An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery.

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a potential vector for human CNS gene therapy.

Dinuclear group IV metal complexes based on a bis(indenyl)-(E/Z)-stilbene platform: a potential prototype of "photoswitchable" catalysts for olefin polymerization.

The preparation of dizirconium complexes based on a novel bis(indenyl)-(E/Z)-stilbene platform was explored. Negishi coupling between the in situ-generated diorganozincates obtained from the respective o/m/p-(E/Z)-dibromostilbenes and the bromo-functionalized zirconocene (η5-Cp*)(η5-2-methyl-4-bromoindenyl)ZrCl2, or, alternatively, the preparation of bis(indene)stilbene pro-ligands {o/m/p-(E/Z)-BisIndSB}H2 through Negishi coupling of the corresponding dibromostilbenes with 4-bromoindene and subsequent metallation/transmetallation with Cp*ZrCl3 or Zr(NMe2)4, allowed the preparation of a series of dinuclear complexes. These were analyzed by NMR spectroscopy and some of them by iASAP-mass spectrometry and by X-ray diffraction studies. Experimental results were compared with DFT modelling of the targeted dinuclear complexes evidencing that the (E)-complexes are more stable by 7-11 kcal mol-1 than their (Z)-analogues. Thermal, uncontrolled isomerization of (Z)- to (E)-stilbene platform was observed experimentally for some systems, in the course of their synthesis, either from the (Z)-dibromostilbene reagent or on the dinuclear complexes resulting from the Negishi coupling. Photoisomerization of the (E)- and (Z)-{BisIndSB}H2 proligands and of complexes {o-(E)-BisIndSB}(Zr(NMe2)3)2 and {m-(E)-BisIndSB}(ZrCl2Cp*)2 was investigated under a variety of conditions. It proved effective for the proligands but induced decomposition of the dizirconium complexes. Time-dependent DFT (TD-DFT) computations were performed to identify unambiguously the nature of the observed absorption bands and account for decomposition of the complexes. Preliminary ethylene/1-hexene homo- and copolymerization investigations did not evidence putative cooperativity phenomena within these dinuclear systems nor significantly differentiated behavior between the (Z)- and (E)-isomers of a given type of complex under the reaction conditions investigated.

Associations between Fluid Intelligence and Physical Fitness in School Children.

Previous research has highlighted that active lifestyles that contribute to improved physical fitness are positively related to cognitive functioning in children and adolescents. Specifically, the increase in physical condition at school age is considered relevant because it is related to better cognitive ability and greater academic performance. Thus, the aim of this study was to analyze the relationships between explosive strength, speed-agility, and fluid reasoning in schoolchildren. To achieve this objective, an associative, comparative, and predictive design was used in this research. A total of 129 children participated in this study (age: M = 9.48; SD = 0.99). To assess fluid reasoning, the Raven test's Standard Progressive Matrices Subtest and the Wechsler Intelligence Scale for Children (WISC-V) were used. To assess physical fitness, the speed-agility test and the horizontal jump test (ALPHA-fitness battery tests), as well as the ball throw test (2 kg), were used. The results showed that the speed-agility test significantly predicted WISC-V Fluid Reasoning Index scores, and the medicine ball toss test significantly predicted Raven test scores. The results obtained highlight the associations between physical condition at these ages and fluid intelligence. This suggests that promoting active lifestyles that improve physical fitness could have a positive impact on children's cognitive health.

Effects of physical exercise on executive functions of individuals with schizophrenia spectrum disorders: Protocol for a systematic review and meta-analysis.

INTRODUCTION: Executive functions are commonly impaired in individuals with schizophrenia spectrum disorders. Physical exercise has the potential for improving executive functions and can be easily implemented as a therapeutic method. However, there are only few systematic reviews of exercise effects in schizophrenia including cognitive outcomes, and no meta-analytical syntheses of effects on "cool" and "hot" executive functions. The purpose of this systematic review and meta-analysis will be to determine the effects of physical exercise on "cool" and "hot" executive functions of adults with schizophrenia spectrum disorders. METHODS AND ANALYSIS: This protocol was guided by PRISMA-P guidelines. Studies will be searched using combinations of keywords and medical terms in the Web of Science, PubMed, Scopus, and EBSCO databases. Inclusion criteria will be determined as per PICOS approach. The risk of bias will be assessed using the Cochrane RoB2 tool. The certainty of evidence (per outcome) will be assessed using the GRADE method. The meta-analyses will be performed using the DerSimonian and Laird random effects model. Effect sizes (Hedges' g) with 95% confidence intervals will be calculated for each main outcome. CONCLUSIONS: The results of this review may be useful for mental health professionals to design treatment plans for adults with schizophrenia spectrum disorders, offering potential benefits related to the quality of life and cognitive abilities of this population. PROSPERO REGISTRATION NUMBER: CRD42023392295.

Associations between Social Support Dimensions and Resilience Factors and Pathways of Influence in Depression and Anxiety Rates in Young Adults.

Emerging adulthood is an important developmental period, associated to mental health risk. Resilience research points to both social and personal protective factors against development of psychopathology, but there is paucity with their comprehensive study in young adults. This study provides and initial integrative approach to model multiple dimensions of perceived social support (i.e., from family, friends, significant others) and personal factor of trait resilience (i.e., coping and persistence during stress, tolerance to negative affect, positive appraisals, trust) and their hypothesized contributions to reducing depression and anxiety rates. The study was conducted with a sample of 500 Spanish emerging adults (18 to 29 years old). Regression analyses and multiple mediation models were performed to test our hypotheses. Results showed that social support from family was the dimension with the highest strength relating individual differences in resilience. Furthermore, analyses supported a differential mediating role of specific resilience factors (coping and persistence during stress, tolerance to negative affect, positive appraisals, trust) in partially accounting for the association between higher social support from family and lower depression and anxiety levels in young adults. These results may inform new programs of mental health during emerging adulthood via the promotion of different sources of social support and their related resilience pathways contributing to low emotional symptomatology at this stage of development.

Negative interpretation bias as a clinical marker and a scar of depression: New insights from a large-scale study of the scrambled sentence task in formerly, subclinically and clinically depressed individuals.

Negative interpretation biases are thought to be clinical markers of depression and risk factors for its recurrence that would remain active after remission. Evidence on the conditions under which negative interpretation biases are active after remission is still unclear, and further studies are required to clarify whether negative interpretation biases are equivalent in magnitude at different depression conditions. A large-scale study of the Scrambled Sentence Task (SST) was conducted (639 participants), where different depression and never-depressed samples were compared in their performance in the SST through three experiments (i.e., formerly - Studies 1 and 2 -, subclinically - Study 2 - and clinically depressed individuals - Study 3 -). Cognitive load manipulations were used while completing the task. Formerly compared to never-depressed individuals showed higher negative interpretation biases at conditions of cognitive load only (Study 1). Formerly and subclinically depressed showed equivalent biases compared to never-depressed individuals (Study 2). Negative interpretation biases were further supported for clinically depressed (Study 3). Comparative analyses showed that both formerly and subclinically differed from clinically depressed individuals in their negative bias magnitude. These results prove the utility of the SST to detect negative interpretation biases in different depression conditions, including those recovered from depression. Results further show that negative bias magnitudes tend to decrease after remission but remain at subclinical levels, potentially conferring risk for depression recurrence.

An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery.

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, that binds human Transferrin Receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a promising vector for human CNS gene therapy.

Unravelling the Mechanistic Pathway of the Hydrogen Evolution Reaction Driven by a Cobalt Catalyst.

A cobalt complex bearing a κ-N3 P2 ligand is presented (1+ or CoI (L), where L is (1E,1'E)-1,1'-(pyridine-2,6-diyl)bis(N-(3-(diphenylphosphanyl)propyl)ethan-1-imine). Complex 1+ is stable under air at oxidation state CoI thanks to the π-acceptor character of the phosphine groups. Electrochemical behavior of 1+ reveals a two-electron CoI /CoIII oxidation process and an additional one-electron reduction, which leads to an enhancement in the current due to hydrogen evolution reaction (HER) at Eonset =-1.6 V vs Fc/Fc+ . In the presence of 1 equiv of bis(trifluoromethane)sulfonimide, 1+ forms the cobalt hydride derivative CoIII (L)-H (22+ ), which has been fully characterized. Further addition of 1 equiv of CoCp*2 (Cp* is pentamethylcyclopentadienyl) affords the reduced CoII (L)-H (2+ ) species, which rapidly forms hydrogen and regenerates the initial CoI (L) (1+ ). The spectroscopic characterization of catalytic intermediates together with DFT calculations support an unusual bimolecular homolytic mechanism in the catalytic HER with 1+ .

Repetitive Negative Thinking Processes Account for Gender Differences in Depression and Anxiety During Adolescence.

Rumination and worry are vulnerability factors involved in the early development of depression and anxiety during adolescence, particularly in girls. Current views conceptualize rumination and worry as transdiagnostic forms of repetitive negative thinking (RNT). However, most of research has analyzed them separately, without considering gender differences. We analyzed common and specific roles of rumination and worry in accounting for depressive and anxiety symptom levels overall and as a function of gender in adolescents (N = 159). Rumination and worry items were loaded into separate RNT factors. Girls showed a higher use of rumination and worry and higher levels of depression and anxiety than boys. Structural equation modeling supported that both RNT factors accounted for gender differences in symptom levels: rumination was the strongest mediator for depression and worry the strongest mediator for anxiety. Our findings support both general and specific contributions of RNT to account for affective symptomatology during adolescence, particularly in girls. Supplementary Information: The online version contains supplementary material available at 10.1007/s41811-022-00133-1.

Task and Ego Orientation in Sport Questionnaire (TEOSQ): Psychometric Properties in Its Digital Version.

The Task and Ego Orientation in Sport Questionnaire's (TEOSQ's) psychometric properties have been explored in previous studies but never in its digital version, which facilitates data collection. The objective of this study was to analyze the psychometric properties of the online TEOSQ by MenPas 1.0. The sample was composed of 2320 users (58.4% women; 41.6% men), between 18 and 65 years old (M = 25.27, SD = 7.39). The methods used were Confirmatory Factor Analysis (CFA) and invariance analysis from the original 13-item model. The CFA was corrected for all samples (CFI = 0.92-0.94, TLI = 0.93-0.95, RMSEA = 0.07, SRMR = 0.06; df = 64; Bollen-Stine Bootstrap p = 0.02-0.07): general sample (χ2 = 720.72, χ2/df = 11.26), women (χ2 = 496.85, χ2/df = 7.76), men (χ2 = 321.67, χ2/df = 5.03), individual sports (χ2 = 525.26, χ2/df = 8.21), and team sports (χ2 = 306.01, χ2/df = 4.78). The results also indicate optimal adjustments for invariance: convergent, discriminant and composite reliability validity. The study evidence demonstrates the adequate psychometric properties of the digital version. To conclude, considering the results obtained, the model shows a good psychometric fit for the sample in its online format. The principal limitations were computer failures, as well as that the large part of the sample were users between 20 and 25 years old, so the heterogeneity should be improved. The practical implications of this study could improve the efficacy of data collection in sports motivation using the online TEOSQ.

Insights into the light-driven hydrogen evolution reaction of mesoporous graphitic carbon nitride decorated with Pt or Ru nanoparticles.

Ru or Pt nanoparticles have been prepared following the organometallic approach and deposited onto the surface of mesoporous graphitic carbon nitride (mpg-CN). Three different Ru-based samples have also been compared to investigate the effect of 4-phenylpyridine as a stabilizing agent. The photocatalytic performance towards the hydrogen evolution reaction (HER) has been tested showing that all hybrid systems clearly outperform the photocatalytic activity of bare mpg-CN. In particular, Pt-decorated mpg-CN yields the largest H2 production upon visible-light irradiation (870 µmol h-1 g-1, TOF = 14.1 h-1, TON = 339 after 24 h) when compared with the Ru-based samples (137-155 µmol h-1 g-1, TOFs between 2.3-2.7 h-1, TONs between 54-57 after 24 h). Long-term photochemical tests (up to 65 h irradiation) show also an improved stability of the Pt-based samples over the Ru counterpart. Photophysical experiments aimed at rationalizing the photocatalytic performance of the different hybrid systems elucidate that the enhanced activity of the Pt-decorated mpg-CN over the Ru-based analogues arises from improved electron transfer kinetics from mpg-CN to the metal nanoparticles.

Clinical Outcomes of Severe COVID-19 Patients Admitted to an Intermediate Respiratory Care Unit.

Introduction: Many severe COVID-19 patients require respiratory support and monitoring. An intermediate respiratory care unit (IMCU) may be a valuable element for optimizing patient care and limited health-care resources management. We aim to assess the clinical outcomes of severe COVID-19 patients admitted to an IMCU. Methods: Observational, retrospective study including patients admitted to the IMCU due to COVID-19 pneumonia during the months of March and April 2020. Patients were stratified based on their requirement of transfer to the intensive care unit (ICU) and on survival status at the end of follow-up. A multivariable Cox proportional hazards method was used to assess risk factors associated with mortality. Results: A total of 253 patients were included. Of them, 68% were male and median age was 65 years (IQR 18 years). Ninety-two patients (36.4%) required ICU transfer. Patients transferred to the ICU had a higher mortality rate (44.6 vs. 24.2%; p < 0.001). Multivariable proportional hazards model showed that age ≥65 years (HR 4.14; 95%CI 2.31-7.42; p < 0.001); chronic respiratory conditions (HR 2.34; 95%CI 1.38-3.99; p = 0.002) and chronic kidney disease (HR 2.96; 95%CI 1.61-5.43; p < 0.001) were independently associated with mortality. High-dose systemic corticosteroids followed by progressive dose tapering showed a lower risk of death (HR 0.15; 95%CI 0.06-0.40; p < 0.001). Conclusions: IMCU may be a useful tool for the multidisciplinary management of severe COVID-19 patients requiring respiratory support and non-invasive monitoring, therefore reducing ICU burden. Older age and chronic respiratory or renal conditions are associated with worse clinical outcomes, while treatment with systemic corticosteroids may have a protective effect on mortality.

