FamEvent: An R Package for Generating and Modeling Time-to-Event Data in Family Designs

FamEvent is a comprehensive R package for simulating and modeling age-at-disease onset in families carrying a rare gene mutation. The package can simulate complex family data for variable time-to-event outcomes under three common family study designs (population, high-risk clinic and multi-stage) with various levels of missing genetic information among family members. Residual familial correlation can be induced through the inclusion of a frailty term or a second gene. Disease-gene carrier probabilities are evaluated assuming Mendelian transmission or empirically from the data. When genetic information on the disease gene is missing, an expectation-maximization algorithm is employed to calculate the carrier probabilities. Penetrance model functions with ascertainment correction adapted to the sampling design provide age-specific cumulative disease risks by sex, mutation status, and other covariates for simulated data as well as real data analysis. Robust standard errors and 95% confidence intervals are available for these estimates. Plots of pedigrees and penetrance functions based on the fitted model provide graphical displays to evaluate and summarize the models

Impairment of Autophagy After Spinal Cord Injury Potentiates Neuroinflammation and Motor Function Deficit in Mice

Autophagy is a catabolic process that degrades cytoplasmic constituents and organelles in the lysosome, thus serving an important role in cellular homeostasis and protection against insults. We previously reported that defects in autophagy contribute to neuronal cell damage in traumatic spinal cord injury (SCI). Recent data from other inflammatory models implicate autophagy in regulation of immune and inflammatory responses, with low levels of autophagic flux associated with pro-inflammatory phenotypes. In the present study, we examined the effects of genetically or pharmacologically manipulating autophagy on posttraumatic neuroinflammation and motor function after SCI in mice. Methods: Young adult male C57BL/6, CX3CR1-GFP, autophagy hypomorph Becn1+/- mice, and their wildtype (WT) littermates were subjected to moderate thoracic spinal cord contusion. Neuroinflammation and autophagic flux in the injured spinal cord were assessed using flow cytometry, immunohistochemistry, and NanoString gene expression analysis. Motor function was evaluated with the Basso Mouse Scale and horizontal ladder test. Lesion volume and spared white matter were evaluated by unbiased stereology. To stimulate autophagy, disaccharide trehalose, or sucrose control, was administered in the drinking water immediately after injury and for up to 6 weeks after SCI. Results: Flow cytometry demonstrated dysregulation of autophagic function in both microglia and infiltrating myeloid cells from the injured spinal cord at 3 days post-injury. Transgenic CX3CR1-GFP mice revealed increased autophagosome formation and inhibition of autophagic flux specifically in activated microglia/macrophages. NanoString analysis using the neuroinflammation panel demonstrated increased expression of proinflammatory genes and decreased expression of genes related to neuroprotection in Becn1+/- mice as compared to WT controls at 3 days post-SCI. These findings were further validated by qPCR, wherein we observed significantly higher expression of proinflammatory cytokines. Western blot analysis confirmed higher protein expression of the microglia/macrophage marker IBA-1, inflammasome marker, NLRP3, and innate immune response markers cGAS and STING in Becn1+/- mice at 3 day after SCI. Flow cytometry demonstrated that autophagy deficit did not affect either microglial or myeloid counts at 3 days post-injury, instead resulting in increased microglial production of proinflammatory cytokines. Finally, locomotor function showed significantly worse impairments in Becn1+/- mice up to 6 weeks after SCI, which was accompanied by worsening tissue damage. Conversely, treatment with a naturally occurring autophagy inducer trehalose, reduced protein levels of p62, an adaptor protein targeting cargo to autophagosomes as well as the NLRP3, STING, and IBA-1 at 3 days post-injury. Six weeks of trehalose treatment after SCI led to improved motor function recovery as compared to control group, which was accompanied by reduced tissue damage. Conclusions: Our data indicate that inhibition of autophagy after SCI potentiates pro-inflammatory activation in microglia and is associated with worse functional outcomes. Conversely, increasing autophagy with trehalose, decreased inflammation and improved outcomes. These findings highlight the importance of autophagy in spinal cord microglia and its role in secondary injury after SCI

The value of the sacroiliac joint area as a new morphological parameter of ankylosing spondylitis.

