Background

Gene regulatory networks with dynamics characterized by multiple stable states underlie cell fate-decisions. Quantitative models that can link molecular-level knowledge of gene regulation to a global understanding of network dynamics have the potential to guide cell-reprogramming strategies. Networks are often modeled by the stochastic Chemical Master Equation, but methods for systematic identification of key properties of the global dynamics are currently lacking.

Results

The method identifies the number, phenotypes, and lifetimes of long-lived states for a set of common gene regulatory network models. Application of transition path theory to the constructed Markov State Model decomposes global dynamics into a set of dominant transition paths and associated relative probabilities for stochastic state-switching.

Conclusions

In this proof-of-concept study, we found that the Markov State Model provides a general framework for analyzing and visualizing stochastic multistability and state-transitions in gene networks. Our results suggest that this framework-adopted from the field of atomistic Molecular Dynamics-can be a useful tool for quantitative Systems Biology at the network scale.

Gene regulatory networks are multistable dynamical systems in which attractor states represent cell phenotypes. Spontaneous, noise-induced transitions between these states are thought to underlie critical cellular processes, including cell developmental fate decisions, phenotypic plasticity in fluctuating environments, and carcinogenesis. As such, there is increasing interest in the development of theoretical and computational approaches that can shed light on the dynamics of these stochastic state transitions in multistable gene networks. We applied a numerical rare-event sampling algorithm to study transition paths of spontaneous noise-induced switching for a ubiquitous gene regulatory network motif, the bistable toggle switch, in which two mutually repressive genes compete for dominant expression. We find that the method can efficiently uncover detailed switching mechanisms that involve fluctuations both in occupancies of DNA regulatory sites and copy numbers of protein products. In addition, we show that the rate parameters governing binding and unbinding of regulatory proteins to DNA strongly influence the switching mechanism. In a regime of slow DNA-binding/unbinding kinetics, spontaneous switching occurs relatively frequently and is driven primarily by fluctuations in DNA-site occupancies. In contrast, in a regime of fast DNA-binding/unbinding kinetics, switching occurs rarely and is driven by fluctuations in levels of expressed protein. Our results demonstrate how spontaneous cell phenotype transitions involve collective behavior of both regulatory proteins and DNA. Computational approaches capable of simulating dynamics over many system variables are thus well suited to exploring dynamic mechanisms in gene networks.

The accuracy of statistical reporting that informs medical and public health practice has generated extensive debate, but no studies have evaluated the frequency or accuracy of effect size (the magnitude of change in outcome as a function of change in predictor) reporting in prominent health journals. To evaluate effect size reporting practices in prominent health journals using the case study of ORs. Articles published in the American Journal of Public Health (AJPH), Journal of the American Medical Association (JAMA), New England Journal of Medicine (NEJM) and PLOS One from 1 January 2010 through 31 December 2019 mentioning the term 'odds ratio' in all searchable fields were obtained using PubMed. One hundred randomly selected articles that reported original research using ORs were sampled per journal for in-depth analysis. We report prevalence of articles using ORs, reporting effect sizes from ORs (reporting the magnitude of change in outcome as a function of change in predictor) and reporting correct effect sizes. The proportion of articles using ORs in the past decade declined in JAMA and AJPH, remained similar in NEJM and increased in PLOS One, with 6124 articles in total. Twenty-four per cent (95% CI 20% to 28%) of articles reported the at least one effect size arising from an OR. Among articles reporting any effect size, 57% (95% CI 47% to 67%) did so incorrectly. Taken together, 10% (95% CI 7% to 13%) of articles included a correct effect size interpretation of an OR. Articles that used ORs in AJPH more frequently reported the effect size (36%, 95% CI 27% to 45%), when compared with NEJM (26%, 95% CI 17.5% to 34.7%), PLOS One (22%, 95% CI 13.9% to 30.2%) and JAMA (10%, 95% CI 3.9% to 16.0%), but the probability of a correct interpretation did not statistically differ between the four journals (χ2=0.56, p=0.90). Articles that used ORs in prominent journals frequently omitted presenting the effect size of their predictor variables. When reported, the presented effect size was usually incorrect. When used, ORs should be paired with accurate effect size interpretations. New editorial and research reporting standards to improve effect size reporting and its accuracy should be considered.

