Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.

Orofaciodigital syndrome (OFD) is a genetically heterogeneous ciliopathy characterized by anomalies of the oral cavity, face, and digits. We describe individuals with OFD from three unrelated families having bi-allelic loss-of-function variants in SCNM1 as the cause of their condition. SCNM1 encodes a protein recently shown to be a component of the human minor spliceosome. However, so far the effect of loss of SCNM1 function on human cells had not been assessed. Using a comparative transcriptome analysis between fibroblasts derived from an OFD-affected individual harboring SCNM1 mutations and control fibroblasts, we identified a set of genes with defective minor intron (U12) processing in the fibroblasts of the affected subject. These results were reproduced in SCNM1 knockout hTERT RPE-1 (RPE-1) cells engineered by CRISPR-Cas9-mediated editing and in SCNM1 siRNA-treated RPE-1 cultures. Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were severely reduced in SCNM1-deficient cells. Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia. Conversely, cilia length and expression of SCNM1-regulated genes were restored in SCNM1-deficient fibroblasts following reintroduction of SCNM1 via retroviral delivery. Additionally, functional analysis in SCNM1-retrotransduced fibroblasts showed that SCNM1 is a positive mediator of Hedgehog (Hh) signaling. Our findings demonstrate that defective U12 intron splicing can lead to a typical ciliopathy such as OFD and reveal that primary cilia length and Hh signaling are regulated by the minor spliceosome through SCNM1 activity.

Processing speed mediates the relationship between DDR1 and psychosocial functioning in euthymic patients with bipolar disorder presenting psychotic symptoms.

The DDR1 locus is associated with the diagnosis of schizophrenia and with processing speed in patients with schizophrenia and first-episode psychosis. Here, we investigated whether DDR1 variants are associated with bipolar disorder (BD) features. First, we performed a case‒control association study comparing DDR1 variants between patients with BD and healthy controls. Second, we performed linear regression analyses to assess the associations of DDR1 variants with neurocognitive domains and psychosocial functioning. Third, we conducted a mediation analysis to explore whether neurocognitive impairment mediated the association between DDR1 variants and psychosocial functioning in patients with BD. Finally, we studied the association between DDR1 variants and white matter microstructure. We did not find any statistically significant associations in the case‒control association study; however, we found that the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse neurocognitive performance in patients with BD with psychotic symptoms. In addition, the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse psychosocial functioning through processing speed. We did not find correlations between white matter microstructure abnormalities and the neurocognitive domains associated with the combined genotypes rs1264323AA-rs2267641AC/CC. Overall, the results suggest that DDR1 may be a marker of worse neurocognitive performance and psychosocial functioning in patients with BD, specifically those with psychotic symptoms.

Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Ocular Mucous Membrane Pemphigoid: The Effect of Risk Factors at Presentation on Treatment Outcomes.

PURPOSE: Analyze the influence of risk factors at presentation in the long-term immunosuppressive therapy (IMT) outcomes of ocular mucous membrane pemphigoid (OMMP). DESIGN: Retrospective multicenter study. PARTICIPANTS: Patients with OMMP seen at the Duke Eye Center, Tecnologico de Monterrey, and Hospital Clinic of Barcelona from 1990 to 2022. METHODS: Data at presentation on demographics, direct immunofluorescence, ocular findings, sites of extraocular manifestations (EOMs), and previous treatments in patients with a clinical or laboratory diagnosis of OMMP, were analyzed with multivariable analysis and Kaplan-Meier plots to identify factors associated with adverse outcomes. MAIN OUTCOME MEASURES: (1) Inflammatory control (no conjunctival inflammation in both eyes at 3 months on IMT); (2) relapse (new-onset inflammation after absolute control in either eye); (3) progression (≥ 1 cicatrizing stage progression in either eye); and (4) vision loss (≥ 2 Snellen lines). RESULTS: A total of 117 patients (234 eyes), 61% (71/117) of whom were women, with a mean age of 66.6 (SD: 12.4) years (range: 37-97 years) and median follow-up of 34 months (interquartile range: 16-66 months; range: 3-265 months), were enrolled. Inflammatory control was achieved in 57% of patients (67/117), with high-risk EOM (HR-EOM), including esophageal, nasopharyngeal, and/or genital involvement (adjusted odds ratio [aOR]: 12.51; 95% confidence interval [CI]: 2.61-59.99; P = 0.002) and corneal scarring (aOR: 3.06; 95% CI, 1.15-8.14; P = 0.025), as significant risk factors for persistent inflammation. Disease relapse, progression, and vision loss occurred in 20% of patients (23/117), 12% of patients (14/117), and 27% of patients (32/117), respectively. Baseline corneal scarring was a risk factor for relapse (adjusted hazard ratio: 4.14; 95% CI: 1.61-10.62; P = 0.003), progression (aOR: 11.46; 95% CI: 1.78-73.75; P = 0.010), and vision loss (aOR: 3.51; 95% CI: 1.35-9.10; P = 0.010). HR-EOM was associated with stage progression (aOR, 34.57; 95% CI, 6.57-181.89; P<0.001) and vision loss (aOR, 8.42; 95% CI, 2.50-28.42; P = 0.001). No significant differences were found between IMT regimes and relapse (P = 0.169). CONCLUSIONS: Ocular mucous membrane pemphigoid presenting with HR-EOMs and corneal scarring has an increased risk of stage progression and vision loss. Corneal scarring and severe inflammation at baseline were associated with an increased risk of relapse. A disease progression staging system incorporating both the HR-EOMs and corneal involvement is required to predict the visual outcome of OMMP better. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Testing the modulation of self-related automatic and others-related controlled processing by chronotype and time-of-day.

We assessed whether self-related automatic and others-related controlled processes are modulated by chronotype and time-of-day. Here, a shape-label matching task composed of three geometrical shapes arbitrarily associated with you, friend, and stranger was used. Twenty Morning-types, and twenty Evening-types performed the task at the optimal and non-optimal times of day (i.e., 8 AM, or 8:30 PM). Morning-types did not exhibit noticeable synchrony effects, thus proving the better adaptation of these participants to non-optimal moments of the day as compared to Evening-types. Contrary to our predictions regarding the absence of automatic-processing modulation and the presence of controlled-processing influences by time-of-day, we found an influence on self-related but not others-related processing only in Evening-type participants. Although brain structures are not directly tackled, we argue that such modulation may be due to the dependence of the activation of the ventromedial prefrontal cortex (VMPFC), an essential component of the self-attention network on circadian rhythms.

Self-prioritization effect in the attentional blink paradigm: Attention-based or familiarity-based effect?

The self-prioritization effect (SPE) refers to the advantage in processing stimuli associated with oneself. Here, we addressed the SPE in an attentional blink (AB) task. In Experiment 1, shapes associated to you, friend, or stranger served as T1, and letter X as T2. The AB effect was larger for you than the other label conditions, and larger for friend condition than for stranger condition. We suggest that self-associated shape increased its perceptual salience, producing greater attentional capture. In Experiment 2 participants trained with a shape-label matching task to increase familiarity with the shape-label associations before performing the AB task. The difference between friend and stranger conditions disappeared, suggesting that the difference between the two conditions observed in Experiment 1 was mainly due to differences in familiarity or frequency of use. Importantly, the advantage of you over friend and stranger conditions remained, suggesting that the SPE is a genuine effect.

Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder.

BACKGROUND: MAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants in MAPKAPK5 were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called 'neurocardiofaciodigital' syndrome. OBJECTIVE AND METHODS: In order to improve characterisation of the clinical features associated with biallelic MAPKAPK5 variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals. RESULTS: In the present study, we identified biallelic loss-of-function and missense MAPKAPK5 variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease. CONCLUSION: In this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome.

Influence of a football match on landing biomechanics and jump performance in female football players.

This study aimed to assess the acute effect of a competitive football match on jump performance and kinematic parameters during jump landing in semiprofessional female football players. Twenty-two semiprofessional players (20 ± 3 years) underwent a drop jump task for a posterior video analysis of the landing phase. These measurements were obtained at (1) baseline, (2) after, and (3) 48 h after a competitive football match. A one-way ANOVA with repeated measures was employed to detect differences over the time. There was a main effect of time for maximal knee flexion angle during drop landing (p = 0.001). In comparison with baseline, maximal knee flexion angle was reduced immediately post-match and was still reduced 48 h after the match (63.4 ± 8.6 vs 57.0 ± 11.7 vs 48.9 ± 19.1, p ≤ 0.038). There was also a main effect of time for drop jump height (p < 0.001). Drop jump height was reduced immediately post-match and remained low 48 h after the match in comparison with baseline (27.3 ± 3.6 vs 24.5 ± 2.8 ~ 25.5 ± 3.0 cm, p ≤ 0.002). There was a main effect of time on hip flexion angle during landing (p = 0.001), but the pairwise comparison revealed that this variable was not affected immediately post-match but was lower 48 h after the match than at baseline (50.1 ± 10.1 ~ 50.8 ± 13.2 vs 38.1 ± 17.8 °, p ≤ 0.005). A competitive football match worsened jump performance and several landing biomechanical parameters in female football players, which were still decreased in comparison with baseline even 48 h after the match.

Comparison of male and female non-refugee immigrants with psychosis: clinical, sociodemographic, and migration-related differences and impact on stress.

PURPOSE: To compare social, clinical, and migration-related factors between male and female immigrants with psychotic disorders and to determine the association between these variables and stress in the last year. METHODS: We administered the Holmes and Rahe Social Readjustment Scale to evaluate psychological stress in 99 non-refugee immigrants (26 women, 73 men) who presented ≥ one psychotic episode (ICD-10 criteria). We compared the two groups in terms of sociodemographic, clinical, cultural, and migration-related variables. A multivariable analysis using a linear regression model (stepwise method) was performed to evaluate potential associations between these variables and stress. RESULTS: Women were more likely to be married and divorced, had less access to welfare payments, and lower unemployment and homeless rates than men. The most common psychiatric diagnosis was psychosis not otherwise specified with more women being affected (61.5% in women vs. 45.2% in men), but the diagnosis of schizophrenia was more common in men (38.4% vs 15.4%). Both groups exhibited very high levels of stress in the past year (mean total distress score > 300). In women, stress was significantly associated with age at first migration and be a racialized person. By contrast, among men stress was significantly associated with language barrier and comorbidity with a physical disorder. CONCLUSIONS: The results of this study reveal important differences between men and women immigrants. These findings underscore the importance of understanding how gender-specific roles and social expectations intersect with the timing and nature of migration to influence stress levels differently in immigrant women and men with psychotic disorders.

Misophonia matters: A case study of the role of brain imaging in debates over new diagnoses.

Misophonia has gained attention in scientific circles that utilise brain imaging to validate diagnoses. The condition is promoted as not merely a symptom of other psychiatric diagnoses but as a discrete clinical entity. We illustrate the social construction of the diagnostic category of misophonia through examining prominent claims in research studies that use brain imaging to substantiate the diagnosis. We show that brain images are insufficient to establish the 'brain basis for misophonia' due to both technical and logical limitations of imaging data. Often misunderstood as providing direct access to the matter of the body, brain images are mediated and manipulated numerical data (Joyce, 2005, Social Studies of Science 35(3), p. 437). Interpretations of brain scans are further shaped by social expectations and attributes considered salient to the data. Causal inferences drawn from these studies are problematic because 'misophonics' are clinically pre-diagnosed before participating. We argue that imaging cannot replace the social process of diagnosis in the case of misophonia, nor validate diagnostic measures or otherwise substantiate the condition. More broadly, we highlight both the cultural authority and inherent limitations of brain imaging in the social construction of contested diagnoses while also illustrating its role in the disaggregation of symptoms into new diagnoses.

Depressive-Like Effects of Foreclosing: A Cross-Sectional Study of Hair Cortisol Concentration.

INTRODUCTION: Foreclosing and home eviction have been associated with various negative health outcomes, probably due to exposure to such stressful circumstance, but there is no evidence about foreclosure and home eviction to elicit cortisol responses. METHODS: Participants who recently had received a court eviction notice were compared to subjects suffering a depressive disorder and to healthy controls in terms of hair cortisol concentrations. RESULTS: Subjects under the stressful circumstance of foreclosure and patients with depression showed comparable concentrations in most of the hair segments while healthy subjects displayed the lowest levels of cortisol. CONCLUSION: The findings show that foreclosure and home eviction are associated with increased cumulative hair cortisol and with depressive-like symptoms. Foreclosing procedures yielded to maintain high levels of cortisol which may increase the risk to develop major depression.

Lessons Learned From Ocular Graft versus Host Disease: An Ocular Surface Inflammatory Disease of Known Time of Onset.

ABSTRACT: The ocular surface inflammatory disorders (OSIDs) comprise a group of conditions characterized by persistent inflammation of the ocular surface and adnexal tissues. Systemic autoimmune diseases and hypersensitivity reactions cause them, and, if left untreated, can result in severe inflammatory dry eye, corneal damage, and vision loss. Ocular graft-versus-host disease (oGVHD) forms part of the ocular surface inflammatory disease umbrella. It is a condition occurring after allogeneic hematopoietic stem cell or bone marrow transplantation, usually in chronic graft-versus-host disease. oGVHD can virtually affect any ocular adnexal tissue, especially the meibomian glands, and cause persistent inflammation, tissue fibrosis, and subsequent chronic, severe dry eye disease. Among the OSIDs, oGVHD has the particularity that it has a "time zero," meaning we know when the disease started. As such, preclinical models have leveraged this to investigate the molecular mechanisms involved in the damage oGVHD causes to the ocular surface. In oGVHD, establishing a "time zero" allows for predicting the clinical course and establishing adequate treatment. This is also possible because the inflammatory infiltration occurs in ocular surface tissues, which are readily accessible. Using oGVHD, we might be able to understand the immune response mechanisms in other OSIDs better (i.e., Sjögren syndrome, Stevens-Johnson syndrome, among others). This review presents an up-to-date overview of the pathogenesis, clinical presentation, and treatment of oGVHD. In addition, we will discuss the value of the "time zero" concept in the study of oGVHD.

Evaluation of gender-affirming care experiences of transgender and gender diverse patients within a LGBTQ+ community pharmacy.

BACKGROUND: Transgender and gender diverse (TGD) populations require personalized care. Lived experiences and needs TGD populations express, compounded by limited care access, negatively shape health care involvement. Manifestations from these barriers may present as health care avoidance, identity concealment, or preventive care hinderance. Community pharmacies remain engagement points for TGD patients, but gender diverse services remain limited. What remains unknown is how TGD pharmacy perceptions and behaviors are influenced with gender-affirming care (GAC) accessibility. OBJECTIVES: The primary objective is to assess how TGD patient perceptions and behaviors toward community pharmacy experiences are affected through a lesbian, gay, bisexual, transgender, queer/questioning, and others (LGBTQ+) community-based health system. METHODS: A cross-sectional, multisite, reflective survey was conducted at 4 LGBTQ+ community pharmacies in central and southwest Ohio. Nine 5-point Likert-item questions and one ordinal question were used to analyze perception and behavior. Participants responded for LGBTQ+ and external pharmacy experiences respectively. Data were analyzed through descriptive methods, paired Student's t test, and Fisher's exact test or c2 test where appropriate. RESULTS: In total, 267 surveys were completed with 96 TGD submissions qualifying for analysis. Perceptions toward pharmacy experience saw statistically significant differences among all evaluations of perception. Behavioral assessment demonstrated statistically significant improvements in pharmacy outreach except for seeking medications from outside sources. Respondents indicated more involvement with the LGBTQ+ pharmacies versus external pharmacies in discussing medications (96.9% vs. 60.4%), care plans (64.6% vs. 41.6%), disclosure of pronouns or gender (97.9% vs. 43.8%), and feeling needs were understood (96.8% vs. 51%). CONCLUSION: Inclusive community pharmacies may positively affect pharmacy perceptions and behaviors of TGD patients. These findings call attention to barriers in the provision of care for TGD patients while highlighting the change community pharmacies can have when providing these services. Community pharmacies should be encouraged to incorporate inclusive environments to improve TGD patient care involvement and access.

Unveiling Novel Urease Inhibitors for Helicobacter pylori: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations.

Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.

Hamstring muscle injury is preceded by a short period of higher running demands in professional football players.

The aim of this study was to examine match running patterns before a hamstring muscle injury occurs during a match in male professional football players. A total of 281 male professional football players belonging to 7 teams from LaLiga were prospectively monitored over three seasons. Among these, 36 players suffered a non-contact hamstring muscle injury during an official match. The injuries were recorded by the medical staff, including the minute when the injury occurred. Running distances at different speed thresholds for 5 min and 15 min before the injury were compared to mean values of the previous 5 matches for the same time points. There were a total of 44 non-contact hamstring muscle injuries, which represents a hamstring muscle injury incidence of 3.34 injuries/1000 h of match exposure. The average time loss for these injuries was 33 ± 28 days (range 7 to 117 days). In the 15 min prior to the injury, players ran a similar distance as in control matches (p from 0.22 to 0.08). However, players ran a greater distance in the 5-min period before the injury than in control matches at 21.0-23.9 km/h (p < 0.001) and at ≥ 24 km/h (p < 0.001). The odds ratio for a hamstring muscle injury was 7.147 for those players who ran > 30.0 m at ≥ 21 km/h in a 5-min period (p < 0.001). Hamstring muscle injuries during competition were preceded by 5 min of higher running demands at > 21 km/h, compared with control matches. This suggests that a short period of unusual running increases the risk of hamstring muscle injury in professional football players.

Changes in physical and technical match performance variables in football players promoted from the Spanish Second Division to the First Division.

The aim of this study was to compare physical and technical match performance variables in football players who competed in the Spanish second division for one season and were promoted to the top (first) division in the following season. A total of 97 male outfield football players who were promoted from the second to the first division of the Spanish professional football league within the same team were analysed. Data were recorded using the TRACAB (ChyronHego, New York, USA) multicamera computerised optical tracking system during five seasons (2015-2016 to 2019-2020). A one-way ANOVA repeated measures analysis showed that players executed a greater number of high-intensity running (HIR) efforts (P < 0.001; ES: 0.258), as well as covering greater HIR distance (P < 0.010; ES: 0.106) and total running distance (TD) (P < 0.010; ES: 0.080), when they played in the first division compared with the second division. Moreover, players performed a lower number of passes (P < 0.01; ES = 0.116), short passes (P < 0.01; ES = 0.106), long passes (P < 0.05; ES = 0.067), dribbles (P < 0.001; ES = 0.146) and shots (P < 0.01; ES = 0.074) in the first division compared to the second division. No significant differences were found for any of the defensive variables evaluated. In conclusion, being promoted from the second to the first division of professional football requires players to adapt to greater physical demands and a reduced number of technical actions.

Technical and tactical evolution of the offensive team sequences in LaLiga between 2008 and 2021. Is Spanish football now a more associative game?

The aim of this investigation was to study the technical and tactical evolution of the offensive team sequences in the Spanish football teams from 2008/09 to 2020/21. A comparative analysis including twelve variables related to the development of offensive sequences in 4940 matches was performed from 2008/09 to 2020/21 seasons of the Spanish professional football league (LaLiga). All match observations were recorded using a validated video tracking system. Multilevel linear mixed models were used to examine the differences across seasons, considering the effects of contextual variables. The number of passes per sequence (2.4 [CI: 2.2-2.5] vs 3.2 [CI: 3.0-3.4]; +33.3%), the passing accuracy (72.1 [CI: 70.6-73.5] vs 76.9 [CI: 75.4-78.3]%; +6.8%) and the average duration of the team sequences (6.4 [CI: 5.9-6.8] vs 8.3 [CI: 7.8-8.7] seconds; +25.76%) showed a small increasing trend over the seasons (P < 0.05). In contrast, variables such as the direct speed of progression (2.2 [CI: 2.1-2.3] vs 1.6 [CI: 1.5-1.7] metres/second; -24.5%), key passes (8.1 [CI: 7.6-8.5] vs 6.8 [CI: 6.3-7.2]; -15.8%), and the sequences that ended in the attacking third (64.8 [CI: 62,7-66.8] vs 57.1 [CI: 55.1-59.2]; -11.7%) or in a shot (13.0 [CI: 12.4-13.6] vs 10.2 [CI: 9.6-10.8]; -21.6%) showed a small decreasing trend from 2008/09 to 2020/21 (P < 0.05). Spanish professional football teams slightly evolved technically and tactically towards a more associative style of play that includes longer passing sequences. This evolution also involved a decreasing speed of progression and fewer technical actions such as through balls, key passes and shots.

Role of cyclin-dependent kinase 5 in psychosis and the modulatory effects of cannabinoids.

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.

Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome.

PRKACA and PRKACB code for two catalytic subunits (Cα and Cß) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cß subunits of PKA during human development.