A narrowed sacroiliac joint (SIJ) space has been considered to be a major morphologic parameter of ankylosing spondylitis (AS). Previous studies revealed that the sacroiliac joint thickness (SIJT) correlated with AS in patients. However, irregular narrowing is different from thickness. Thus, we devised a method using the sacroiliac joint cross-sectional area (SIJA) as a new morphological parameter for use in evaluating AS. We hypothesized that the SIJA is a key morphologic parameter in diagnosing AS. SIJ samples were collected from 107 patients with AS, and from 85 control subjects who underwent SIJ-view X-rays that revealed no evidence of AS. We measured the SIJT and SIJA at the SIJ margin on X-rays using our picture archiving and communications system. The SIJT was measured at the narrowest point between the sacrum and the ilium. The SIJA was measured as the entire cross-sectional joint space area of the SIJ in the X-ray images. The average SIJT was 3.09 ± 0.61 mm in the control group, and 1.59 ± 0.52 mm in the AS group. The average SIJA was 166.74 ± 39.98 mm2 in the control group, and 68.65 ± 24.11 mm2 in the AS group. AS patients had significantly lower SIJT (P < .001) and SIJA (P < .001) than the control subjects. Receiver operating characteristics curve analysis showed that the best cutoff point for the SIJT was 2.33 mm, with 92.5% sensitivity, 94.1% specificity, and an area under the curve of 0.97 (95% confidence interval: 0.95-0.99). The optimal cutoff point for the SIJA was 106.19 mm2, with 93.5% sensitivity, 95.3% specificity, and an area under the curve of 0.98 (95% confidence interval: 0.97-1.00). Although the SIJT and SIJA were both significantly associated with AS, the SIJA parameter was a more sensitive measurement. We concluded that the SIJA is an easy-to-use, fast, cheap, and useful new morphological parameter for predicting AS

FAK Promotes Early Osteoprogenitor Cell Proliferation by Enhancing mTORC1 Signaling

Focal adhesion kinase (FAK) has important functions in bone homeostasis but its role in early osteoprogenitor cells is unknown. We show herein that mice lacking FAK in Dermo1- expressing cells exhibited low bone mass and decreased osteoblast number. Mechanistically, FAK- deficient early osteoprogenitor cells had decreased proliferation and significantly reduced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, a central regulator of cell growth and proliferation. Furthermore, our data showed that the pharmacological inhibition of FAK kinase- dependent function alone was sufficient to decrease the proliferation and compromise the mineralization of early osteoprogenitor cells. In contrast to the Fak deletion in early osteoprogenitor cells, FAK loss in Col3.6 Cre- targeted osteoblasts did not cause bone loss, and Fak deletion in osteoblasts did not affect proliferation, differentiation, and mTORC1 signaling but increased the level of active proline- rich tyrosine kinase 2 (PYK2), which belongs to the same non- receptor tyrosine kinase family as FAK. Importantly, mTORC1 signaling in bone marrow stromal cells (BMSCs) was reduced if FAK kinase was inhibited at the early osteogenic differentiation stage. In contrast, mTORC1 signaling in BMSCs was not affected if FAK kinase was inhibited at a later osteogenic differentiation stage, in which, however, the concomitant inhibition of both FAK kinase and PYK2 kinase reduced mTORC1 signaling. In summary, our data suggest that FAK promotes early osteoprogenitor cell proliferation by enhancing mTORC1 signaling via its kinase- dependent function and the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2. © 2020 American Society for Bone and Mineral Research.Schematic model of the differential roles of FAK in the cells of osteoblast lineage. The model depicts the mechanisms of FAK action at three distinct stages of osteoblast lineage in which the roles of FAK have been addressed by genetic and pharmacological approaches as well as the respective Cre transgenes used to target Fak, including Dermo1- Cre (this study), Osterix- Cre,(10) Col3.6- Cre (this study), and Col2.3- Cre.(9) Red - indicates that the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/3/jbmr4029-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/2/jbmr4029_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/1/jbmr4029.pd

