Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores

Background: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. Methods: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein-protein-interactions), were used for final prioritization. Conclusion: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.Funding information: The present study was supported by the German Research Foundation (DFG)-Grants BE 3828/8-1, LU 1944/2-1, MA 2546/5-1, and LU1944/3-1. ACKNOWLEDGMENTS: The authors thank all patients, relatives, and control individuals for their participation. We thank the German support group for individuals with cleft lip and/or palate (Wolfgang Rosenthal Gesellschaft) for assistance with recruitment.We acknowledge the invaluable assistance of all clinical, laboratory, and bioinformatic personnel. The authors thank the Next Generation Sequencing Core Facility of the Medical Faculty of the University of Bonn for sequencing the samples that were used in this study. DbGaP datasets were accessed through dbGaP accession number phs000094.v1.p1 (Supplemental Acknowledgments). Finally, the authors thank the Genome Aggregation Database (gnomAD), and all groups that provided exome and genome variant data to this resource. A full list of gnomAD contributors is provided in the gnomAD flagship paper (Karczewski et al., 2020). Open Access funding enabled and organized by Projekt DEAL

Social Media and Mental Health

Julia Burk ’23Marketing and Psychology major Adam Henschel ’23Marketing majorSociology minor Meghan Smith ’23Marketing majorSociology minor Julianna Raho ’23Marketing majorFilm minor Facutly Mentors: Dr. Kevin Newman and Dr. Mark DeFanti, Marketing We decided to study the negative ramifications of social media use on mental health. Our research problem became why are college aged people overusing social media and what are the consequences of this? We created a 10-minute survey asking questions dealing with one’s personal relationship with social media and their mental health and we collected data from over 100 PC students. We learned through our data collection that most students were actually well-aware of the negative effects of overusing social media, but continued to do so anyways, so we created three insightful and original recommendations for PC students to implement

Molecular and Functional Characterization of Different BrainSphere Models for Use in Neurotoxicity Testing on Microelectrode Arrays

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100% NESTIN-positive hiPSC-derived neural progenitor cells (hiNPCs), though with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed to apply such MEA-based spike sorting. These models are promising tools not only in toxicology but also for drug development and disease modeling

PANDEMIA DE COVID-19 E DESENCADEAMENTO DA PSICOSE

The paper is the result of research on the impact of the humanitarian emergency of COVID-19 on pre-existing forms of psychological suffering - in particular, psychosis. In this sense, the aim of the article is to discuss the impact of the pandemic on psychosis based on the concept of triggering and the hypothesis that the pandemic works, in these clinical situations, as a triggering situation. A discussion of bibliographical references on the triggering of psychosis in contexts of humanitarian/health emergencies is presented. These references narrow the research down to the biological impact and brain damage caused by viruses. Within the framework of these references, the article locates the relevance of the psychoanalytic concept of triggering in the light of the clinical-conceptual elaboration of foreclosure to elucidate the vulnerability of psychotic subjects to situations of humanitarian/sanitary emergencies.El artículo es el resultado de una investigación sobre el impacto de la emergencia humanitaria del COVID-19 en las formas preexistentes de sufrimiento psicológico, en particular, la psicosis. En este sentido, el objetivo del artículo es discutir el impacto de la pandemia en la psicosis a partir del concepto de desencadenante y la hipótesis de que la pandemia funciona, en estas situaciones clínicas, como situación desencadenante. Se presenta una discusión de referencias bibliográficas sobre el desencadenamiento de psicosis en contextos de emergencias humanitarias/sanitarias. Estas referencias reducen la investigación al impacto biológico y al daño cerebral causado por los virus. En el marco de estas referencias, el artículo ubica la relevancia del concepto psicoanalítico de desencadenamiento a la luz de la elaboración clínico-conceptual de forclusión para dilucidar la vulnerabilidad de los sujetos psicóticos ante situaciones de emergencia humanitaria/sanitaria.O artigo resulta da pesquisa acerca do impacto da emergência humanitária de COVID-19 em formas de sofrimento psíquico pré-existentes – em especial, na psicose. Seu objetivo é discutir o impacto da pandemia na psicose a partir do conceito de desencadeamento e da hipótese de que a pandemia funciona como conjuntura de desencadeamento. É apresentada uma discussão acerca de referências sobre o desencadeamento da psicose em contextos de emergências humanitárias/sanitárias que reduzem essa investigação ao impacto biológico e os danos cerebrais provocados pelos vírus. Nesse quadro de referências, o artigo localiza a atualidade do conceito psicanalítico de desencadeamento à luz da elaboração clínico-conceitual de foraclusão para a elucidação quanto a vulnerabilidade de sujeitos psicóticos a conjunturas de emergências humanitárias/sanitárias

Dynamic stabilization with active locking plates delivers faster, stronger, and more symmetric fracture-healing

BACKGROUND: Axial dynamization of fractures can promote healing, and overly stiff fixation can suppress healing. A novel technology, termed active plating, provides controlled axial dynamization by the elastic suspension of locking holes within the plate. This prospective, controlled animal study evaluated the effect of active plates on fracture-healing in an established ovine osteotomy model. We hypothesized that symmetric axial dynamization with active plates stimulates circumferential callus and delivers faster and stronger healing relative to standard locking plates. METHODS: Twelve sheep were randomly assigned to receive a standard locking plate or an active locking plate for stabilization of a 3-mm tibial osteotomy gap. The only difference between plates was that locking holes of active plates were elastically suspended, allowing up to 1.5 mm of axial motion at the fracture. Fracture-healing was analyzed weekly on radiographs. After sacrifice at nine weeks postoperatively, callus volume and distribution were assessed by computed tomography. Finally, to determine their strength, healed tibiae and contralateral tibiae were tested in torsion until failure. RESULTS: At each follow-up, the active locking plate group had more callus (p < 0.001) than the standard locking plate group. At postoperative week 6, all active locking plate group specimens had bridging callus at the three visible cortices. In standard locking plate group specimens, only 50% of these cortices had bridged. Computed tomography demonstrated that all active locking plate group specimens and one of the six standard locking plate group specimens had developed circumferential callus. Torsion tests after plate removal demonstrated that active locking plate group specimens recovered 81% of their native strength and were 399% stronger than standard locking plate group specimens (p < 0.001), which had recovered only 17% of their native strength. All active locking plate group specimens failed by spiral fracture outside the callus zone, but standard locking plate group specimens fractured through the osteotomy gap. CONCLUSIONS: Symmetric axial dynamization with active locking plates stimulates circumferential callus and yields faster and stronger healing than standard locking plates. CLINICAL RELEVANCE: The stimulatory effect of controlled motion on fracture-healing by active locking plates has the potential to reduce healing complications and to shorten the time to return to function