activities Predict Later Wellbeing? A Latent Class Analysis.

Participation in arts, culture, and entertainment (PACE) activities may promote adolescent wellbeing. However, little is known about how such activities cluster together, and previous research has used small samples, cross-sectional designs, focused on single activities, and/or has not considered the influence of socio-demographic factors on participation. Using latent class analysis, the aims of this study were to establish: (i) classes of adolescent PACE activities; (ii) associations between socio-demographic characteristics and PACE classification; and, (iii) whether PACE classification predicts later wellbeing. Longitudinal data from the #BeeWell study (N = 18,224 adolescents; mean age at T1 = 12 years 7 months (±3.56 months); 50.54% female) were analyzed. Four latent classes were established: the 'Dynamic Doers' (high, wide-ranging participation; 11.87%); the 'Mind and Body Crew' (reading, arts, videogames, sports/exercise; 39.81%); the 'Game and Gain Squad' (videogames and sports/exercise; 29.05%); and the 'Activity Free Adolescents' (uniformly low participation; 19.27%). Associations between socio-demographic characteristics and PACE classification were observed (e.g., socio-economic disadvantage increased the likelihood of Activity Free Adolescents classification, compared to Game and Gain Squad classification). Finally, PACE classification predicted later wellbeing (e.g., Dynamic Doers reported significantly higher wellbeing than Activity Free Adolescents). These findings are discussed in relation to the need to improve accessibility and appeal of arts, culture, and entertainment provision for adolescents as a means to optimize their wellbeing. PRE-REGISTRATION: The analysis plan for this study was pre-registered on the Open Science Framework and can be found here: https://osf.io/2jtpd.

Efficacy and safety in patients with haemophilia A switching to octocog alfa (BAY 81-8973): Final results of the global real-world study, TAURUS.

OBJECTIVES: To report the final results of the 2-year TAURUS study, assessing weekly prophylaxis dosing regimens of octocog alfa (Kovaltry®/BAY 81-8973) used in standard clinical practice in patients with moderate-to-severe haemophilia A. METHODS: TAURUS (NCT02830477) is a phase 4, multinational, prospective, non-interventional, single-arm study in patients of any age with moderate or severe haemophilia A (≤5% factor [F]VIII activity). TAURUS was designed to primarily investigate weekly prophylaxis dosing regimens used in standard clinical practice. Annualised bleeding rates (ABRs), treatment satisfaction and adherence, and safety were also assessed. RESULTS: Of 302 patients included in the full analysis set, 84.4% (n = 255) maintained their octocog alfa prophylaxis baseline regimen throughout the study, with a majority of patients (76.5%, n = 231) on two times or three times weekly regimens at the end of the observation period (≥1-≤2 years). ABRs, treatment satisfaction, and adherence remained stable during the observation period. Octocog alfa was well tolerated and there were no new or unexpected adverse events. CONCLUSIONS: These data show that a smooth transition is observed when switching to octocog alfa from a previous FVIII treatment, with no safety issues and stable bleeding rates in a real-world setting of patients with moderate-to-severe haemophilia A.

Neighbourhood effects on loneliness among adolescents.

BACKGROUND: Loneliness is a growing public health concern, but little is known about how place affects loneliness, especially during adolescence. This is the first study to examine the influence of neighbourhoods on loneliness in early-to-mid adolescence. METHODS: Baseline data from the #BeeWell cohort study in Greater Manchester (England), including 36 141 adolescents (aged 12-15 years) across 1590 neighbourhoods, were linked to neighbourhood characteristics using administrative data at the level of lower super output areas and analysed using multilevel regression. RESULTS: Neighbourhood differences explained 1.18% of the variation in loneliness. Ethnic, gender and sexual orientation inequalities in loneliness varied across neighbourhoods. Several neighbourhood characteristics predicted loneliness at the individual level, including skills deprivation among children and young people, lower population density and perceptions of the local area (feeling safe; trust in local people; feeling supported by local people; seeing neighbours as helpful; the availability of good places to spend free time). Finally, a longer distance from home to school was associated with significantly higher loneliness. CONCLUSIONS: Neighbourhoods account for a small but significant proportion of the variation in adolescent loneliness, with some neighbourhood characteristics predicting loneliness at the individual level, and loneliness disparities for some groups differing across neighbourhoods.

Effect of coccidioidomycosis prophylaxis in selecting non-Candida albicans species amongst solid organ transplant recipients in Arizona.

BACKGROUND: Invasive candidiasis carries an increased risk of morbidity and mortality. The rates of non-albicans Candida species (NAC) infections are on the rise secondary to frequent azole antifungal use. NAC incidence and risk amongst solid organ transplant (SOT) recipients in Arizona receiving prolonged azole course for coccidioidomycosis prophylaxis have not been well elucidated. METHODS: We retrospectively evaluated SOT recipients hospitalised between 2017 and 2021 with a positive Candida spp. culture. RESULTS: There were 66 SOT recipients with 74 hospitalisations and 79 Candida spp. isolates. The median age was 59 (IQR 45-66), 68% were male, 58% were non-Hispanic White, and the most common SOT 38/74 (51%) was a liver transplant. Median time from transplant to the identification of any NAC (infection or colonisation) was significantly shorter, 8 months (IQR 3-78) vs 128 months (IQR 10-282) for Candida albicans isolates, p = .03. Prior use of azoles was significantly higher in NAC-associated post-transplant colonisation and invasive disease hospitalisations (83%) than in those with C. albicans (17%), p < .001. There were 59 hospitalisations with invasive disease, with the majority having NAC isolates of 49 (83%). CONCLUSION: The universal azole prophylaxis has reduced the incidence of coccidioidomycosis complications amongst SOT recipients in Arizona; however, there is an increased risk of developing NAC colonisation and infections, which can complicate the care of the SOT recipients with invasive candidiasis. Future studies are needed to investigate methods of reducing the risk of NAC infections whilst preventing coccidioidomycosis amongst SOT recipients.

Di-phosphorylated BAF shows altered structural dynamics and binding to DNA, but interacts with its nuclear envelope partners.

Barrier-to-autointegration factor (BAF), encoded by the BANF1 gene, is an abundant and ubiquitously expressed metazoan protein that has multiple functions during the cell cycle. Through its ability to cross-bridge two double-stranded DNA (dsDNA), it favours chromosome compaction, participates in post-mitotic nuclear envelope reassembly and is essential for the repair of large nuclear ruptures. BAF forms a ternary complex with the nuclear envelope proteins lamin A/C and emerin, and its interaction with lamin A/C is defective in patients with recessive accelerated aging syndromes. Phosphorylation of BAF by the vaccinia-related kinase 1 (VRK1) is a key regulator of BAF localization and function. Here, we demonstrate that VRK1 successively phosphorylates BAF on Ser4 and Thr3. The crystal structures of BAF before and after phosphorylation are extremely similar. However, in solution, the extensive flexibility of the N-terminal helix α1 and loop α1α2 in BAF is strongly reduced in di-phosphorylated BAF, due to interactions between the phosphorylated residues and the positively charged C-terminal helix α6. These regions are involved in DNA and lamin A/C binding. Consistently, phosphorylation causes a 5000-fold loss of affinity for dsDNA. However, it does not impair binding to lamin A/C Igfold domain and emerin nucleoplasmic region, which leaves open the question of the regulation of these interactions.

A ribonuclease III involved in virulence of Mucorales fungi has evolved to cut exclusively single-stranded RNA.

Members of the ribonuclease III (RNase III) family regulate gene expression by processing double-stranded RNA (dsRNA). This family includes eukaryotic Dicer and Drosha enzymes that generate small dsRNAs in the RNA interference (RNAi) pathway. The fungus Mucor lusitanicus, which causes the deadly infection mucormycosis, has a complex RNAi system encompassing a non-canonical RNAi pathway (NCRIP) that regulates virulence by degrading specific mRNAs. In this pathway, Dicer function is replaced by R3B2, an atypical class I RNase III, and small single-stranded RNAs (ssRNAs) are produced instead of small dsRNA as Dicer-dependent RNAi pathways. Here, we show that R3B2 forms a homodimer that binds to ssRNA and dsRNA molecules, but exclusively cuts ssRNA, in contrast to all known RNase III. The dsRNA cleavage inability stems from its unusual RNase III domain (RIIID) because its replacement by a canonical RIIID allows dsRNA processing. A crystal structure of R3B2 RIIID resembles canonical RIIIDs, despite the low sequence conservation. However, the groove that accommodates dsRNA in canonical RNases III is narrower in the R3B2 homodimer, suggesting that this feature could be responsible for the cleavage specificity for ssRNA. Conservation of this activity in R3B2 proteins from other mucormycosis-causing Mucorales fungi indicates an early evolutionary acquisition.

Gender and sexual identity-based inequalities in adolescent wellbeing: findings from the #BeeWell Study.

BACKGROUND: Gender and sexual minority adolescents experience greater symptoms of psychological distress than their peers, but little is known about broader aspects of their wellbeing. This study examines wellbeing inequalities relating to gender and sexual identity among adolescents from Greater Manchester in the United Kingdom. METHOD: 37,978 adolescents (aged 12-15, attending 165 secondary schools) completed surveys of life satisfaction, positive and negative affect (hedonic framework); autonomy, self-esteem, optimism, and positive relationships (eudaimonic framework); and, symptoms of distress and mental wellbeing (complete state framework). Structural correlated factors models were used to assess gender and sexual identity wellbeing inequalities. RESULTS: The magnitude of wellbeing inequalities pertaining to gender and sexual identity were routinely substantially greater than those concerning other characteristics (e.g., socio-economic disadvantage). Gender identity wellbeing inequalities followed a consistent pattern, with the largest disparities evident between gender diverse adolescents and boys. Sexual identity wellbeing inequalities also followed a consistent pattern, with the largest disparities evident between sexual minority youth (both gay/lesbian and bi/pansexual) and their heterosexual peers. Finally, variation was evident across wellbeing domains. For example, observed gender identity (boys vs. girls) and sexual identity (heterosexual vs. sexual minority) disparities were substantially greater for symptoms of distress than for mental wellbeing in the complete state model. CONCLUSIONS: LGBTQ + adolescents experience lower wellbeing than their peers, and this is evident across a range of wellbeing domains. Accordingly, there is an urgent need for the prioritisation of improved prevention and intervention efforts that can better meet the needs of gender diverse and sexual minority youth, and future research should be conducted to improve understanding of the mechanisms underpinning the wellbeing inequalities observed.

This is the place: a multi-level analysis of neighbourhood correlates of adolescent wellbeing.

OBJECTIVE: Adolescent wellbeing is a key research and policy priority, but little is known about neighbourhood-level influences. This study examined the extent to which adolescents' life satisfaction and internalising symptoms vary between neighbourhoods, and which neighbourhood characteristics are associated with individual outcomes. METHOD: Baseline data from the #BeeWell cohort study in Greater Manchester (England) including 35,902 adolescents (aged 12-15) across 243 neighbourhoods were linked to neighbourhood characteristics (e.g. access to education and health services, leisure facilities) from the Co-op's Community Wellbeing Index and analysed using multi-level regression. RESULTS: Neighbourhoods explained 0.61% and 1.17% of the variation in life satisfaction and internalising symptoms, respectively. Socio-demographic inequalities in these outcomes varied across neighbourhoods. Several neighbourhood characteristics were associated with wellbeing, but differences across model specifications were observed (e.g. adjusted vs unadjusted; unique associations vs grouped domains). However, higher levels of perceived wellbeing support from local people were associated with lower internalising symptoms in all models. Other characteristics associated with better wellbeing outcomes in various models included lower GP antidepressant prescription rates, and better access to health services, areas for leisure, and good places to spend free time. CONCLUSION: Neighbourhoods account for a small but significant proportion of the variance in adolescent life satisfaction and internalising symptoms. Some neighbourhood characteristics (notably neighbourhood social capital) are associated with these outcomes at the individual level, and disparities in these outcomes for some groups vary across neighbourhoods. Our findings speak to the role of place as a determinant of adolescent wellbeing, with consequent implications for intervention.

Vitamin D and adolescent idiopathic scoliosis, should we stop the hype? A cross-sectional observational prospective study based on a geometric morphometrics approach.

