Runtime Distributions and Criteria for Restarts

Randomized algorithms sometimes employ a restart strategy. After a certain number of steps, the current computation is aborted and restarted with a new, independent random seed. In some cases, this results in an improved overall expected runtime. This work introduces properties of the underlying runtime distribution which determine whether restarts are advantageous. The most commonly used probability distributions admit the use of a scale and a location parameter. Location parameters shift the density function to the right, while scale parameters affect the spread of the distribution. It is shown that for all distributions scale parameters do not influence the usefulness of restarts and that location parameters only have a limited influence. This result simplifies the analysis of the usefulness of restarts. The most important runtime probability distributions are the log-normal, the Weibull, and the Pareto distribution. In this work, these distributions are analyzed for the usefulness of restarts. Secondly, a condition for the optimal restart time (if it exists) is provided. The log-normal, the Weibull, and the generalized Pareto distribution are analyzed in this respect. Moreover, it is shown that the optimal restart time is also not influenced by scale parameters and that the influence of location parameters is only linear

The Antidepressant and Anxiolytic Effects of Cannabinoids in Chronic Unpredictable Stress: A Preclinical Systematic Review and Meta-Analysis

Neuroscience research presents contradictory evidence in support of both the protective and destructive effects of cannabinoids in depression. Therefore, this systematic review and meta-analysis summarizes the existing preclinical literature on the effects of cannabinoid administration in the chronic unpredictable stress model of depression in order to evaluate the effects of cannabinoids and identify gaps in the literature. After protocol registration (PROSPERO #CRD42020219986), we systematically searched Scopus, Embase, Psychology & Behavioral Sciences Collection, APA PsychINFO, PubMed, CINAHL Complete, and ProQuest Dissertations & Theses Global from the earliest record of the databases, February 1964, to November 2020 for articles that met inclusion criteria (e.g., rodent subjects and administration of a cannabinoid. A total of 26 articles were included representing a sample size estimate of 1132 rodents with the majority of articles administering daily intraperitoneal injections during chronic unpredictable stress. These articles were evaluated using a modified SYRCLE\u27s risk-of-bias tool. For each continuous behavioral measure, the standardized mean difference was calculated between cannabinoid and vehicle groups in rodents subjected to chronic unpredictable stress. The effects of cannabinoids on depressive-like behavior was evaluated using a multilevel mixed-effects model with effect size weights nested within control groups. Cannabinoid administration moderately improved the pooled negative effects of chronic unpredictable stress on anhedonia, learned helplessness, novelty suppressed feeding, time in the anxiogenic context, and entries into the anxiogenic context. Although the interpretations are limited, these findings suggest that with further investigation, cannabinoids may be a viable long-term treatment for stress-related psychopathologies such as depression

The Transition from Proliferation to Differentiation Is Delayed in Satellite Cells from Mice Lacking MyoD

AbstractSatellite cells from adult rat muscle coexpress proliferating cell nuclear antigen and MyoD upon entry into the cell cycle, suggesting that MyoD plays a role during the recruitment of satellite cells. Moreover, the finding that muscle regeneration is compromised in MyoD−/− mice, has provided evidence for the role of MyoD during myogenesis in adult muscle. In order to gain further insight into the role of MyoD during myogenesis in the adult, we compared satellite cells from MyoD−/− and wildtype mice as they progress through myogenesis in single-myofiber cultures and in tissue-dissociated cell cultures (primary cultures). Satellite cells undergoing proliferation and differentiation were traced immunohistochemically using antibodies against various regulatory proteins. In addition, an antibody against the mitogen-activated protein kinases ERK1 and ERK2 was used to localize the cytoplasm of the fiber-associated satellite cells regardless of their ability to express specific myogenic regulatory factor proteins. We show that during the initial days in culture the myofibers isolated from both the MyoD−/− and the wildtype mice contain the same number of proliferating, ERK+ satellite cells. However, the MyoD−/− satellite cells continue to proliferate and only a very small number of cells transit into the myogenin+ state, whereas the wildtype cells exit the proliferative compartment and enter the myogenin+ stage. Analyzing tissue-dissociated cultures of MyoD−/− satellite cells, we identified numerous cells whose nuclei were positive for the Myf5 protein. In contrast, quantification of Myf5+ cells in the wildtype cultures was difficult due to the low level of Myf5 protein present. The Myf5+ cells in the MyoD−/− cultures were often positive for desmin, similar to the MyoD+ cells in the wildtype cultures. Myogenin+ cells were identified in the MyoD−/− primary cultures, but their appearance was delayed compared to the wildtype cells. These “delayed” myogenin+ cells can express other differentiation markers such as MEF2A and cyclin D3 and fuse into myotubes. Taken together, our studies suggest that the presence of MyoD is critical for the normal progression of satellite cells into the myogenin+, differentiative state. It is further proposed that the Myf5+/MyoD− phenotype may represent the myogenic stem cell compartment which is capable of maintaining the myogenic precursor pool in the adult muscle

Financial Incentive Increases CPAP Acceptance in Patients from Low Socioeconomic Background

OBJECTIVE: We explored whether financial incentives have a role in patients' decisions to accept (purchase) a continuous positive airway pressure (CPAP) device in a healthcare system that requires cost sharing. DESIGN: Longitudinal interventional study. PATIENTS: The group receiving financial incentive (n = 137, 50.8±10.6 years, apnea/hypopnea index (AHI) 38.7±19.9 events/hr) and the control group (n = 121, 50.9±10.3 years, AHI 39.9±22) underwent attendant titration and a two-week adaptation to CPAP. Patients in the control group had a co-payment of $330-660; the financial incentive group paid a subsidized price of$55. RESULTS: CPAP acceptance was 43% greater (p = 0.02) in the financial incentive group. CPAP acceptance among the low socioeconomic strata (n = 113) (adjusting for age, gender, BMI, tobacco smoking) was enhanced by financial incentive (OR, 95% CI) (3.43, 1.09-10.85), age (1.1, 1.03-1.17), AHI (>30 vs. <30) (4.87, 1.56-15.2), and by family/friends who had positive experience with CPAP (4.29, 1.05-17.51). Among average/high-income patients (n = 145) CPAP acceptance was affected by AHI (>30 vs. <30) (3.16, 1.14-8.75), living with a partner (8.82, 1.03-75.8) but not by the financial incentive. At one-year follow-up CPAP adherence was similar in the financial incentive and control groups, 35% and 39%, respectively (p = 0.82). Adherence rate was sensitive to education (+yr) (1.28, 1.06-1.55) and AHI (>30 vs. <30) (5.25, 1.34-18.5). CONCLUSIONS: Minimizing cost sharing reduces a barrier for CPAP acceptance among low socioeconomic status patients. Thus, financial incentive should be applied as a policy to encourage CPAP treatment, especially among low socioeconomic strata patients

Immune cell C/EBPβ deficiency is associated with hepatic mononuclear defects and spontaneous hepatitis but not steatohepatitis induced liver fibrosis

BACKGROUND: CCAAT/enhancer-binding protein ß (C/EBPß) is a transcription factor known to be involved in macrophage differentiation and function, steatohepatitis and liver fibrosis. METHODS: Immune restricted C/EBPß deficient and control mice were investigated in steady-state and in the CDA-HFD steatohepatitis model. Mice were assessed for weight change, liver biochemical profile, histology and hepatic phagocytes composition. RESULTS: Flow cytometry analysis of hepatic nonparenchymal cells revealed reduced numbers of hepatic monocytes and Kupffer cells and an increase in hepatic MHC class II positive myeloid cells in immune cells restricted C/EBPß deficient mice. Immune-restricted C/EBPß deficiency resulted in decreased weight gain and appearance of mild spontaneous liver inflammation. Nevertheless, In the CDA-HFD steatohepatitis model, immune restricted C/EBPß deficient and proficient mice exhibit similar grade of hepatic steatosis, liver enzymes levels and fibrosis stage. CONCLUSIONS: Immune-restricted C/EBPß deficiency leads to significant alteration in hepatic mononuclear phagocytes composition associated with spontaneous mild hepatitis. Steatohepatitis associated fibrosis is not dependent on C/EBPß expression by immune cells

