Rare recurrent copy number variations in metabotropic glutamate receptor interacting genes in children with neurodevelopmental disorders.

Background: Neurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number variations (CNVs). Both of these NDDs have been shown to share similar biological etiologies as well as genetic pleiotropy.

Attitudes among Parents towards Return of Disease-Related Polygenic Risk Scores (PRS) for Their Children.

The electronic MEdical Records and GEnomics (eMERGE) consortium will return risk reports pertaining to specific diseases, a key component of which will be polygenic risk scores (PRS), to 25,000 participants, including 5000 children. Understanding comprehension and the perceived value of these PRS-based reports among parents will be critical for effective return of results in children. To address this issue, we conducted semi-structured interviews with 40 African American and Hispanic parents at The Children's Hospital of Philadelphia and Boston Children's Hospital.

Comparing human and model-based forecasts of COVID-19 in Germany and Poland.

Forecasts based on epidemiological modelling have played an important role in shaping public policy throughout the COVID-19 pandemic. This modelling combines knowledge about infectious disease dynamics with the subjective opinion of the researcher who develops and refines the model and often also adjusts model outputs. Developing a forecast model is difficult, resource- and time-consuming.

Do research participants share genomic screening results with family members?

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown.

Inducible knockout of Clec16a in mice results in sensory neurodegeneration.

CLEC16A has been shown to play a role in autophagy/mitophagy processes. Additionally, genetic variants in CLEC16A have been implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout, Clec16a mice, to investigate the loss of function of CLEC16A.

JAK/STAT inhibitor therapy partially rescues the lipodystrophic autoimmune phenotype in Clec16a KO mice.

CLEC16A is implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout (KO), Clec16a mice to address the role of CLEC16A loss of function. KO mice exhibited loss of adipose tissue and severe weight loss in response to defective autophagic flux and exaggerated endoplasmic reticulum (ER) stress and robust cytokine storm.

The Autoimmune Disorder Susceptibility Gene Restrains NK Cell Function in YTS NK Cell Line and Knockout Mice.

locus polymorphisms have been associated with several autoimmune diseases. We overexpressed in YTS natural killer (NK) cells and observed reduced NK cell cytotoxicity and IFN-γ release, delayed dendritic cell (DC) maturation, decreased conjugate formation, cell-surface receptor downregulation and increased autophagy. In contrast, siRNA mediated knockdown resulted in increased NK cell cytotoxicity, reversal of receptor expression and disrupted mitophagy.

CLEC16A regulates splenocyte and NK cell function in part through MEK signaling.

CLEC16A is implicated in multiple autoimmune diseases. We generated Clec16a inducible knockout (KO) mice to examine the functional link between CLEC16A auto-inflammation and autoimmunity. Clec16a KO mice exhibited weight loss and thymic and splenic atrophy.

Genome-wide association study for acute otitis media in children identifies FNDC1 as disease contributing gene.

Acute otitis media (AOM) is among the most common pediatric diseases, and the most frequent reason for antibiotic treatment in children. Risk of AOM is dependent on environmental and host factors, as well as a significant genetic component. We identify genome-wide significance at a locus on 6q25.

The Added Value of Family Material in the Discovery of Multiple Sclerosis Genes.

A mutation in a nuclear receptor (NR1H3) gene was detected in a familial, progressive form of multiple sclerosis (PPMS). Further analyses showed a significant association between a common NR1H3 variant in PPMS patients and loss of function for the encoded protein.

Effect of a Novel, Orally Active Matrix Metalloproteinase-2 and -9 Inhibitor in Spinal and Trigeminal Rat Models of Neuropathic Pain.

Aims: To study the effects of a novel matrix metalloproteinase-2 (MMP-2) and MMP-9 inhibitor, AQU-118, on mechanical allodynia in the spinal nerve ligation (SNL) model of neuropathic pain and the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic orofacial pain.

Methods: Five groups of SNL rats were given daily oral doses of AQU-118 (5, 10, 20 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then paw withdrawal threshold was measured with von Frey filaments (VF).

Anticonvulsant activity of pregabalin in the maximal electroshock-induced seizure assay in α2δ1 (R217A) and α2δ2 (R279A) mouse mutants.

