Genes for Good: Engaging the Public in Genetics Research via Social Media.

The Genes for Good study uses social media to engage a large, diverse participant pool in genetics research and education. Health history and daily tracking surveys are administered through a Facebook application, and participants who complete a minimum number of surveys are mailed a saliva sample kit ("spit kit") to collect DNA for genotyping. As of March 2019, we engaged >80,000 individuals, sent spit kits to >32,000 individuals who met minimum participation requirements, and collected >27,000 spit kits. Participants come from all 50 states and include a diversity of ancestral backgrounds. Rates of important chronic health indicators are consistent with those estimated for the general U.S. population using more traditional study designs. However, our sample is younger and contains a greater percentage of females than the general population. As one means of verifying data quality, we have replicated genome-wide association studies (GWASs) for exemplar traits, such as asthma, diabetes, body mass index (BMI), and pigmentation. The flexible framework of the web application makes it relatively simple to add new questionnaires and for other researchers to collaborate. We anticipate that the study sample will continue to grow and that future analyses may further capitalize on the strengths of the longitudinal data in combination with genetic information.

Myxoma virus induces type I interferon production in murine plasmacytoid dendritic cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-dependent pathway.

Poxviruses are large DNA viruses that replicate in the cytoplasm of infected cells. Myxoma virus is a rabbit poxvirus that belongs to the Leporipoxvirus genus. It causes a lethal disease called myxomatosis in European rabbits but cannot sustain any detectable infection in nonlagomorphs. Vaccinia virus is a prototypal orthopoxvirus that was used as a vaccine to eradicate smallpox. Myxoma virus is nonpathogenic in mice, whereas systemic infection with vaccinia virus can be lethal even in immunocompetent mice. Plasmacytoid dendritic cells (pDCs) are potent type I interferon (IFN)-producing cells that play important roles in antiviral innate immunity. How poxviruses are sensed by pDCs to induce type I IFN production is not well understood. Here we report that infection of primary murine pDCs with myxoma virus, but not with vaccinia virus, induces IFN-α, IFN-ß, tumor necrosis factor (TNF), and interleukin-12p70 (IL-12p70) production. Using pDCs derived from genetic knockout mice, we show that the myxoma virus-induced innate immune response requires the endosomal DNA sensor TLR9 and its adaptor MyD88, transcription factors IRF5 and IRF7, and the type I IFN positive-feedback loop mediated by IFNAR1. It is independent of the cytoplasmic RNA sensing pathway mediated by the mitochondrial adaptor molecule MAVS, the TLR3 adaptor TRIF, or the transcription factor IRF3. Using pharmacological inhibitors, we demonstrate that myxoma virus-induced type I IFN and IL-12p70 production in murine pDCs is also dependent on phosphatidylinositol 3-kinase (PI3K) and Akt. Furthermore, our results reveal that the N-terminal Z-DNA/RNA binding domain of vaccinia virulence factor E3, which is missing in the orthologous M029 protein expressed by myxoma virus, plays an inhibitory role in poxvirus sensing and innate cytokine production by murine pDCs.

Vaccinia virus subverts a mitochondrial antiviral signaling protein-dependent innate immune response in keratinocytes through its double-stranded RNA binding protein, E3.

Skin keratinocytes provide a first line of defense against invading microorganisms in two ways: (i) by acting as a physical barrier to pathogen entry and (ii) by initiating a vigorous innate immune response upon sensing danger signals. How keratinocytes detect virus infections and generate antiviral immune responses is not well understood. Orthopoxviruses are dermatotropic DNA viruses that cause lethal disease in humans. Virulence in animal models depends on the virus-encoded bifunctional Z-DNA/double-stranded RNA (dsRNA)-binding protein E3. Here, we report that infection of mouse primary keratinocytes with a vaccinia DeltaE3L mutant virus triggers the production of beta interferon (IFN-beta), interleukin-6 (IL-6), CCL4, and CCL5. None of these immune mediators is produced by keratinocytes infected with wild-type vaccinia virus. The dsRNA-binding domain of E3 suffices to prevent activation of the innate immune response. DeltaE3L induction of IFN-beta, IL-6, CCL4, and CCL5 secretion requires mitochondrial antiviral signaling protein (MAVS; an adaptor for the cytoplasmic viral RNA sensors RIG-I and MDA5) and the transcription factor IRF3. IRF3 phosphorylation is induced in keratinocytes infected with DeltaE3L, an event that depends on MAVS. The response of keratinocytes to DeltaE3L is unaffected by genetic ablation of Toll-like receptor 3 (TLR3), TRIF, TLR9, and MyD88.

Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism.

Clinical observations suggest that abnormalities within the cerebellum and/or the cerebellum--cholinergic forebrain connections may be key to explain the severe behavioral deficits and increases in seizures seen in autism. In order to explore functional relationships between brain areas implicated in many of the core behavioral features of autism, experiments utilizing animal models for specific autism-like behaviors have increased in recent years. In the current study, we used a rodent model for the autism-like behavior of environment exploration deficits to examine the role of the cerebellum and its connectivity to the forebrain. In addition, due to the possible common neural pathways between seizures and autism-like behaviors, we explored the possibility for limiting autism-like behaviors via antiseizure brainstem and cerebellar circuitry. In two experiments, adult male rats showed a significant decrease in exploration behavior following developmental cerebellar suction lesions (experiment 1) or i.c.v. saporin injections specifically targeting Purkinje cells, but not after the addition of saporin-induced cholinergic forebrain lesions (experiment 2). In both experiments, the anticonvulsant treatment of inhibition of the medullary nucleus tractus solitarius (NTS) restored exploration behavior to control levels. These findings suggest that specific neuronal populations within the cerebellum are responsible for mediating exploration behavior, and these neuronal populations are similar to the circuitry involved in limbic motor seizures in that they are sensitive to brainstem inhibition. Furthermore, these results suggest this connection could be utilized in order to control behavioral deficits seen in autism with treatments, such as vagal nerve stimulation, which are effective against pharmaco-resistant seizures.

Amyopathic dermatomyositis or dermatomyositis-like skin disease: retrospective review of 16 cases with amyopathic dermatomyositis.

Amyopathic dermatomyositis (ADM) is characterized by the presence of dermatomyositis (DM) for 6 months or more in individuals who have normal muscle enzymes and no clinically significant muscle weakness. The aim of the study was to investigate the initial laboratory data, clinical manifestations, complications, and clinical outcomes of patients with the diagnosis of ADM. We reported 16 cases with the cutaneous findings of dermatomyositis without clinical or laboratory evidence of muscle disease for at least 2 years after onset of the skin manifestations in the Department of Dermatology and Rheumatology at Shanghai Ruijin Hospital between 1998 and 2004. All patients had Gottron's papules, periungual erythema/telangiectasia, and violaceous discoloration of the face, neck, upper chest, and back at some time during the course of their disease. Follow-up of 1 to 10 years after diagnosis found muscle weakness in three patients (18.75%) within 5 years of diagnosis. One patient (6.15%) was rediagnosed as chronic cutaneous lupus erythematosus (CCLE). Four patients (25%) had associated malignancies. Twelve patients (75%) had radiographic evidence indicative of interstitial fibrosis irrespective of respiratory symptoms. Patients with ADM appear to be at risk for developing the same potentially fatal disease complications as those patients with DM (e.g., interstitial lung disease and internal malignancy). These cases further emphasize that the cutaneous manifestations of dermatomyositis are pathognomonic for DM and we propose the term dermatomyositis-like skin disease as a better designation than amyopathic dermatomyositis to describe this distinctive subset of cutaneous symptoms. Dermatomyositis-like skin disease is a complex syndrome, which includes the characteristic cutaneous eruption of dermatomyositis without clinical evidence of muscle disease. Our findings suggest that patients diagnosed with this syndrome are at risk for fatal interstitial lung disease, malignancy, and/or delayed onset of DM or CCLE. Cautious systematic clinical trials should be considered for this group of patients.