TESTS AND ESTIMATORS OF MULTIPLICATIVE MODELS FOR VARIETY TRIALS

Some recently obtained results on cross validation, hypothesis test and estimation procedures for multiplicative models applied to multi-site crop variety trials are presented. The PRESS statistic is more sensitive to overfitting and choice of model form than data-splitting cross-validation. Because of their extreme liberality, Gollob F-tests should not be used to test multiplicative terms. FGH tests effectively control Type I error, but are conservative for tests of terms for which the previous term is small. Simulation tests have greater power than FGH tests, but still effectively control Type I error rates. Simulation results and cross validation in two examples suggest that BLUP style shrinkage estimators of multiplicative terms produce fitted models with predictive value at least as good as the best truncated models and would eliminate the need for cross validation as a criterion for model choice. Shrinkage estimators of multiplicative models were better than BLUPs computed under the assumption of random unpatterened interaction in one example and were at least as good in the second example. Both were much better than empirical cell means in both examples. It is suggested that variety performance estimates derived from shrinkage estimators of multiplicative models should replace empirical cell means routinely reported in experiment station crop variety trial bulletins

CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation

SignificanceMultiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by accumulation of myeloid cells in the central nervous system (CNS). Both harmful and beneficial myeloid cells are present in EAE/MS, and a goal of MS therapy is to preferentially remove harmful myeloid cells. The receptor for CSF-1 (CSF-1R) is found on myeloid cells and is important for their survival. CSF-1R can bind two ligands, CSF-1 and IL-34, but it is not known whether their functions in EAE/MS differ. We found that blocking CSF-1 depleted only harmful myeloid cells in the CNS and suppressed EAE, whereas blocking IL-34 had no effect. Thus, we propose that blocking CSF-1 could be a therapy for MS

IL-11 Induces NLRP3 Inflammasome Activation in Monocytes and Inflammatory Cell Migration to the Central Nervous System

The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes, and IL-11R+ neutrophils in comparison to matched healthy controls. IL-11+ and granulocyte-macrophage colony-stimulating factor (GM-CSF)+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single-cell RNA sequencing, revealed the highest number of differentially expressed genes in classical monocytes, including up-regulated NFKB1, NLRP3, and IL1B. All CD4+ cell subsets had increased expression of S100A8/9 alarmin genes involved in NLRP3 inflammasome activation. In IL-11R+-sorted cells from the CSF, classical and intermediate monocytes significantly up-regulated the expression of multiple NLRP3 inflammasome-related genes, including complement, IL18, and migratory genes (VEGFA/B) in comparison to blood-derived cells. Therapeutic targeting of this pathway with αIL-11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates, and demyelination. αIL-11 mAb treatment decreased the numbers of NFκBp65+, NLRP3+, and IL-1β+ monocytes in the CNS of mice with EAE. The results suggest that IL-11/IL-11R signaling in monocytes represents a therapeutic target in RRMS