Distinct spatiotemporal contribution of morphogenetic events and mechanical tissue coupling during Xenopus neural tube closure.

Neural tube closure (NTC) is a fundamental process during vertebrate development and is indispensable for the formation of the central nervous system. Here, using Xenopus laevis embryos, live imaging, single-cell tracking, optogenetics and loss-of-function experiments, we examine the roles of convergent extension and apical constriction, and define the role of the surface ectoderm during NTC. We show that NTC is a two-stage process with distinct spatiotemporal contributions of convergent extension and apical constriction at each stage. Convergent extension takes place during the first stage and is spatially restricted at the posterior tissue, whereas apical constriction occurs during the second stage throughout the neural plate. We also show that the surface ectoderm is mechanically coupled with the neural plate and its movement during NTC is driven by neural plate morphogenesis. Finally, we show that an increase in surface ectoderm resistive forces is detrimental for neural plate morphogenesis.

H2 inhalation therapy in patients with moderate COVID-19 (H2COVID): a prospective ascending-dose phase I clinical trial.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for COVID-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy. This phase I study, characterized by an open-label, prospective, monocentric, and single ascending-dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3 + 3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3). We concluded that the maximum tolerated duration is at least 3 days. Every patient showed clinical improvement and excellent tolerance to H2 therapy. To the best of our knowledge, this phase I clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized COVID-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04633980.

Psychosis brain subtypes validated in first-episode cohorts and related to illness remission: results from the PHENOM consortium.

Using machine learning, we recently decomposed the neuroanatomical heterogeneity of established schizophrenia to discover two volumetric subgroups-a 'lower brain volume' subgroup (SG1) and an 'higher striatal volume' subgroup (SG2) with otherwise normal brain structure. In this study, we investigated whether the MRI signatures of these subgroups were also already present at the time of the first-episode of psychosis (FEP) and whether they were related to clinical presentation and clinical remission over 1-, 3-, and 5-years. We included 572 FEP and 424 healthy controls (HC) from 4 sites (Sao Paulo, Santander, London, Melbourne) of the PHENOM consortium. Our prior MRI subgrouping models (671 participants; USA, Germany, and China) were applied to both FEP and HC. Participants were assigned into 1 of 4 categories: subgroup 1 (SG1), subgroup 2 (SG2), no subgroup membership ('None'), and mixed SG1 + SG2 subgroups ('Mixed'). Voxel-wise analyses characterized SG1 and SG2 subgroups. Supervised machine learning analyses characterized baseline and remission signatures related to SG1 and SG2 membership. The two dominant patterns of 'lower brain volume' in SG1 and 'higher striatal volume' (with otherwise normal neuromorphology) in SG2 were identified already at the first episode of psychosis. SG1 had a significantly higher proportion of FEP (32%) vs. HC (19%) than SG2 (FEP, 21%; HC, 23%). Clinical multivariate signatures separated the SG1 and SG2 subgroups (balanced accuracy = 64%; p < 0.0001), with SG2 showing higher education but also greater positive psychosis symptoms at first presentation, and an association with symptom remission at 1-year, 5-year, and when timepoints were combined. Neuromorphological subtypes of schizophrenia are already evident at illness onset, separated by distinct clinical presentations, and differentially associated with subsequent remission. These results suggest that the subgroups may be underlying risk phenotypes that could be targeted in future treatment trials and are critical to consider when interpreting neuroimaging literature.

Psychopathology and the Validity of Gastrointestisnal Symptom Reporting as Revealed Through Cluster Analyses of MMPI-2-RF Results.

BACKGROUND: Psychological state, self-reported gut symptoms, and somatic complaints are recognized relationships that can impact health assessment and subsequent treatment. AIM: To investigate the impact of psychological state and personality on symptom self-reporting and somatization. METHODS: Sixty-two (62) participants from the Hunter region of NSW (Australia) undertook a survey of health and lifestyle along with an MMPI-2-RF assessment of personality, psychopathology, and test-taking attitude. Participants also completed the Rome Criteria to assess functional gastrointestinal disorders (FGIDs). To assist the interpretation of MMPI-2-RF results, clustering was applied to identify similar responses and sub-cohort profiles of reporting. RESULTS: Cluster analysis revealed four sub-cohorts, stratified by psychopathology, gut-related symptoms, and the validity of self-reported somatic complaints. Sample clustering identified one sub-cohort defined by high rates of negative affectivity and suicidal ideation. Apart from these differences, clusters were uniform for age, sex, smoking, mental health diagnoses, as well as for gut-related conditions. CONCLUSION: Results provide further evidence of the interaction of the gut-brain axis and its relationship to serious mental health conditions. It also points to the need to assess the veracity of self-reported symptomatology that may be both pathognomonic for psychopathology but might also be a consequence of gut dysbiosis. Clustering assisted these investigations by defining distinct sub-cohorts based on participant MMPI-2-RF responses.

The effect of hyperoxia on muscle sympathetic nerve activity: a systematic review and meta-analysis.

PURPOSE: We conducted a meta-analysis to determine the effect of hyperoxia on muscle sympathetic nerve activity in healthy individuals and those with cardio-metabolic diseases. METHODS: A comprehensive search of electronic databases was performed until August 2022. All study designs (except reviews) were included: population (humans; apparently healthy or with at least one chronic disease); exposures (muscle sympathetic nerve activity during hyperoxia or hyperbaria); comparators (hyperoxia or hyperbaria vs. normoxia); and outcomes (muscle sympathetic nerve activity, heart rate, blood pressure, minute ventilation). Forty-nine studies were ultimately included in the meta-analysis. RESULTS: In healthy individuals, hyperoxia had no effect on sympathetic burst frequency (mean difference [MD] - 1.07 bursts/min; 95% confidence interval [CI] - 2.17, 0.04bursts/min; P = 0.06), burst incidence (MD 0.27 bursts/100 heartbeats [hb]; 95% CI - 2.10, 2.64 bursts/100 hb; P = 0.82), burst amplitude (P = 0.85), or total activity (P = 0.31). In those with chronic diseases, hyperoxia decreased burst frequency (MD - 5.57 bursts/min; 95% CI - 7.48, - 3.67 bursts/min; P < 0.001) and burst incidence (MD - 4.44 bursts/100 hb; 95% CI - 7.94, - 0.94 bursts/100 hb; P = 0.01), but had no effect on burst amplitude (P = 0.36) or total activity (P = 0.90). Our meta-regression analyses identified an inverse relationship between normoxic burst frequency and change in burst frequency with hyperoxia. In both groups, hyperoxia decreased heart rate but had no effect on any measure of blood pressure. CONCLUSION: Hyperoxia does not change sympathetic activity in healthy humans. Conversely, in those with chronic diseases, hyperoxia decreases sympathetic activity. Regardless of disease status, resting sympathetic burst frequency predicts the degree of change in burst frequency, with larger decreases for those with higher resting activity.

Impact of postpartum physical activity on cardiometabolic health, breastfeeding, injury and infant growth and development: a systematic review and meta-analysis.

OBJECTIVE: To examine the relationship between postpartum physical activity and maternal postnatal cardiometabolic health, breastfeeding, injury, and infant growth and development. DESIGN: Systematic review with random-effects meta-analysis and meta-regression. DATA SOURCES: Eight online databases were searched up until 12 January 2024. ELIGIBILITY CRITERIA: Studies of all designs in all languages were eligible (except case studies and reviews) if they contained information on the population (postpartum people), intervention (frequency, intensity, duration, volume, or type of exercise, alone ('exercise-only') or in combination with other intervention components (eg, dietary; 'exercise+co-intervention'), comparator (no or low volumes of physical activity), and outcomes: hypertension, diabetes, cardiometabolic risk factors (systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, high density lipoproteins, low density lipoproteins, and triglycerides, glycated hemoglobin (HbA1C), glucose and insulin concentration), breastfeeding (breast milk quality and volume), infant growth (length and weight) and development, or postpartum injury. RESULTS: 46 unique studies (n=8766 participants) from 20 countries were included. Moderate certainty of evidence showed exercise+co-interventions reduced the odds of developing diabetes by 28% (7 randomised controlled trials (RCTs), n=2496; OR 0.72 95% CI 0.54, 0.98, I2 12%), reduced SBP (10 RCTs, n=2753; mean difference (MD) -2.15 95% CI -3.89 to -0.40, I2 73%) and DBP (9 RCTs, n=2575; MD -1.38 95% CI -2.60 to -0.15, I2 66%) compared with controls. Infant growth and development, breast milk quality and quantity, and risk of injury were not different between exercise and control groups. CONCLUSIONS: Physical activity improves cardiometabolic health without adversely impacting breast milk supply or quality, infant growth or maternal injury.

Mimicry in misophonia: A large-scale survey of prevalence and relationship with trigger sounds.

BACKGROUND: Misophonia is often referred to as a disorder that is characterized by excessive negative emotional responses, including anger and anxiety, to "trigger sounds" which are typically day-to-day sounds, such as those generated from people eating, chewing, and breathing. Misophonia (literally "hatred of sounds") has commonly been understood within an auditory processing framework where sounds cause distress due to aberrant processing in the auditory and emotional systems of the brain. However, a recent proposal suggests that it is the perceived action (e.g., mouth movement in eating/chewing sounds as triggers) of the trigger person, and not the sounds per se, that drives the distress in misophonia. Since observation or listening to sounds of actions of others are known to prompt mimicry in perceivers, we hypothesized that mimicking the action of the trigger person may be prevalent in misophonia. Apart from a few case studies and anecdotal information, a relation between mimicking and misophonia has not been systematically evaluated. METHOD: In this work, we addressed this limitation by collecting data on misophonia symptoms and mimicry behavior using online questionnaires from 676 participants. RESULTS: Analysis of these data shows that (i) more than 45% of individuals with misophonia reported mimicry, indicating its wide prevalence, (ii) the tendency to mimic varies in direct proportion to misophonia severity, (iii) compared to other human and environmental sounds, trigger sounds of eating and chewing are more likely to trigger mimicking, and (iv) the act of mimicking provides some degree of relief from distress to people with misophonia. CONCLUSION: This study shows prevalence of mimicry and its relation to misophonia severity and trigger types. The theoretical framework of misophonia needs to incorporate the phenomenon of mimicry and its effect on management of misophonia distress.

FMR protein: Evidence of an emerging role in retinal aging?

Aging is a multifactorial process that affects the entire organism by cumulative alterations. Visual function impairments that go along with aging are commonly observed, causing lower visual acuity, lower contrast sensitivity, and impaired dark adaptation. Electroretinogram analysis revealed that the amplitudes of rod- and cone-mediated responses are reduced in aged mice and humans. Reports suggested that age-related changes observed in both rod and cone photoreceptor functionality were linked to oxidative stress regulation or free radical production homeostasis. Interestingly, several recent reports linked the fragile X mental retardation protein (FMRP) cellular activity with oxidative stress regulation in several tissue including brain tissue where FMRP participates to the response to stress via protein translation in neurite or is involved in free radical production and abnormal glutathione homeostasis. Based on these recent literatures, we raised the question about the effect of FMRP absence in the aging retina of Fmr1-/y compared to their WT littermates. Indeed, up to now, only young or adult mice (<6 months) were investigated and have shown a specific retinal phenotype. Herein, we demonstrated that Fmr1-/y mice do not present the aging effect on retinal function observed in WT littermates since ERG a- and b-waves amplitudes as well as oscillatory potentials amplitudes were not collapsed with age (12/18 months old). Absence of FMRP and its consequences seem to protect the retina against aging effect, rising a pivotal role of FMRP in retinal aging process.

A systematic review of relationships and sex education outcomes for students with intellectual disability reported in the international literature.

BACKGROUND: Little is known about how to evaluate relationships and sex education (RSE) delivered to students with intellectual disability and what stakeholders perceive are important outcomes. The present study aimed to systematically review existing studies on outcomes of RSE, as the first step in the development of a core outcome set (COS) for students with intellectual disability. METHOD: A systematic literature process included two stages: (1) searching for studies reporting on RSE outcomes for students with intellectual disability and (2) studies reporting on measurement properties (e.g. validity, reliability and responsiveness) of standardised instruments identified in stage 1. RESULTS: A total of 135 RSE outcomes were extracted from 42 studies: 43 outcomes for students in secondary education and 92 outcomes for students in further education. No RSE outcomes were reported for primary education. Outcomes referred to the human body, hygiene, relationships, sexuality, sex and its consequences, inappropriate and appropriate social and sexual behaviour, keeping safe, emotional vocabulary and positive self-esteem. Outcomes were predominantly knowledge-based, rather than relating to skills and attitudes development. Students with intellectual disability, parents and teachers perceive different RSE outcomes meaningful. Five instruments were used to measure the outcomes, but none have established psychometric properties with this population. CONCLUSIONS: The comprehensive list of RSE outcomes for students with intellectual disability will be used to inform the next steps of a Core Outcome Set needed for RSE evaluations in research and education settings. There is an urgent need to develop standardised instruments validated for students with intellectual disability.

FAK displacement from focal adhesions: a promising strategy to target processes implicated in cancer progression and metastasis.

BACKGROUND: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed or activated in several advanced-stage solid cancers. It is known to play both kinase-dependent and -independent roles in promoting tumor progression and metastasis. Numerous inhibitors, targeting either the enzymatic or scaffolding activities of FAK have been generated, with varying degree of success. Here, we describe a novel approach to site-specifically target both kinase-dependent and -independent FAK functions at focal adhesions (FAs), the primary sites at which the kinase exerts its activity. METHODS: We took advantage of the well-characterized interactions between the paxillin LD motifs and the FAK FAT domain and generated a polypeptide (LD2-LD3-LD4) expected to compete with interactions with paxillin. Co-immunoprecipitation experiments were performed to examine the interaction between the LD2-LD3-LD4 polypeptide and FAK. The effects of LD2-LD3-LD4 in the localization and functions of FAK, as well as FA composition, were evaluated using quantitative immunofluorescence, cell fractionation, FA isolation and Western Blot analysis. Live cell imaging, as well as 2-D migration and cell invasion assays were used to examine the effects on FA turnover and tumor cell migration and invasion. RESULTS: Expression of the LD2-LD3-LD4 polypeptide prevents FAK localization at FAs, in a controlled and dose-dependent manner, by competing with endogenous paxillin for FAK binding. Importantly, the LD2-LD3-LD4 peptide did not otherwise affect FA composition or integrin activation. LD2-LD3-LD4 inhibited FAK-dependent downstream integrin signaling and, unlike existing inhibitors, also blocked FAK's scaffolding functions. We further show that LD2-LD3-LD4 expression markedly reduces FA turnover and inhibits tumor cell migration and invasion. Finally, we show that dimers of a single motif, linked through a flexible linker of the proper size, are sufficient for the displacement of FAK from FAs and for inhibition of tumor cell migration. This work raises the possibility of using a synthetic peptide as an antimetastatic agent, given that effective displacement of FAK from FAs only requires dimers of a single LD motif linked by a short flexible linker. CONCLUSION: In conclusion, these results suggest that FAK displacement from FAs is a promising new strategy to target critical processes implicated in cancer progression and metastasis. Video abstract.

Climate mitigation in the Mediterranean Europe: An assessment of regional and city-level plans.

In Europe, regions in the Mediterranean area share common characteristics in terms of high sensitivity to climate change impacts. Does this translate into specificities regarding climate action that could arise from these Mediterranean characteristics? This paper sheds light on regional and local climate mitigation actions of the Mediterranean Europe, focusing on the plans to reduce greenhouse gases emissions in a representative sample of 51 regions and 73 cities across 9 Mediterranean countries (Croatia, Cyprus, France, Greece, Italy, Malta, Portugal, Slovenia, Spain). The study investigates: (i) the availability of local and regional mitigation plans, (ii) their goals in term of greenhouse gas emissions reduction targets on the short and medium-long term, and (iii) the impact of transnational climate networks on such local and regional climate mitigation planning. Results of this study indicate an uneven and fragmented planning, that shows a Mediterranean West-East divide, and a link with population size. However, overall, both regional and city action seem insufficiently ambitious with regards to meeting the Paris Agreement, at least at city level. While national frameworks are currently weak in influencing regional and local actions, transnational networks seem to be engaging factors for commitment (at city level) and ambitiousness (at regional level). The uneven and fragmented progress revealed by this study, does not align with the characteristics shared by investigated regions and cities in terms of environmental, socio-political, climatic and economic conditions. The results support the call of a common green deal at the Mediterranean level to further address specific Mediterranean challenges and related needs. This will allow to capitalise on available resources, generate local-specific knowledge, build capacities, and support Mediterranean regions and cities in preparing the next generation of more ambitious mitigation plans.

Addressing the Functional Determinants of FAK during Ciliogenesis in Multiciliated Cells.

We previously identified focal adhesion kinase (FAK) as an important regulator of ciliogenesis in multiciliated cells. FAK and other focal adhesion (FA) proteins associate with the basal bodies and their striated rootlets and form complexes named ciliary adhesions (CAs). CAs display similarities with FAs but are established in an integrin independent fashion and are responsible for anchoring basal bodies to the actin cytoskeleton during ciliogenesis as well as in mature multiciliated cells. FAK down-regulation leads to aberrant ciliogenesis due to impaired association between the basal bodies and the actin cytoskeleton, suggesting that FAK is an important regulator of the CA complex. However, the mechanism through which FAK functions in the complex is not clear, and in this study we examined the role of this protein in both ciliogenesis and ciliary function. We show that localization of FAK at CAs depends on interactions taking place at the amino-terminal (FERM) and carboxyl-terminal (FAT) domains and that both domains are required for proper ciliogenesis and ciliary function. Furthermore, we show that an interaction with another CA protein, paxillin, is essential for correct localization of FAK in multiciliated cells. This interaction is indispensable for both ciliogenesis and ciliary function. Finally, we provide evidence that despite the fact that FAK is in the active, open conformation at CAs, its kinase activity is dispensable for ciliogenesis and ciliary function revealing that FAK plays a scaffolding role in multiciliated cells. Overall these data show that the role of FAK at CAs displays similarities but also important differences compared with its role at FAs.

"Metabolic and cardiovascular response to exercise in patients with type 1 diabetes".

PURPOSE: Physical activity is an effective therapeutic tool for cardiovascular risk prevention. However, exercise aerobic capacity of patients with type 1 diabetes (T1DM) has not been thoroughly investigated. Aim of the present study is to evaluate exercise aerobic capacity in patients with T1DM compared to a normal control population. METHODS: This observational study included 17 T1DM patients and 17 matched healthy volunteers. Cardiopulmonary exercise test (CPET) was conducted on an electronically-braked cycle ergometer. Blood samples were collected for evaluation of glycemia and lactate levels. RESULTS: Mean oxygen uptake at peak exercise (V'O2,peak) was significantly lower in T1DM subjects (V'O2,peak T1DM 2200 ± 132ml/min vs V'O2,peak Healthy subjects of 2659 ± 120 ml/min p = 0.035). Cardiovascular response analysis did not show statistically significant differences. Respiratory exchange ratio (RER) was significantly higher in healthy subjects at peak exercise and at the first minute of recovery (p = 0.022, p = 0.024). Peak exercise lactate levels were significantly higher in healthy subjects. There was no statistical correlation between CPET results and diabetes-related parameters. CONCLUSIONS: Patients affected by T1DM have a worse exercise tolerance than normal subjects. The two groups differed by RER which can be greatly influenced by the substrate type utilized to produce energy. Because of the impaired carbohydrate utilization, T1DM subjects may use a larger amount of lipid substrates, such hypothesis could be strengthened by the lower lactate levels found in T1DM group at peak exercise. The lack of correlation between exercise tolerance and disease-related variables suggests that the alterations found could be independent from the glycemic levels.

Post-lunch triglyceridaemia associates with HDLc and insulin resistance in fasting normotriglyceridaemic menopausal women.

OBJECTIVES: Post-prandial hypertriglyceridaemia (P-HTG) is associated with cardiovascular disease. This association is of paramount importance during menopause, which is also related to reduced high-density lipoprotein-cholesterol (HDLc) and elevated triglyceride (TG) levels. We aimed to provide a self-assesing tool to screen for P-HTG in menopausal women who were normotriglyceridaemic at fasting and adhered to a Mediterranean-style eating pattern. METHODS: We performed oral fat loading tests (OFLT) in combination with self-measurements of diurnal capillary TG at fixed time-points (DC-TG) in 29 healthy menopausal women. TG levels >220 mg dL-1 at any given time during the OFLT served as diagnostic criteria for P-HTG. Subsequently, DC-TG profiles were examined to determine the best mealtime (breakfast, lunch or dinner), as well as optimal cut-off points to classify these women as having P-HTG according to the OFLT. Insulin resistance was defined as the upper tertile of the homeostatic model assessment of insulin resistance. RESULTS: We found that, despite having normal fasting TG levels, P-HTG was highly prevalent (approximately 40%). Moreover, self-assessed 3-h post-lunch TG levels >165 mg dL-1 increased the odds of having hypo-HDL cholesterolaemia by 14.1-fold (P = 0.026) and the odds of having insulin resistance by 31.6-fold (P = 0.007), adjusted for total fat intake in women adhering to a Mediterranean eating pattern having their highest energy intake at lunch. CONCLUSIONS: Self-assessed 3-h post-lunch TG can be used to study post-prandial TG metabolism in Southern European menopausal women who are normotriglyceridaemic at fasting. Characterising an individual's post-prandial response may help menopausal women to evaluate their risk of cardiovascular disease.

A dominant-negative provides new insights into FAK regulation and function in early embryonic morphogenesis.

FAK is a non-receptor tyrosine kinase involved in a wide variety of biological processes and crucial for embryonic development. In this manuscript, we report the generation of a new FAK dominant negative (FF), composed of the C terminus (FRNK) and the FERM domain of the protein. FF, unlike FRNK and FERM, mimics the localization of active FAK in the embryo, demonstrating that both domains are necessary to target FAK to its complexes in vivo. We show that the FERM domain has a role in the recruitment of FAK on focal adhesions and controls the dynamics of the protein on these complexes. Expression of FF blocks focal adhesion turnover and, unlike FRNK, acts as a dominant negative in vivo. FF expression in Xenopus results in an overall phenotype remarkably similar to the FAK knockout in mice, including loss of mesodermal tissues. Expression of FF in the animal cap revealed a previously unidentified role of FAK in early morphogenesis and specifically epiboly. We show that a fibronectin-derived signal transduced by FAK governs polarity and cell intercalation. Finally, failure of epiboly results in severe gastrulation problems that can be rescued by either mechanical or pharmacological relief of tension within the animal cap, demonstrating that epiboly is permissive for gastrulation. Overall, this work introduces a powerful new tool for the study of FAK, uncovers new roles for FAK in morphogenesis and reveals new mechanisms through which the FERM domain regulates the localization and dynamics of FAK.

Enhancing the Quality of Prevention Research Supported by the National Institutes of Health.

As the nation's premier biomedical research agency, the National Institutes of Health (NIH) has supported most of the research that underlies the prevention services that are provided to citizens in the United States and around the world. Within the NIH, the Office of Disease Prevention (ODP) has as its mission to improve the public health by increasing the scope, quality, dissemination, and effect of prevention research supported by the NIH. In today's environment, the ODP needs to focus its efforts to address this mission. To do so, the ODP has developed a strategic plan for 2014 to 2018. We provide background on the ODP and key points from the strategic plan.

Xenopus laevis nucleotide binding protein 1 (xNubp1) is important for convergent extension movements and controls ciliogenesis via regulation of the actin cytoskeleton.

Nucleotide binding protein 1 (Nubp1) is a highly conserved phosphate loop (P-loop) ATPase involved in diverse processes including iron-sulfur protein assembly, centrosome duplication and lung development. Here, we report the cloning, expression and functional characterization of Xenopus laevis Nubp1. We show that xNubp1 is expressed maternally, displays elevated expression in neural tissues and is required for convergent extension movements and neural tube closure. In addition, xNubp1knockdown leads to defective ciliogenesis of the multi-ciliated cells of the epidermis as well as the monociliated cells of the gastrocoel roof plate. Specifically, xNubp1 is required for basal body migration, spacing and docking in multi-ciliated cells and basal body positioning and axoneme elongation in monociliated gastrocoel roof plate cells. Live imaging of the different pools of actin and basal body migration during the process of ciliated cell intercalation revealed that two independent pools of actin are present from the onset of cell intercalation; an internal network surrounding the basal bodies, anchoring them to the cell cortex and an apical pool of punctate actin which eventually matures into the characteristic apical actin network. We show that xNubp1 colocalizes with the apical actin network of multiciliated cells and that problems in basal body transport in xNubp1 morphants are associated with defects of the internal network of actin, while spacing and polarity issues are due to a failure of the apical and sub-apical actin pools to mature into a network. Effects of xNubp1 knockdown on the actin cytoskeleton are independent of RhoA localization and activation, suggesting that xNubp1 may have a direct role in the regulation of the actin cytoskeleton.

Calpain2 protease: A new member of the Wnt/Ca(2+) pathway modulating convergent extension movements in Xenopus.

