Importance Sampling for Coded-Modulation Error Probability Estimation

This paper proposes an efficient simulation method based on importance sampling to estimate the random-coding error probability of coded modulation. The technique is valid for complex-valued modulations over Gaussian channels, channels with memory, and naturally extends to fading channels. The simulation method is built on two nested importance samplers to respectively estimate the pairwise error probability and generate the channel input and output. The effect of the respective number of samples on the overall bias and variance of the estimate of the error probability is characterized. For a memoryless channel, the estimator is shown to be consistent and with a small variance, growing with the square root of the code length, rather than the exponential growth of a standard Monte Carlo estimator.This work has been funded in part by the European Research Council under ERC grant agreement 725411, and by the Spanish Ministry of Economy and Competitiveness under grant TEC2016-78434-C3-1-R

Mismatched decoding: Error exponents, second-order rates and saddlepoint approximations

This paper considers the problem of channel coding with a given (possibly suboptimal) maximum-metric decoding rule. A cost-constrained random-coding ensemble with multiple auxiliary costs is introduced, and is shown to achieve error exponents and second-order coding rates matching those of constant-composition random coding, while being directly applicable to channels with infinite or continuous alphabets. The number of auxiliary costs required to match the error exponents and second-order rates of constant-composition coding is studied, and is shown to be at most two. For independent identically distributed random coding, asymptotic estimates of two well-known non-asymptotic bounds are given using saddlepoint approximations. Each expression is shown to characterize the asymptotic behavior of the corresponding random-coding bound at both fixed and varying rates, thus unifying the regimes characterized by error exponents, second-order rates, and moderate deviations. For fixed rates, novel exact asymptotics expressions are obtained to within a multiplicative 1+o(1) term. Using numerical examples, it is shown that the saddlepoint approximations are highly accurate even at short block lengths.This work was supported in part by the European Research Council under Grant 259663, in part by the European Union’s 7th Framework Programme under Grant 303633, and in part by the Spanish Ministry of Economy and Competitiveness under Grants RYC-2011-08150 and TEC2012-38800-C03-03

Mismatched Multi-Letter Successive Decoding for the Multiple-Access Channel

This paper studies channel coding for the discrete memoryless multiple-access channel with a given (possibly suboptimal) decoding rule. A multi-letter successive decoding rule depending on an arbitrary non-negative decoding metric is considered, and achievable rate regions and error exponents are derived both for the standard MAC (independent codebooks), and for the cognitive MAC (one user knows both messages) with superposition coding. In the cognitive case, the rate region and error exponent are shown to be tight with respect to the ensemble average. The rate regions are compared with those of the commonly considered decoder that chooses the message pair maximizing the decoding metric, and numerical examples are given for which successive decoding yields a strictly higher sum rate for a given pair of input distributions.This work was supported in part by the European Research Council through ERC under Grant 259663 and Grant 725411, in part by the European Union’s 7th Framework Programme under Grant 303633, and in part by the Spanish Ministry of Economy and Competitiveness under Grant RYC-2011-08150, Grant TEC2012-38800-C03- 03, and Grant TEC2016-78434-C3-1-R

Multiuser Random Coding Techniques for Mismatched Decoding

This paper studies multiuser random coding techniques for channel coding with a given (possibly suboptimal) decoding rule. For the mismatched discrete memoryless multiple-access channel, an error exponent is obtained that is tight with respect to the ensemble average, and positive within the interior of Lapidoth's achievable rate region. This exponent proves the ensemble tightness of the exponent of Liu and Hughes in the case of maximum-likelihood decoding. An equivalent dual form of Lapidoth's achievable rate region is given, and the latter is shown to immediately extend to channels with infinite and continuous alphabets. In the setting of single-user mismatched decoding, similar analysis techniques are applied to a refined version of superposition coding, which is shown to achieve rates at least as high as standard superposition coding for any set of random-coding parameters

Second-order rate region of constant-composition codes for the multiple-access channel

This paper studies the second-order asymptotics of coding rates for the discrete memoryless multiple-access channel with a fixed target error probability. Using constant-composition random coding, coded time-sharing, and a variant of Hoeffding's combinatorial central limit theorem, an inner bound on the set of locally achievable second-order coding rates is given for each point on the boundary of the capacity region. It is shown that the inner bound for constant-composition random coding includes that recovered by i.i.d. random coding, and that the inclusion may be strict. The inner bound is extended to the Gaussian multiple-access channel via an increasingly fine quantization of the inputs.Comment: (v2) Results/proofs given in matrix notation, det(V)=0 handled more rigorously, Berry-Esseen derivation given. (v3) Gaussian case added (v4) Significant change of presentation; added local dispersion results; added new method to obtain non-standard tangent vector terms using coded time-sharing; (v5) Final version (IEEE Transactions on Information Theory

PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells

CD4+ T cell differentiation into multiple T helper (Th) cell lineages is critical for optimal adaptive immune responses. This report identifies an intrinsic mechanism by which programmed death-1 receptor (PD-1) signaling imparted regulatory phenotype to Foxp3+ Th1 cells (denoted as Tbet+iTregPDL1 cells) and inducible regulatory T (iTreg) cells. Tbet+iTregPDL1 cells prevented inflammation in murine models of experimental colitis and experimental graft versus host disease (GvHD). Programmed death ligand-1 (PDL-1) binding to PD-1 imparted regulatory function to Tbet+iTregPDL1 cells and iTreg cells by specifically downregulating endo-lysosomal protease asparaginyl endopeptidase (AEP). AEP regulated Foxp3 stability and blocking AEP imparted regulatory function in Tbet+iTreg cells. Also, Aep−/− iTreg cells significantly inhibited GvHD and maintained Foxp3 expression. PD-1-mediated Foxp3 maintenance in Tbet+ Th1 cells occurred both in tumor infiltrating lymphocytes (TILs) and during chronic viral infection. Collectively, this report has identified an intrinsic function for PD-1 in maintaining Foxp3 through proteolytic pathway.Bio-organic Synthesi

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses

Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modeling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorgylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease