(s,S)-type policy for a production inventory . . .

A production inventory problem with limited backlogging and with stockouts is described in a discrete time, stochastic optimal control framework with finite horizon. It is proved by dynamic programming methods that an optimal policy is of (s, S)-type. This means that in every period the policy is completely determined by two fixed levels of the stochastic inventory process considered.

Dormant Pathogenic CD4(+) T Cells Are Prevalent in the Peripheral Repertoire of Healthy Mice

Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. Regardless, an unknown number of autoreactive CD4+Foxp3− T cells escape negative selection and in the periphery require continuous suppression by CD4+Foxp3+ regulatory cells (Tregs). Here, we compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4+Foxp3− cells from converting to pathogenic effectors in healthy mice. These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including selfpeptides that select them in the thymus. Our data thus suggest that identification of most potentially autoreactive CD4+ T cells in the peripheral repertoire is critical to harness or redirect these cells for therapeutic advantage

On an Asymptotic Series of Ramanujan

An asymptotic series in Ramanujan's second notebook (Entry 10, Chapter 3) is concerned with the behavior of the expected value of $\phi(X)$ for large $\lambda$ where $X$ is a Poisson random variable with mean $\lambda$ and $\phi$ is a function satisfying certain growth conditions. We generalize this by studying the asymptotics of the expected value of $\phi(X)$ when the distribution of $X$ belongs to a suitable family indexed by a convolution parameter. Examples include the problem of inverse moments for distribution families such as the binomial or the negative binomial.Comment: To appear, Ramanujan

Quantifying the Population-level Effect of the COVID-19 Mass Vaccination Campaign in Israel: a Modeling Study

BackgroundEstimating real-world vaccine effectiveness is challenging since a variety of population factors can impact vaccine effectiveness.We aimed to assess the population-level reduction in cumulative SARS-CoV-2 cases, hospitalizations and mortality due to the BNT162b2 mRNA COVID-19 vaccination campaign in Israel during January-February, 2021.MethodsAn SIR model and a Dynamic Survival Analysis (DSA) statistical approach was used. Daily counts of tested positive and of vaccine doses administered obtained from the Israeli Ministry of Health, were used to calibrate the model. The model was parameterized using values derived from a previous phase of the pandemic during which similar lockdown and other preventive measures were implemented in order to take into account the effect of these preventing measures on COVID-19 spread.ResultsOur model predicts for the total population a reduction of 648,585 SARS-CoV-2 cases (75% confidence interval [CI]: 25,877–1,396,963) during the first 2 months of the vaccination campaign. The number of averted hospitalizations for moderate – severe conditions were 16,101 (75 % CI: 2,010–33,035) and reduction of death was estimated as 5,123 (CI: 388–10,815) fatalities.Among children aged 0-19 years, we estimated a reduction of 163,436 (CI: 0–433,233) SARS-CoV-2 cases which we consider as an indirect effect of the vaccine.ConclusionsOur results suggest that the rapid vaccination campaign prevented hundreds of thousands of new cases as well as thousands of hospitalizations and fatalities and has probably averted a major health care crisis

Non-Canonicaly Recruited TCRαβCD8αα IELs Recognize Microbial Antigens

In the gut, various subsets of intraepithelial T cells (IELs) respond to self or non-self-antigens derived from the body, diet, commensal and pathogenic microbiota. Dominant subset of IELs in the small intestine are TCRαβCD8αα+ cells, which are derived from immature thymocytes that express self-reactive TCRs. Although most of TCRαβCD8αα+ IELs are thymus-derived, their repertoire adapts to microbial flora. Here, using high throughput TCR sequencing we examined how clonal diversity of TCRαβCD8αα+ IELs changes upon exposure to commensal-derived antigens. We found that fraction of CD8αα+ IELs and CD4+ T cells express identical αβTCRs and this overlap raised parallel to a surge in the diversity of microbial flora. We also found that an opportunistic pathogen (Staphylococcus aureus) isolated from mouse small intestine specifically activated CD8αα+ IELs and CD4+ derived T cell hybridomas suggesting that some of TCRαβCD8αα+ clones with microbial specificities have extrathymic origin. We also report that CD8ααCD4+ IELs and Foxp3CD4+ T cells from the small intestine shared many αβTCRs, regardless whether the later subset was isolated from Foxp3CNS1 sufficient or Foxp3CNS1 deficient mice that lacks peripherally-derived Tregs. Overall, our results imply that repertoire of TCRαβCD8αα+ in small intestine expends in situ in response to changes in microbial flora

Epigenetic Silencing of Nucleolar rRNA Genes in Alzheimer's Disease

Background: Ribosomal deficits are documented in mild cognitive impairment (MCI), which often represents an early stage Alzheimer’s disease (AD), as well as in advanced AD. The nucleolar rRNA genes (rDNA), transcription of which is critical for ribosomal biogenesis, are regulated by epigenetic silencing including promoter CpG methylation. Methodology/Principal Findings: To assess whether CpG methylation of the rDNA promoter was dysregulated across the AD spectrum, we analyzed brain samples from 10 MCI-, 23 AD-, and, 24 age-matched control individuals using bisulfite mapping. The rDNA promoter became hypermethylated in cerebro-cortical samples from MCI and AD groups. In parietal cortex, the rDNA promoter was hypermethylated more in MCI than in advanced AD. The cytosine methylation of total genomic DNA was similar in AD, MCI, and control samples. Consistent with a notion that hypermethylation-mediated silencing of the nucleolar chromatin stabilizes rDNA loci, preventing their senescence-associated loss, genomic rDNA content was elevated in cerebrocortical samples from MCI and AD groups. Conclusions/Significance: In conclusion, rDNA hypermethylation could be a new epigenetic marker of AD. Moreover, silencing of nucleolar chromatin may occur during early stages of AD pathology and play a role in AD-related ribosoma