Pregabalin has been shown to have anticonvulsant, analgesic, and anxiolytic activity in animal models. Pregabalin binds with high affinity to the α2δ1 and α2δ2 subunits of voltage-gated calcium channels. In order to better understand the relative contribution that binding to either the α2δ1 or α2δ2 subunits confers on the anticonvulsant activity of pregabalin, we characterized the anticonvulsant activity of pregabalin in different wild-type (WT) and mutant mouse strains.

Possible therapeutic effect of trilostane in rodent models of inflammation and nociception.

Background: Trilostane was identified in an in vivo screen of compounds in a lipopolysaccharide model of inflammation to support a repurposing effort. There is no previous documentation of any anti-inflammatory effects of trilostane.

Objective: The aim of this study was to elucidate the novel pharmacologic activity of trilostane in a series of inflammation and nociception signal-finding models.

Chemical and electrochemical insertion of Li into the spinel structure of CuCr2Se4: ex situ and in situ observations by X-ray diffraction and scanning electron microscopy.

The chemical and electrochemical insertion of lithium into the spinel structure of CuCr(2)Se(4) was studied and the chemical reaction pathway was followed by ex situ X-ray diffraction on samples with different Li contents. The electrochemical reaction was investigated by in situ X-ray diffraction and in situ scanning electron microscopy. In the early steps of chemical intercalation, two phases with a different Li content coexist and Cu is extruded from the host material.

Study of local structure and Li dynamics in Li(4+x)Ti(5)O(12) (0 ≤ x ≤ 5) using (6)Li and (7)Li NMR spectroscopy.

We studied the local structure and the Li ion dynamics in electrochemically and chemically prepared Li(4+x)Ti(5)O(12) with x = 0…5. We used magic-angle spinning (7)Li NMR on samples with different Li contents to investigate the sites that are occupied/emptied during Li insertion/removal. While the electrochemical measurements show a lithium insertion in two steps, 1D MAS NMR as a function of the lithium content shows that the overall spectral evolution observed during lithium insertion is inverted during lithium removal.

Anti-inflammatory and immunomodulatory effects of bortezomib in various in vivo models.

Bortezomib (Velcade®) is a proteasome inhibitor that has been approved for the treatment of multiple myeloma and mantle cell lymphoma. It has been shown to inhibit the expression of cell adhesion molecules, co-stimulatory molecules, and NFκB activation, to deplete alloreactive T lymphocytes, and to decrease Th1 cytokine production. The anti-inflammatory effects of bortezomib were further investigated in this current set of studies.

Genomic loci and candidate genes underlying inflammatory nociception.

Heritable genetic factors contribute significantly to inflammatory nociception. To determine candidate genes underlying inflammatory nociception, the current study used a mouse model of abdominal inflammatory pain. BXD recombinant inbred (RI) mouse strains were administered the intraperitoneal acetic acid test, and genome-wide quantitative trait locus (QTL) mapping was performed on the mean number of abdominal contraction and extension movements in 3 distinct groups of BXD RI mouse strains in 2 separate experiments.

An extensive phenotypic characterization of the hTNFalpha transgenic mice.

Background: Tumor necrosis factor alpha (TNFalpha) is implicated in a wide variety of pathological and physiological processes, including chronic inflammatory conditions, coronary artery disease, diabetes, obesity, and cachexia. Transgenic mice expressing human TNFalpha (hTNFalpha) have previously been described as a model for progressive rheumatoid arthritis. In this report, we describe extensive characterization of an hTNFalpha transgenic mouse line.

[The Rapunzel syndrome: rare manifestation of a trichobezoar of the upper gastrointestinal tract].

The Rapunzel syndrome is a rare manifestation of a gastric trichobezoar with a "tail" extending throughout the small intestine and sometimes even to the colon. We report on the surgical removal of such a bezoar in a 4-year-old patient by gastrotomy--the third published case in the German literature. The syndrome is mainly seen in young girls with trichophagia psychodynamically associated with early childhood deprivation and a high comorbidity of serious pediatric psychiatric disorders.

Identification of quantitative trait loci for chemical/inflammatory nociception in mice.

Sensitivity to pain is widely variable, and much of this variability is genetic in origin. The specific genes responsible have begun to be identified, but only for thermal nociception. In order to facilitate the identification of polymorphic, pain-related genes with more clinical relevance, we performed quantitative trait locus (QTL) mapping studies of the most common assay of inflammatory nociception, the formalin test.