Calpains are a family of calcium-dependent intracellular cysteine proteases that regulate several physiological processes by limited cleavage of different substrates. The role of Calpain2 in embryogenesis is not clear with conflicting evidence from a number of mouse knockouts. Here we report the temporal and spatial expression of Calpain2 in Xenopus laevis embryos and address its role in Xenopus development. We show that Calpain2 is expressed maternally with elevated expression in neural tissues and that Calpain2 activity is spatially and temporally regulated. Using a Calpain inhibitor, a dominant negative and a morpholino oligonoucleotide we demonstrate that impaired Calpain2 activity results in defective convergent extension both in mesodermal and neural tissues. Specifically, Calpain2 downregulation results in loss of tissue polarity and blockage of mediolateral intercalation in Keller explants without affecting adherens junction turnover. We further show that Calpain2 is activated in response to Wnt5a and that the inhibitory effect of Wnt5a expression on animal cap elongation can be rescued by blocking Calpain2 function. This suggests that Calpain2 activity needs to be tightly regulated during convergent extension. Finally we show that expression of Xdd1 blocks the membrane translocation of Calpain2 suggesting that Calpain2 activation is downstream of Dishevelled. Overall our data show that Calpain2 activation through the Wnt/Ca(2+) pathway and Dishevelled can modulate convergent extension movements.

Towards a consensus roadmap for a new diagnostic framework for mental disorders.

Current nosology claims to separate mental disorders into distinct categories that do not overlap with each other. This nosological separation is not based on underlying pathophysiology but on convention-based clustering of qualitative symptoms of disorders which are typically measured subjectively. Yet, clinical heterogeneity and diagnostic overlap in disease symptoms and dimensions within and across different diagnostic categories of mental disorders is huge. While diagnostic categories provide the basis for general clinical management, they do not describe the underlying neurobiology that gives rise to individual symptomatic presentations. The ability to incorporate neurobiology into the diagnostic framework and to stratify patients accordingly will be a critical step forward for the development of new treatments for mental disorders. Furthermore, it will also allow physicians to provide patients with a better understanding of their illness's complexities and management. To realize this ambition, a paradigm shift is needed to build an understanding of how neuropsychiatric conditions can be defined more precisely using quantitative (multimodal) biological processes and markers and thus to significantly improve treatment success. The ECNP New Frontiers Meeting 2024 set out to develop a consensus roadmap for building a new diagnostic framework for mental disorders by discussing its rationale, outlook, and consequences with all stakeholders involved. This framework would instantiate a set of principles and procedures by which research could continuously improve precision diagnostics while moving away from traditional nosology. In this meeting report, the speakers' summaries from their presentations are combined to address three key elements for generating such a roadmap, namely, the application of innovative technologies, understanding the biology of mental illness, and translating biological understanding into new approaches. In general, the meeting indicated a crucial need for a biology-informed framework to establish more precise diagnosis and treatment for mental disorders to facilitate bringing the right treatment to the right patient at the right time.

Predicting treatment resistance in positive and negative symptom domains from first episode psychosis: Development of a clinical prediction model.

BACKGROUND: Treatment resistance (TR) in schizophrenia may be defined by the persistence of positive and/or negative symptoms despite adequate treatment. Whilst previous investigations have focused on positive symptoms, negative symptoms are highly prevalent, impactful, and difficult to treat. In the current study we aimed to develop easily employable prediction models to predict TR in positive and negative symptom domains from first episode psychosis (FEP). METHODS: Longitudinal cohort data from 1027 individuals with FEP was utilised. Using a robust definition of TR, n = 51 (4.97 %) participants were treatment resistant in the positive domain and n = 56 (5.46 %) treatment resistant in the negative domain 12 months after first presentation. 20 predictor variables, selected by existing evidence and availability in clinical practice, were entered into two LASSO regression models. We estimated the models using repeated nested cross-validation (NCV) and assessed performance using discrimination and calibration measures. RESULTS: The prediction model for TR in the positive domain showed good discrimination (AUC = 0.72). Twelve predictor variables (male gender, cannabis use, age, positive symptom severity, depression and academic and social functioning) were retained by each outer fold of the NCV procedure, indicating importance in prediction of the outcome. However, our negative domain model failed to discriminate those with and without TR, with results only just over chance (AUC = 0.56). CONCLUSIONS: Treatment resistance of positive symptoms can be accurately predicted from FEP using routinely collected baseline data, however prediction of negative domain-TR remains a challenge. Detailed negative symptom domains, clinical data, and biomarkers should be considered in future longitudinal studies.