Mean first-passage time of surface-mediated diffusion in spherical domains

We present an exact calculation of the mean first-passage time to a target on the surface of a 2D or 3D spherical domain, for a molecule alternating phases of surface diffusion on the domain boundary and phases of bulk diffusion. The presented approach is based on an integral equation which can be solved analytically. Numerically validated approximation schemes, which provide more tractable expressions of the mean first-passage time are also proposed. In the framework of this minimal model of surface-mediated reactions, we show analytically that the mean reaction time can be minimized as a function of the desorption rate from the surface.Comment: to appear in J. Stat. Phy

Absence of CD34 on Murine Skeletal Muscle Satellite Cells Marks a Reversible State of Activation during Acute Injury

Background: Skeletal muscle satellite cells are myogenic progenitors that reside on myofiber surface beneath the basal lamina. In recent years satellite cells have been identified and isolated based on their expression of CD34, a sialomucin surface receptor traditionally used as a marker of hematopoietic stem cells. Interestingly, a minority of satellite cells lacking CD34 has been described. Methodology/Principal Findings: In order to elucidate the relationship between CD34+ and CD34- satellite cells we utilized fluorescence-activated cell sorting (FACS) to isolate each population for molecular analysis, culture and transplantation studies. Here we show that unless used in combination with a7 integrin, CD34 alone is inadequate for purifying satellite cells. Furthermore, the absence of CD34 marks a reversible state of activation dependent on muscle injury. Conclusions/Significance: Following acute injury CD34- cells become the major myogenic population whereas the percentage of CD34+ cells remains constant. In turn activated CD34- cells can reverse their activation to maintain the pool of CD34+ reserve cells. Such activation switching and maintenance of reserve pool suggests the satellite cell compartment is tightly regulated during muscle regeneration

Lightning as a space-weather hazard: UK thunderstorm activity modulated by the passage of the heliospheric current sheet

Lightning flash rates, RL, are modulated by corotating interaction regions (CIRs) and the polarity of the heliospheric magnetic field (HMF) in near-Earth space. As the HMF polarity reverses at the heliospheric current sheet (HCS), typically within a CIR, these phenomena are likely related. In this study, RL is found to be significantly enhanced at the HCS and at 27 days prior/after. The strength of the enhancement depends on the polarity of the HMF reversal at the HCS. Near-Earth solar and galactic energetic particle fluxes are also ordered by HMF polarity, though the variations qualitatively differ from RL, with the main increase occurring prior to the HCS crossing. Thus, the CIR effect on lightning is either the result of compression/amplification of the HMF (and its subsequent interaction with the terrestrial system) or that energetic particle preconditioning of the Earth system prior to the HMF polarity change is central to solar wind lightning coupling mechanism

LRP5 Is Required for Vascular Development in Deeper Layers of the Retina

Background: The low-density lipoprotein receptor-related protein 5 (LRP5) plays an important role in the development of retinal vasculature. LRP5 loss-of-function mutations cause incomplete development of retinal vessel network in humans as well as in mice. To understand the underlying mechanism for how LRP5 mutations lead to retinal vascular abnormalities, we have determined the retinal cell types that express LRP5 and investigated specific molecular and cellular functions that may be regulated by LRP5 signaling in the retina. Methods and Findings: We characterized the development of retinal vasculature in LRP5 mutant mice using specific retinal cell makers and a GFP transgene expressed in retinal endothelial cells. Our data revealed that retinal vascular endothelial cells predominantly formed cell clusters in the inner-plexiform layer of LRP5 mutant retina rather than sprouting out or migrating into deeper layers to form normal vascular network in the retina. The IRES-b-galactosidase (LacZ) report gene under the control of the endogenous LRP5 promoter was highly expressed in Müller cells and was also weakly detected in endothelial cells of the retinal surface vasculature. Moreover, the LRP5 mutant mice had a reduction of a Müller cell-specific glutamine transporter, Slc38a5, and showed a decrease in b-wave amplitude of electroretinogram. Conclusions: LRP5 is not only essential for vascular endothelial cells to sprout, migrate and/or anastomose in the deeper plexus during retinal vasculature development but is also important for the functions of Müller cells and retina