Extraction of Electron Self-Energy and Gap Function in the Superconducting State of Bi_2Sr_2CaCu_2O_8 Superconductor via Laser-Based Angle-Resolved Photoemission

Super-high resolution laser-based angle-resolved photoemission measurements have been performed on a high temperature superconductor Bi_2Sr_2CaCu_2O_8. The band back-bending characteristic of the Bogoliubov-like quasiparticle dispersion is clearly revealed at low temperature in the superconducting state. This makes it possible for the first time to experimentally extract the complex electron self-energy and the complex gap function in the superconducting state. The resultant electron self-energy and gap function exhibit features at ~54 meV and ~40 meV, in addition to the superconducting gap-induced structure at lower binding energy and a broad featureless structure at higher binding energy. These information will provide key insight and constraints on the origin of electron pairing in high temperature superconductors.Comment: 4 pages, 4 figure

SARS-CoV-2 Omicron variant causes brain infection with lymphoid depletion in a mouse COVID-19 model

Background The Omicron variant has become the most prevalent SARS-CoV-2 variant. Omicron is known to induce milder lesions compared to the original Wuhan strain. Fatal infection of the Wuhan strain into the brain has been well documented in COVID-19 mouse models and human COVID-19 cases, but apparent infections into the brain by Omicron have not been reported in human adult cases or animal models. In this study, we investigated whether Omicron could spread to the brain using K18-hACE2 mice susceptible to SARS-CoV-2 infection. Results K18-hACE2 mice were intranasally infected with 1 × 105 PFU of the original Wuhan strain and the Omicron variant of SARS-CoV-2. A follow-up was conducted 7days post infection. All Wuhan-infected mice showed > 20% body weight loss, defined as the lethal condition, whereas two out of five Omicron-infected mice (40%) lost > 20% body weight. Histopathological analysis based on H&E staining revealed inflammatory responses in the brains of these two Omicron-infected mice. Immunostaining analysis of viral nucleocapsid protein revealed severe infection of neuron cells in the brains of these two Omicron-infected mice. Lymphoid depletion and apoptosis were observed in the spleen of Omicron-infected mice with brain infection. Conclusion Lethal conditions, such as severe body weight loss and encephalopathy, can occur in Omicron-infected K18-hACE2 mice. Our study reports, for the first time, that Omicron can induce brain infection with lymphoid depletion in the mouse COVID-19 model

GSTM1 and GSTP1 Polymorphisms as Potential Factors for Modifying the Effect of Smoking on Inflammatory Response

Inflammation has been known to be an important underlying condition for development of various diseases including cancer. The aims of this study were to investigate whether tobacco smoke exposure increases the level of inflammation biomarkers and the GSTM1 and GSTP1 gene polymorphisms are associated with inflammatory response due to tobacco smoke exposure. We measured urinary cotinine level in 300 healthy university students. Total serum TNF-α levels and blood WBC counts were determined to evaluate inflammatory response. Allelic loss of the GSTM1 and the GSTP1 (Ile105Val) polymorphism were determined by PCR and RFLP. Tobacco smoke exposure was found to be associated with increase of both TNF-α level and WBC count. Particularly, smokers with combination of GSTM1 null and GSTP1 AG or GG genotypes showed higher TNF-α level than those with the other genotype combinations (p=0.07). This result suggests that smoking may induce inflammation measured as TNF-α level or WBC count and combinations of the GSTM1 and GSTP1 polymorphisms may modify the effect of smoking on serum TNF-α level

Ginsenoside Rd and ischemic stroke; a short review of literatures

Panax ginseng is a well-known economic medical plant which is broadly used in Chinese traditional medicine. This species contains unique class of natural products, namely ginsenosides. Recent clinical and experimental studies lined a plethora of evidences up for the promising role of ginsenosides on different diseases including neurodegenerative, cardiovascular, certain types of cancer, etc. Nowadays, much attention has been paid to ginsenoside Rd as neuroprotective agent to attenuate ischemic stroke damages. Several evidences reported that ginsenoside Rd ameliorate ischemic stroke-induced damages through the suppression of oxidative stress and inflammation. Ginsenoside Rd can prolong neural cells survival through up-regulation of endogenous antioxidant system, PI3K/AKT and ERK1/2 pathways, preservation of mitochondrial membrane potential, suppression of the nuclear factor (NF)-Kappa B, transient receptor potential melastatin, acid sensing ion channels 1a, Poly (ADP-ribose) polymerase-1, protein tyrosine kinase activation, as well as decreasing of cytochrome-C releasing and apoptosis-inducing factor. In the current work, we review the available reports on the promising role of ginsenoside Rd on ischemic stroke. We also discuss about its chemistry, source and molecular mechanism underlying this effects

Fabrication of Copper Window Electrodes with ≈10⁸Apertures cm⁻² for Organic Photovoltaics

A powerful approach to increasing the far‐field transparency of copper film window electrodes which simultaneously reduces intraband absorption losses for wavelengths 550 nm is reported. The approach is based on incorporation of a random array of ≈100 million circular apertures per cm2 into an optically thin copper film, with a mean aperture diameter of ≈500 nm. A method for the fabrication of these electrodes is described that exploits a binary polymer blend mask that self‐organizes at room temperature from a single solution, and so is simple to implement. Additionally all of the materials used in electrode fabrication are low cost, low toxicity, and widely available. It is shown that these nanostructured copper electrodes offer an average far‐field transparency of ≥80% and sheet resistance of ≤10 Ω sq−1 when used in conjunction with a conventional solution processed ZnO electron transport layer and their utility in inverted organic photovoltaic devices is demonstrated

Endoplasmic Reticulum Stress Pathway-Mediated Apoptosis in Macrophages Contributes to the Survival of Mycobacterium tuberculosis

BACKGROUND: Apoptosis is thought to play a role in host defenses against intracellular pathogens, including Mycobacterium tuberculosis (Mtb), by preventing the release of intracellular components and the spread of mycobacterial infection. This study aims to investigate the role of endoplasmic reticulum (ER) stress mediated apoptosis in mycobacteria infected macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that ER stress-induced apoptosis is associated with Mtb H37Rv-induced cell death of Raw264.7 murine macrophages. We have shown that Mtb H37Rv induced apoptosis are involved in activation of caspase-12, which resides on the cytoplasmic district of the ER. Mtb infection increase levels of other ER stress indicators in a time-dependent manner. Phosphorylation of eIF2α was decreased gradually after Mtb H37Rv infection signifying that Mtb H37Rv infection may affect eIF2α phosphorylation in an attempt to survive within macrophages. Interestingly, the survival of mycobacteria in macrophages was enhanced by silencing CHOP expression. In contrast, survival rate of mycobacteria was reduced by phosphorylation of the eIF2α. Futhermore, the levels of ROS, NO or CHOP expression were significantly increased by live Mtb H37Rv compared to heat-killed Mtb H37Rv indicating that live Mtb H37Rv could induce ER stress response. CONCLUSION/SIGNIFICANCE: These findings indicate that eIF2α/CHOP pathway may influence intracellular survival of Mtb H37Rv in macrophages and only live Mtb H37Rv can induce ER stress response. The data support the ER stress pathway plays an important role in the pathogenesis and persistence of mycobacteria