Cell fate regulation during preimplantation development: A view of adhesion-linked molecular interactions

AbstractIn the developmental process of the early mammalian embryo, it is crucial to understand how the identical cells in the early embryo later develop different fates. Along with existing models, many recently discovered molecular, cellular and developmental factors play roles in cell position, cell polarity and transcriptional networks in cell fate regulation during preimplantation. A structuring process known as compaction provides the “start signal” for cells to differentiate and orchestrates the developmental cascade. The proper intercellular junctional complexes assembled between blastomeres act as a conducting mechanism governing cellular diversification. Here, we provide an overview of the diversification process during preimplantation development as it relates to intercellular junctional complexes. We also evaluate transcriptional differences between embryonic lineages according to cell- cell adhesion and the contributions of adhesion to lineage commitment. These series of processes indicate that proper cell fate specification in the early mammalian embryo depends on junctional interactions and communication, which play essential roles during early morphogenesis

Development of a Software for Design and Design Comparison of Prestressed I-Beam for Highway and Railway Bridges Based on International Standards

New computer software is being developed within Bridgewiz R&D Co. for the aim of rapidly comparing design solutions for a prestressed I-beam (highway or railway bridge) according to different international specifications. The software will perform a series of beam designs based on user inputs and then make a comparison in terms of dimensions, material quantities, and total costs (using either user-defined or autoacquired unit prices). The design and comparison results will be presented to the user in the form of a PDF report (as well as an on-screen window) which includes tables and charts for easy visualization. The initial specifications that are planned to be included in the software are AASHTO-LRFD, EUROCODE, and Turkish Highway Bridge Specifications for highway bridges and AREMA, EUROCODE, and Turkish Railway Bridge Specifications for railway bridges. Fresh engineers will be able to use the program for verifying their designs and experienced engineers can utilize the program for staying up-to-date with requirements of contemporary specifications. The parameters that will be designed by the software are the optimum number of girders, their geometry, girder lateral spacing, number of prestressing tendons and jacking forces (taking the losses into account), prestressing tendon distribution, deck reinforcement area, and deck section stresses. The development is supported by KOSGEB - a Turkish government organization for supporting micro and small companies on research and development projects

Comparison of adjacent segment degeneration in patients using cervical cage and disc prosthesis in anterior cervical surgery

Aim: To examine the prevalence of adjacent segment degeneration associated with the use of cages and disc prostheses in patients who underwent cervical disc surgery via an anterior cervical approach. Methods: We retrospectively reviewed the medical records of 60 patients who underwent cervical disc surgery via an anterior cervical approach at our clinic between 2018 and 2023. The patients were divided into two groups based on the type of implant used: those with a cervical cage (Group 1) and those with a cervical disc prosthesis (Group 2). Patients' demographic and clinical details, including age, gender, smoking habits, follow-up durations, and any additional comorbid diseases, were recorded. Radiological evaluations focused on degeneration rates in the segments adjacent to where either the cage or disc prosthesis was implanted. Results: In the study comparing two groups, participants' average ages were 48.9 in Group 1 and 48.1 in Group 2 (p=0.720). Group 1 had a higher proportion of smokers (p=0.052) and more discopathy (p=0.196). In terms of disc degenerations, variations existed but were not statistically significant (p=0.259). Utilizing the Pfirrmann grading, Group 1 had more Grade III degeneration (p=0.088) and a significantly higher presence of ossification or osteophytes (p=0.038). Both groups showed high rates of adjacent segment degeneration, yet Group 1 had notably more proximal degeneration (p=0.012). Stenosis and facet hypertrophy differences were not significant (p=0.417, p=0.071). Follow-up duration averaged around 38 months for both groups (p=0.929). Conclusions: No substantial difference in the overall incidence of adjacent segment degeneration between the two procedures. Nevertheless, further large-scale and long-term studies are essential to draw comprehensive conclusions regarding the optimal surgical intervention for cervical disc ailments

Explainable 2D Vision Models for 3D Medical Data

Training Artificial Intelligence (AI) models on three-dimensional image data presents unique challenges compared to the two-dimensional case: Firstly, the computational resources are significantly higher, and secondly, the availability of large pretraining datasets is often limited, impeding training success. In this study, we propose a simple approach of adapting 2D networks with an intermediate feature representation for processing 3D volumes. Our method involves sequentially applying these networks to slices of a 3D volume from all orientations. Subsequently, a feature reduction module combines the extracted slice features into a single representation, which is then used for classification. We evaluate our approach on medical classification benchmarks and a real-world clinical dataset, demonstrating comparable results to existing methods. Furthermore, by employing attention pooling as a feature reduction module we obtain weighted importance values for each slice during the forward pass. We show that slices deemed important by our approach allow the inspection of the basis of a model's prediction

Replicated evidence that endophenotypic expression of schizophrenia polygenic risk is greater in healthy siblings of patients compared to controls, suggesting gene-environment interaction. The EUGEI study

Background First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes. Methods We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS. Results In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group. Conclusions The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder

Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Background. A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls. Methods. This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate. Results. ES-SCZ was associated with the GAF dimensions in patients (symptom: B = 1.53, p-value = 0.001; disability: B = 1.44, p-value = 0.001), siblings (symptom: B = 3.07, p-value < 0.001; disability: B = 2.52, p-value < 0.001), and healthy controls (symptom: B = 1.50, p-value < 0.001; disability: B = 1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group. Conclusions. Our findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p <0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p <0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p <0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p <0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p <0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders

Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study

Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy‐genetic liability measures suggest gene‐environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS‐SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene‐environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS‐SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early‐life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS‐SCZ at 75% with alternative cut‐points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures