Reliability Modeling for Humidity Sensors Subject to Multiple Dependent Competing Failure Processes with Self-Recovery.

Recent developments in humidity sensors have heightened the need for reliability. Seeing as many products such as humidity sensors experience multiple dependent competing failure processes (MDCFPs) with self-recovery, this paper proposes a new general reliability model. Previous research into MDCFPs has primarily focused on the processes of degradation and random shocks, which are appropriate for most products. However, the existing reliability models for MDCFPs cannot fully characterize the failure processes of products such as humidity sensors with significant self-recovery, leading to an underestimation of reliability. In this paper, the effect of self-recovery on degradation was analyzed using a conditional probability. A reliability model for soft failure with self-recovery was obtained. Then, combined with the model of hard failure due to random shocks, a general reliability model with self-recovery was established. Finally, reliability tests of the humidity sensors were presented to verify the proposed reliability model. Reliability modeling for products subject to MDCFPs with considering self-recovery can provide a better understanding of the mechanism of failure and offer an alternative method to predict the reliability of products.

10-Year observation of a rare presentation of pure fibromyxoid nephrogenic adenoma in the renal pelvis.

Nephrogenic adenoma (NA) is an unusual benign epithelial tumor in the genitourinary tract. Here we report a fibromyxoid nephrogenic adenoma in a 37-year-old female presenting with over 10-year slow-growing renal pelvic mass that was diagnosed with bland spindle cell lesion in multiple previous biopsies. This is the first reported case of pure fibromyxoid NA in renal pelvis with close comparison and correlation of biopsy and resection findings over a 10-year span. This will enhance awareness of pathologists to consider this unusual entity when examining spindle cell lesions in this setting, and prevent misdiagnosis and overtreatment of a typically benign process.

The Double-Edged Sword Effect of Paradoxical Leadership to Organizational Citizenship Behavior.

Purpose: Drawing on social exchange theory and attribution theory, this study aims to explore the influencing mechanism of paradoxical leadership on organizational citizenship behavior. Participants and Methods: According to the research purpose, this study selects enterprises in the manufacturing, financial and high-tech industries in Shandong Province as the research objects, and collects data on the leaders and employees of the human resources departments and marketing departments in the enterprises. Data were collected from 77 leaders and 473 employees in China by a two-wave questionnaire survey. Hierarchical regression analysis and structural equation model approach were employed to test hypotheses. Results: This study found that perceived insider status and psychological entitlement play mediating roles about paradoxical leadership and organizational citizenship behavior; Collectivism moderates the relationship between paradoxical leadership and perceived insider status, and moderates the positive mediating role played by perceived insider status in the relationship of paradoxical leadership and organizational citizenship behavior; Leader-member exchange differentiation moderates the relationship about paradoxical leadership and psychological entitlement, and moderates negative mediating role played by psychological entitlement in the relationship of paradoxical leadership's and organizational citizenship behavior. Conclusion: The findings of this study offer guidance for managers to better undermine the negative effects of paradoxical leadership, and improve organizational citizenship behavior. Innovations: First, this study extends the literature on paradoxical leadership by verifying the double-edged sword effect of paradoxical leadership to organizational citizenship behavior. Second, this study enriches one's understanding of the "black box" underlying the link between paradoxical leadership and its consequences by demonstrating the mediating roles of perceived insider status and psychological entitlement. Third, by verifying the moderating roles of collectivism and leader-member exchange differentiation, this study provides insights into the boundary conditions of the impact of paradoxical leadership.

Altered H3 histone acetylation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7.

A common mechanism in inherited ataxia is a vulnerability of DNA damage. Spinocerebellar ataxia type 7 (SCA7) is a CAG-polyglutamine-repeat disorder characterized by cerebellar and retinal degeneration. Polyglutamine-expanded ataxin-7 protein incorporates into STAGA co-activator complex and interferes with transcription by altering histone acetylation. We performed chromatic immunoprecipitation sequencing ChIP-seq on cerebellum from SCA7 mice and observed increased H3K9-promoter acetylation in DNA repair genes, resulting in increased expression. After detecting increased DNA damage in SCA7 cells, mouse primary cerebellar neurons, and patient stem-cell-derived neurons, we documented reduced homology-directed repair (HDR) and single-strand annealing (SSA). To evaluate repair at endogenous DNA in native chromosome context, we modified linear amplification-mediated high-throughput genome-wide translocation sequencing and found that DNA translocations are less frequent in SCA7 models, consistent with decreased HDR and SSA. Altered DNA repair function in SCA7 may predispose the subject to excessive DNA damage, leading to neuron demise and highlights DNA repair as a therapy target.

Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7.

Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase capable of countering age-related neurodegeneration, but the basis of Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited CAG-polyglutamine repeat disorder. Transcriptome analysis of SCA7 mice revealed downregulation of calcium flux genes accompanied by abnormal calcium-dependent cerebellar membrane excitability. Transcription-factor binding-site analysis of downregulated genes yielded Sirt1 target sites, and we observed reduced Sirt1 activity in the SCA7 mouse cerebellum with NAD+ depletion. SCA7 patients displayed increased poly(ADP-ribose) in cerebellar neurons, supporting poly(ADP-ribose) polymerase-1 upregulation. We crossed Sirt1-overexpressing mice with SCA7 mice and noted rescue of neurodegeneration and calcium flux defects. NAD+ repletion via nicotinamide riboside ameliorated disease phenotypes in SCA7 mice and patient stem cell-derived neurons. Sirt1 thus achieves neuroprotection by promoting calcium regulation, and NAD+ dysregulation underlies Sirt1 dysfunction in SCA7, indicating that cerebellar ataxias exhibit altered calcium homeostasis because of metabolic dysregulation, suggesting shared therapy targets.

Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.

Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7.

Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar and retinal degeneration, and is caused by a CAG-polyglutamine repeat expansion in the ATAXIN-7 gene. Patients with SCA7 develop progressive cone-rod dystrophy, typically resulting in blindness. Antisense oligonucleotides (ASOs) are single-stranded chemically modified nucleic acids designed to mediate the destruction, prevent the translation, or modify the processing of targeted RNAs. Here, we evaluated ASOs as treatments for SCA7 retinal degeneration in representative mouse models of the disease after injection into the vitreous humor of the eye. Using Ataxin-7 aggregation, visual function, retinal histopathology, gene expression, and epigenetic dysregulation as outcome measures, we found that ASO-mediated Ataxin-7 knockdown yielded improvements in treated SCA7 mice. In SCA7 mice with retinal disease, intravitreal injection of Ataxin-7 ASOs also improved visual function despite initiating treatment after symptom onset. Using color fundus photography and autofluorescence imaging, we also determined the nature of retinal degeneration in human SCA7 patients. We observed variable disease severity and cataloged rapidly progressive retinal degeneration. Given the accessibility of neural retina, availability of objective, quantitative readouts for monitoring therapeutic response, and the rapid disease progression in SCA7, ASOs targeting ATAXIN-7 might represent a viable treatment for SCA7 retinal degeneration.

Identification of protein kinase C isoforms involved in cerebral hypoxic preconditioning of mice.

Recently, accumulated studies have suggested that protein kinases C (PKC) play a central role in the development of ischemic-hypoxic preconditioning (I/HPC) in the brain. However, which types of PKC isoforms might be responsible for neuroprotection is still not clear, especially when the systematic investigation of PKC isoform-specific changes in brain regions was rare in animals with ischemic-hypoxic preconditioning. By using Western blot, we have demonstrated that the levels of cPKC betaII and gamma membrane translocation were increased in the early phase of cerebral hypoxic preconditioning. In this study, we combined the Western blot and immunostaining methods to investigate the effects of repetitive hypoxic exposure (H1-H4, n = 6 for each group) on membrane translocation and protein expression of several types of PKC isoforms, both in the cortex and hippocampus of mice. We found that the increased membrane translocation of nPKCepsilon (P < 0.05, versus normoxic H0) but not its protein expression levels in both the cortex and hippocampus during development of cerebral HPC in mice. However, there were no significant changes in both membrane translocation and protein expression levels of nPKCdelta, theta, eta, mu, and aPKC iota/lambda, zeta in these brain areas after hypoxic preconditioning. Similarly, an extensive subcellular redistribution of cPKCbetaII, gamma, and nPKCepsilon was observed by immunostaining in the cortex after three series of hypoxic exposures (H3). These results indicate that activation of cPKCbetaII, gamma, and nPKCepsilon might be involved in the development of cerebral hypoxic preconditioning of mice.

Changes in cPKC isoform-specific membrane translocation and protein expression in the brain of hypoxic preconditioned mice.

Previous studies have shown that the level of total conventional protein kinase C (cPKC) membrane translocation (activation) was increased in the brain of hypoxic preconditioned mice. In order to find out which isoform of cPKC may participate in the development of cerebral hypoxic preconditioning (HPC), we used Western bolt and immunohistochemistry to observe the effects of repetitive hypoxic exposure (H1-H6, n = 6 for each group) on the level of cPKC isoform-specific protein expression and its membrane translocation in the cortex and hippocampus of mice. We found that the levels of cPKC betaII and gamma membrane translocation were increased significantly (p < 0.05 versus normoxic H0 group, n = 6) in response to repetitive hypoxic exposure (H1-H4) at an early phase of hypoxic preconditioning, but no significant changes of cPKC alpha and betaI membrane translocation were found during cPKC alpha, betaI, betaII and gamma protein expression both in hippocampus and cortex. In addition, an extensive subcellular redistribution of cPKC betaII and gamma was detected by immunohistochemistry staining in the cortex after repetitive hypoxic exposures (H3). However, a significant decrease in the expression of cPKC gamma protein (p < 0.05 versus H0 group) was found only in the cortex of delayed hypoxic preconditioned mice (H5-H6). These results suggest that the activation of cPKC betaII and gamma may be involved in the early phase of cerebral hypoxic preconditioning and the changes in cPKC gamma protein expression may participate in the development of the late phase of cerebral hypoxic preconditioning as well as selective vulnerability to hypoxia both in cortex and hippocampus.

Neuroprotective signaling mechanisms of telomerase are regulated by brain-derived neurotrophic factor in rat spinal cord motor neurons.

Telomerase can promote neuron survival and can be regulated by growth factors such as brain-derived neurotrophic factor (BDNF). Increases of BDNF expression and telomerase activity after brain injury suggest that telomerase may be involved in BDNF-mediated neuroprotection. We investigated BDNF regulation of telomerase in rat spinal cord motor neurons (SMNs). Our results indicate that BDNF increases telomerase expression and activity levels in SMNs and activates mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2 and phosphatidylinositol-3-OH kinase/protein kinase B signals, and their downstream transcription factors nuclear factor-κB, c-Myc, and Sp1. Administration of the tyrosine kinase receptor B inhibitor K-252a, the mitogen-activated protein kinase 1 inhibitor PD98059, and the phosphatidylinositol-3-OH kinase inhibitor LY294002 abolished BDNF-induced upregulation of these transcription factors and telomerase expression. The nuclear factor-κB inhibitor Bay11-7082 also attenuated c-Myc and Sp1 expression and increased telomerase promoter activity. Spinal cord motor neurons with higher telomerase levels induced by BDNF became more resistant to apoptosis; survival of SMNs that overexpressed the catalytic protein component of telomerase with reverse transcriptase activity was also enhanced against apoptosis. The neuronal survival-promoting effect of telomerase was mediated through the regulation of Bcl-2, Bax, p53, and maintenance of mitochondrial membrane potential. Taken together, these data suggest that the neuroprotective effect of BDNF via telomerase is mediated by inhibition of apoptotic pathways.

[Effect of repetitive hypoxia on MMP-2/9 expression and activation in murine brain].

AIM: To explore the changes of MMP-2/9 protein expression and excitation in brain of repetitive hypoxic mice. METHODS: The biochemistry techniques of SDS-PAGE, Western bolt and Gel Goc Image Analysis System were applied to determine the level of MMP-2 and MMP-9 expression and activation in cortex and hippocampus of mice. The animals were randomly divided into 5 groups: the normal control group (H0), acute hypoxic (H1, hypoxic exposure once), repetitive hypoxic groups (H2-H4, repetitive hypoxia for 2-4 runs respectively). RESULTS: (1) The MMP- 2 expression level was increased first then decreased in hippocampus and the significant decrease was found in H4 group (P < 0.05, n=6), but no significant changes among the 5 groups in cortex. In addition, no activated form of 66 kD MMP-2 had been detected both in hippocampus and cortex. (2) Along with the development of brain hypoxic preconditioning, the level MMP-9 protein expression also increased first then decreased gradually in hippocampus, and the significant changes were found both in H1 and H4 groups (P < 0.05, n=7 for each group). The same trace of changes was also found in the activation of MMP-9 (include 82 and 78 kD forms) in hippocampus, and the significance both in H1 and H4 (P < 0.05, n=7 for each group) were detected. However, there was not any significant change in the level of MMP-9 protein expression or activation to be found in cortex. CONCLUSION: These results suggested that MMP-2 and MMP-9 might play certain role in the development of cerebral hypoxic preconditioning, the different changes of MMP-2/9 protein expression and activation both in cortex and hippocampus might be involved in their selective vulnerability to hypoxia.