PURPOSE: There is strong evidence supporting the presence of fluctuating asymmetry (FA) in Adolescents with Idiopathic Scoliosis (AIS). Additionally, recent research investigating the relationship between vitamin D and AIS found a relation between them. We hypothesize a negative correlation between FA and vitamin D. METHODS: We performed a surface scan of the torso of 53 AIS patients, a blood test to measure vitamin D and the radiographic Cobb angle. A correlation analysis between vitamin D and FA was carried out to test our hypothesis, and a regression of vitamin D on 3D shape was performed to observe shape differences between the vitamin D deficiency and insufficiency groups. RESULTS: There was no correlation between vitamin D and FA. We found a strong negative correlation between vitamin D and the Cobb angle only in the premenarche group (n = 7; r = - 0.92). Differences in shape were observed between the deficiency and insufficiency groups, and that differences were related to the width of the torso, but not the rotation or lateral flexion. CONCLUSIONS: Our results do not support the massive screening of vitamin D in AIS. Shape analysis revealed differences between the shape of the deficiency and insufficiency groups related to robustness. However, this finding had no relation with the scoliosis characteristics, it just reflected different body composition, and its importance should be explored in future.

Does the use of postoperative brace help preventing mechanical complications following adult deformity surgery?

PURPOSE: There is scarce information regarding the effectiveness of postoperative braces in decreasing mechanical complications and reinterventions following adult deformity surgery. METHODS: Retrospective matched cohort study from a prospective adult deformity multicenter database. We selected operated patients, fused to the pelvis, > 6 instrumented levels, and minimum 2 year follow-up. Three hundred and eighty patients were separated into two groups (Brace-3 months TLSO-vs No Brace) and then matched controlling for age, gender and frailty. We studied demographic, intraoperative, and postoperative spinopelvic parameters. Both groups were compared regarding complications and reinterventions in the first 2 postoperative years, using univariate and multivariate logistic regression analysis. RESULTS: We finally analyzed 359 matched patients, mean age of 65.3 ± 8.9 years, frailty-index (0.43 ± 0.15), and mostly females (84%). 224 patients wore a postoperative brace (B) and 135 didn't (NoB). They showed no difference in intraoperative variables and postoperative spinopelvic alignment. They differed (P < 0.05) in: Pelvic incidence (B:58° ± 13 vs NoB:54.5° ± 13); BMI (B:25.8 ± 4 vs NoB:27.4 ± 5); upper instrumented vertebra (B:81.7% T8-L1 vs NoB:72.6% T8-L1), and the use of multiple rods (B:47.3% vs NoB:18.5%). Univariate analysis showed a higher rate of mechanical complications and reinterventions when not using a brace. As well as higher NRS-back and leg pain at 6 weeks. However, multivariate analysis selected the use of multiple rods as the only independent factor protecting against mechanical complications (OR: 0.38; CI 95% 0.22-0.64) and reinterventions (OR: 0.41; CI 95% 0.216-0.783). CONCLUSION: After controlling for potential confounders, our study could not identify the protective effect of postoperative braces preventing mechanical complications and reinterventions in the first two postoperative years.

Sagittal realignment: surgical restoration of the global alignment and proportion score parameters: a subgroup analysis. What are the consequences of failing to realign?

INTRODUCTION: The Global Alignment and Proportion (GAP) score incorporates three domains directly modified with surgery (relative pelvic version-RPV, relative lumbar lordosis-RLL, lumbar distribution index-LDI) and one indirectly restored (relative spinopelvic alignment-RSA). We analyzed our surgical realignment performance and the consequences of domain-specific realignment failure on mechanical complications and PROMs. MATERIALS AND METHODS: From an adult spinal deformity prospective multicenter database, we selected patients: fused to pelvis, upper instrumented vertebra at or above L1, and 2 years of follow-up. Descriptive, univariate and multivariate analyses were employed. RESULTS: The sample included 333 patients. RLL-6w showed the highest success rate (58.3% aligned), but 16.5% of patients were classified in the "Severe hypolordosis" and "Hyperlordosis" subgroups. RPV-6w was the most challenging to realign, with 51.6% moderate or severe retroversion. Regarding RSA-6w, 21.9% had severe positive malalignment. Correct alignment of RPV-6w (p = 0.025) and RSA-6w (p = 0.002) proved to be protective factors against the development of mechanical complications. Severe pelvic retroversion (p = 0.026) and severe positive malalignment (p = 0.007) were risk factors for mechanical complications. RSA-6w "Severe positive malalignment" was associated with less improvement in PROMs: ∆ODI (8.83 vs 17.2; p = 0.011), ∆SRS-22 total (0.54 vs 0.87; p = 0.007), and ∆SF-36PCS (3.47 vs 7.76; p = 0.04); MCID for ODI (37.0 vs 55.5%; p = 0.023), and SRS-22 (40.8 vs 60.1%; p = 0.015); and PASS for ODI (17.6 vs 31.7%; p = 0.047). CONCLUSIONS: RPV was the most underperformed modifiable parameter. Severe pelvic retroversion and severe positive malalignment influenced the occurrence of mechanical complications. Severe positive malalignment affected PROMs improvement.

Training of Classification Models via Federated Learning and Homomorphic Encryption.

With the rise of social networks and the introduction of data protection laws, companies are training machine learning models using data generated locally by their users or customers in various types of devices. The data may include sensitive information such as family information, medical records, personal habits, or financial records that, if leaked, can generate problems. For this reason, this paper aims to introduce a protocol for training Multi-Layer Perceptron (MLP) neural networks via combining federated learning and homomorphic encryption, where the data are distributed in multiple clients, and the data privacy is preserved. This proposal was validated by running several simulations using a dataset for a multi-class classification problem, different MLP neural network architectures, and different numbers of participating clients. The results are shown for several metrics in the local and federated settings, and a comparative analysis is carried out. Additionally, the privacy guarantees of the proposal are formally analyzed under a set of defined assumptions, and the added value of the proposed protocol is identified compared with previous works in the same area of knowledge.

Molecular Mechanisms of the Protective Effects of Olive Leaf Polyphenols against Alzheimer's Disease.

Alzheimer's Disease (AD) is the cause of around 60-70% of global cases of dementia and approximately 50 million people have been reported to suffer this disease worldwide. The leaves of olive trees (Olea europaea) are the most abundant by-products of the olive grove industry. These by-products have been highlighted due to the wide variety of bioactive compounds such as oleuropein (OLE) and hydroxytyrosol (HT) with demonstrated medicinal properties to fight AD. In particular, the olive leaf (OL), OLE, and HT reduced not only amyloid-ß formation but also neurofibrillary tangles formation through amyloid protein precursor processing modulation. Although the isolated olive phytochemicals exerted lower cholinesterase inhibitory activity, OL demonstrated high inhibitory activity in the cholinergic tests evaluated. The mechanisms underlying these protective effects may be associated with decreased neuroinflammation and oxidative stress via NF-κB and Nrf2 modulation, respectively. Despite the limited research, evidence indicates that OL consumption promotes autophagy and restores loss of proteostasis, which was reflected in lower toxic protein aggregation in AD models. Therefore, olive phytochemicals may be a promising tool as an adjuvant in the treatment of AD.

Bioactive Properties of Tagetes erecta Edible Flowers: Polyphenol and Antioxidant Characterization and Therapeutic Activity against Ovarian Tumoral Cells and Caenorhabditis elegans Tauopathy.

Tagetes erecta is an edible flower deeply rooted in traditional Mexican culture. It holds a central role in the most popular and iconic Mexican celebration, "the Day of the Dead". Furthermore, it is currently receiving interest as a potential therapeutic agent, motivated mainly by its polyphenol content. The present study aims to evaluate the biological activity of an extract synthesized from the petals of the edible flower T. erecta. This extract showed significant antioxidant scores measured by the most common in vitro methodologies (FRAP, ABTS, and DPPH), with values of 1475.3 µM trolox/g extr, 1950.3 µM trolox/g extr, and 977.7 µM trolox/g extr, respectively. In addition, up to 36 individual polyphenols were identified by chromatography. Regarding the biomedical aspects of the petal extract, it exhibited antitumoral activity against ovarian carcinoma cells evaluated by the MTS assay, revealing a lower value of IC50 compared to other flower extracts. For example, the extract from T. erecta reported an IC50 value half as low as an extract from Rosa × hybrida and six times lower than another extract from Tulbaghia violacea. This antitumoral effect of T. erecta arises from the induction of the apoptotic process; thus, incubating ovarian carcinoma cells with the petal extract increased the rate of apoptotic cells measured by flow cytometry. Moreover, the extract also demonstrated efficacy as a therapeutic agent against tauopathy, a feature of Alzheimer's disease (AD) in the Caenorhabditis elegans experimental model. Treating worms with the experimental extract prevented disfunction in several motility parameters such as wavelength and swimming speed. Furthermore, the T. erecta petal extract prevented the release of Reactive Oxygen Species (ROS), which are associated with the progression of AD. Thus, treatment with the extract resulted in an approximate 20% reduction in ROS production. These findings suggest that these petals could serve as a suitable source of polyphenols for biomedical applications.