Food insecurity in the United States has been exacerbated due to the socioeconomic strain of the coronavirus disease 2019 (COVID-19) pandemic. Populations experiencing poverty and, as a consequence, food insecurity in the United States are disproportionately affected by obesity, which was identified early in the pandemic as a major risk factor for increased susceptibility to COVID-19 infection and mortality. Given the focus on obesity and its role in immune dysregulation, it is also important to note the role of micronutrient deficiency, another sequalae of food insecurity. Micronutrients play an important role in the ability of the immune system to mount an appropriate response. Moreover, OBESE individuals are more likely to be micronutrient deficient. This review will explore the role of micronutrients, vitamin A, vitamin D, vitamin C, and zinc in respiratory immunity and COVID-19 and how micronutrient deficiency may be a possible confounder in obesity's association with severe outcomes. By illuminating the role of micronutrients in COVID-19, this paper expands the discussion from food insecurity and obesity to include micronutrient deficiency and how all of these interact in respiratory illnesses such as COVID-19.

The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure. Prematurity, low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment. In the developing brain, oligodendrocyte (OL) maturation occurs perinatally, and immature OLs are particularly vulnerable. Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity. We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1 (TSC1). Here, considering cell replacement and integration as therapeutic goals, we examined if OL progenitors (OLPs) grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury. For that purpose, we used a well-established model of glutamate excitotoxic injury. Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma. Energetics and expression of stress proteins and OL developmental specific markers were examined. A comparison of the proteomic profile per treatment was also ascertained. We found that OLPs did not survive in the excitotoxic environment when grafted alone. In contrast, when combined with TSC1, survival and integration of grafted OLPs was observed. Further, energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1. The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate. These changes were reversed in the presence of TSC1 and ubiquitination was decreased. The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration. We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain. Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at (UCLA) (ARC #1992-034-61) on July 1, 2010.

This cross-sectional study examines the spread of misinformation regarding the Danish Study to Assess Face Masks for the Protection Against COVID-19 Infection on Facebook.

PURPOSE:To estimate the proportion of children with trachomatous inflammation-follicular (TF) and adults with trachomatous trichiasis (TT) in internally displaced persons (IDP) camps in the Darfur States of Sudan and to evaluate associated risk factors. METHODS:IDP camps were identified from government census data. We conducted a subanalysis of data collected in these camps during 2014-2015 as part of surveys covering 37 districts of the Darfur States within the Global Trachoma Mapping Project. A random-effects hierarchical model was used to evaluate factors associated with TF in children or TT in adults. RESULTS:Thirty-six IDP camps were represented in the survey data, in which 1926 children aged 1-9 y were examined, of whom 38 (8%) had TF. Poor sanitation, younger age and living in a household that purchased water from a vendor were associated with TF in children aged 1-9 y. Of 2139 individuals examined aged ≥15 y, 16 (0.7%) had TT. TT was strongly independently associated with being older and living alone. CONCLUSION:Trachoma is found at low levels in these camps, but still at levels where intervention is needed. Disease elimination in conflict-related settings presents a unique challenge for the trachoma community, and may require an innovative approach. Understanding how best to undertake trachoma elimination interventions in these areas should be prioritized.

INTRODUCTION: We conducted a population-based observational study of all medical examiner cases in Los Angeles County from January 2012 through June 2021 in which methamphetamine was listed as a cause of or contributing factor to death (n = 6125). We aimed to characterize demographics, comorbidities, and co-involved substances in methamphetamine-related deaths longitudinally in Los Angeles County, California. METHODS: We used detailed death record data to manually classify fatalities by involvement of each organ system, opioids, alcohol, cocaine, other drugs or medications, and external/traumatic causes. Primary outcomes included: the number of methamphetamine-involved deaths, demographics of decedents, percentage of methamphetamine deaths also involving other drugs, and percentage of methamphetamine deaths involving different organ systems. We performed Mann Kendall tests of trends to identify statistically significant longitudinal changes. RESULTS: During the study period, the percentage of methamphetamine-related deaths involving opioids significantly increased from 16 % in 2012 to 54 % in 2021 (p < 0.001). Concurrently, the percentage involving cardiovascular causes significantly decreased from 47 % to 26 % (p < 0.05). Methamphetamine-related deaths in LAC increasingly affected people experiencing homelessness, for whom the percentage tripled from 13 % in 2012 to 35 % in 2021. The share of decedents under 40 years old increased from 33 % to 41 %. The percentage of Black or African American decedents increased over five-fold from 3 % to 17 %. CONCLUSIONS: Methamphetamine-related deaths involving opioids more than tripled in Los Angeles County from 2012 to 2021, reflecting the drug supplys shift to illicit fentanyl. More than a quarter involved cardiovascular causes. These findings have implications for treatment and prevention, including scaling up contingency management, distributing naloxone to people who primarily use stimulants, and including cardiovascular care alongside these interventions directly targeted to reduce harms of methamphetamine use.