School Satisfaction and Happiness in 10-Year-Old Children from Seven European Countries.

School satisfaction is conceptualized as a crucial factor influencing children´s happiness and consequent healthy functioning in multiple developmental areas. Research to date has mainly evaluated how contextual factors related to the interactions between the student, teachers and classmates influence children's happiness, not considering other important factors more related to their own student experiences. The aim of the present study was to examine the effect of school satisfaction on happiness in 10-year-old children from Europe. Children's global school satisfaction levels, as well as different separate indicators of school satisfaction (i.e., satisfaction with other children in class; school marks; school life experience as a student; things they have learned; and relationships with teachers) were considered. The study comprised a sample of 7.445 10-year-old children from seven European countries. First, correlation analysis showed that the overall school satisfaction measure, as well as its different indicators, had positive associations with happiness levels. Second, regression analyses confirmed the effect by indicators of global school satisfaction on happiness. The indicators with the strongest effects were the satisfaction with their life as a student and the satisfaction with other children in the class, while the smallest effects were found regarding the satisfaction with the relationships with teachers and the things learned. These results point out the need to consider personal and contextual indicators of school satisfaction in a program design to foster happiness in 10-year-old children.

The immunophilin Zonda controls regulated exocytosis in endocrine and exocrine tissues.

Exocytosis is a fundamental process in physiology, that ensures communication between cells, organs and even organisms. Hormones, neuropeptides and antibodies, among other cargoes are packed in exocytic vesicles that need to reach and fuse with the plasma membrane to release their content to the extracellular milieu. Hundreds of proteins participate in this process and several others in its regulation. We report here a novel component of the exocytic machinery, the Drosophila transmembrane immunophilin Zonda (Zda), previously found to participate in autophagy. Zda is highly expressed in secretory tissues, and regulates exocytosis in at least three of them: the ring gland, insulin-producing cells and the salivary gland. Using the salivary gland as a model system, we found that Zda is required at final steps of the exocytic process for fusion of secretory granules to the plasma membrane. In a genetic screen we identified the small GTPase RalA as a crucial regulator of secretory granule exocytosis that is required, similarly to Zda, for fusion between the secretory granule and the plasma membrane.

Translation and Validation of the Facial Clinimetric Evaluation Scale to Spanish.

OBJECTIVE: Peripheral facial palsy is a disabling condition; thus, assessing its impact on quality of life is one of the greatest challenges within this discipline. The Facial Clinimetric Evaluation (FaCE) Scale has been validated for this purpose. The aim of this study is to translate and validate the Spanish version of the FaCE Scale. STUDY DESIGN: We performed a forward-backward translation of the original English FaCE Scale. A pilot test and a posterior prospective validation study were performed. SETTING: A pilot test and a posterior prospective validation study were conducted in a specialized facial palsy unit in a tertiary hospital. METHODS: A validation study was carried out in 85 patients to calculate the scale's internal consistency and validity and to compare outcomes with the Sunnybrook Facial Grading System and the Facial Disability Index (FDI). RESULTS: Internal consistency was evaluated by Cronbach's α coefficient, which showed a value of 0.841 (95% CI, 0.786-0.886). The total FaCE Scale score correlates well with the Sunnybrook, FDI physical function, and FDI social/well-being function scores: r = 0.773, r = 0.883, and r = 0.523, respectively. The FDI social/well-being function has the highest correlation with the FaCE Scale social function domain (r = 0.595). CONCLUSION: The Spanish version of the FaCE Scale demonstrated a high psychometric property that allows it to be used for clinical practice to assess the quality of life of Spanish-speaking patients with peripheral facial palsy.

Effect of Ligand Chelation and Sacrificial Oxidant on the Integrity of Triazole-Based Carbene Iridium Water Oxidation Catalysts.

We report the effect of replacing the pyridine group in the chelating trz Ir-water oxidation catalysts by a benzoxazole and a thiazole moiety. We have also evaluated if the presence of bidentate ligands is crucial for high activities and to avoid the decomposition into undesired heterogeneous layers. The catalytic performance of these benzoxazole/thiazole-triazolidene Ir-complexes in water oxidation was studied at variable pH using either CAN (pH = 1) or NaIO4 (pH = 5.6 and 7). Electrocatalytic experiments indicated that while CAN-mediated water oxidation led to catalyst heterogeneization irrespective of the triazolylidene substituent, periodate as sacrificial oxidant preserved a homogeneously active species. Repetitive additions of sacrificial oxidant indicates higher integrity of the Ir-complex with a thiazole-substituted triazolylidene compared to ligands featuring a benzoxazole as chelating donor or no chelating group at all. Rigid chelation of the thiazole group was also established from stability measurements under highly acidic, oxidizing, and high ionic strength conditions.

Organocatalytic vs. Ru-based electrochemical hydrogenation of nitrobenzene in competition with the hydrogen evolution reaction.

The electrochemical reduction of organic contaminants allows their removal from water. In this contribution, the electrocatalytic hydrogenation of nitrobenzene is studied using both oxidized carbon fibres and ruthenium nanoparticles supported on unmodified carbon fibres as catalysts. The two systems produce azoxynitrobenzene as the main product, while aniline is only observed in minor quantities. Although PhNO2 hydrogenation is the favoured reaction, the hydrogen evolution reaction (HER) competes in both systems under catalytic conditions. H2 formation occurs in larger amounts when using the Ru nanoparticle based catalyst. While similar reaction outputs were observed for both catalytic systems, DFT calculations revealed some significant differences related to distinct interactions between the catalytic material and the organic substrates or products, which could pave the way for the design of new catalytic materials.

Growth and Maturation in Development: A Fly's Perspective.

In mammals like humans, adult fitness is improved due to resource allocation, investing energy in the developmental growth process during the juvenile period, and in reproduction at the adult stage. Therefore, the attainment of their target body height/size co-occurs with the acquisition of maturation, implying a need for coordination between mechanisms that regulate organismal growth and maturation timing. Insects like Drosophila melanogaster also define their adult body size by the end of the juvenile larval period. Recent studies in the fly have shown evolutionary conservation of the regulatory pathways controlling growth and maturation, suggesting the existence of common coordinator mechanisms between them. In this review, we will present an overview of the significant advancements in the coordination mechanisms ensuring developmental robustness in Drosophila. We will include (i) the characterization of feedback mechanisms between maturation and growth hormones, (ii) the recognition of a relaxin-like peptide Dilp8 as a central processor coordinating juvenile regeneration and time of maturation, and (iii) the identification of a novel coordinator mechanism involving the AstA/KISS system.

Timing the Juvenile-Adult Neurohormonal Transition: Functions and Evolution.

Puberty and metamorphosis are two major developmental transitions linked to the reproductive maturation. In mammals and vertebrates, the central brain acts as a gatekeeper, timing the developmental transition through the activation of a neuroendocrine circuitry. In addition to reproduction, these neuroendocrine axes and the sustaining genetic network play additional roles in metabolism, sleep and behavior. Although neurohormonal axes regulating juvenile-adult transition have been classically considered the result of convergent evolution (i.e., analogous) between mammals and insects, recent findings challenge this idea, suggesting that at least some neuroendocrine circuits might be present in the common bilaterian ancestor Urbilateria. The initial signaling pathways that trigger the transition in different species appear to be of a single evolutionary origin and, consequently, many of the resulting functions are conserved with a few other molecular players being co-opted during evolution.

Ruthenium Nanoparticles for Catalytic Water Splitting.

Both global warming and limited fossil resources make the transition from fossil to solar fuels an urgent matter. In this regard, the splitting of water activated by sunlight is a sustainable and carbon-free new energy conversion scheme able to produce efficient technological devices. The availability of appropriate catalysts is essential for the proper kinetics of the two key processes involved, namely, the oxygen evolution reaction (OER) and the hydrogen evolution reaction (HER). During the last decade, ruthenium nanoparticle derivatives have emerged as true potential substitutes for the state-of-the-art platinum and iridium oxide species for the HER and OER, respectively. Thus, after a summary of the most common methods for catalyst benchmarking, this review covers the most significant developments of ruthenium-based nanoparticles used as catalysts for the water-splitting process. Furthermore, the key factors that govern the catalytic performance of these nanocatalysts are discussed in view of future research directions.