Crystal structure of the phospholipase A and acyltransferase 4 (PLAAT4) catalytic domain.

Phospholipase A and Acyltransferase 4 (PLAAT4) is a class II tumor suppressor, that also plays a role as a restrictor of intracellular Toxoplasma gondii infection through restriction of parasitic vacuole size. The catalytic N-terminal domain (NTD) interacts with the C-terminal domain (CTD), which is important for sub-cellular targeting and enzymatic function. The dynamics of the NTD main (L1) loop and the L2(B6) loop adjacent to the active site, have been shown to be important regulators of enzymatic activity. Here, we present the crystal structure of PLAAT4 NTD, determined from severely intergrown crystals using automated, laser-based crystal harvesting and data reduction technologies. The structure showed the L1 loop in two distinct conformations, highlighting a complex network of interactions likely influencing its conformational flexibility. Ensemble refinement of the crystal structure recapitulates the major correlated motions observed in solution by NMR. Our analysis offers useful insights on millisecond dynamics based on the crystal structure, complementing NMR studies which preclude structural information at this time scale.

Molecular bases for the use of functional foods in the management of healthy aging: Berries, curcumin, virgin olive oil and honey; three realities and a promise.

As the number of older people has grown in recent decades, the search for new approaches to manage or delay aging is also growing. Among the modifiable factors, diet plays a crucial role in healthy aging and in the prevention of age-related diseases. Thus, the interest in the use of foods, which are rich in bioactive compounds such as functional foods with anti-aging effects is a growing market. This review summarizes the current knowledge about the molecular mechanisms of action of foods considered as functional foods in aging, namely berries, curcumin, and virgin olive oil. Moreover, honey is also analyzed as a food with well-known healthy benefits, but which has not been deeply evaluated from the point of view of aging. The effects of these foods on aging are analyzed from the point of view of molecular mechanisms including oxidative stress, mitochondrial dysfunction, inflammation, genomic stability, telomere attrition, cellular senescence, and deregulated nutrient-sensing. A comprehensive study of the scientific literature shows that the aforementioned foods have demonstrated positive effects on certain aspects of aging, which might justify their use as functional foods in elderly. However, more research is needed, especially in humans, designed to understand in depth the mechanisms of action through which they act.

Utility of the IMPACT score for predicting heart transplant mortality. Analysis on a contemporary cohort of the Spanish Heart Transplant Registry.

INTRODUCTION AND OBJECTIVES: The Index for Mortality Prediction After Cardiac Transplantation (IMPACT) score was derived and validated as a predictor of mortality after heart transplantation (HT). The primary objective of this work is to externally validate the IMPACT score in a contemporary Spanish cohort. METHODS: Spanish Heart Transplant Registry data were used to identify adult (>16 years) HT patients between January 2000 and December 2015. Retransplantation, multiorgan transplantation and patients in whom at least one of the variables required to calculate the IMPACT score was missing were excluded from the analysis (N = 2810). RESULTS: Median value of the IMPACT score was five points (IQR: 3, 8). Overall, 1-year survival rate was 79.1%. Kaplan-Meier 1-year survival rates by IMPACT score categories (0-2, 3-5, 6-9, 10-14, ≥15) were 84.4%, 81.5%, 79.3%, 77.3%, and 58.5%, respectively (Log-Rank test: p < .001). Performance analysis showed a good calibration (Hosmer-Lemeshow chi-square for 1 year was 7.56; p = .47) and poor discrimination ability (AUC-ROC .59) of the IMPACT score as a predictive model. CONCLUSIONS: In a contemporary Spanish cohort, the IMPACT score failed to accurately predict the risk of death after HT.