PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression

Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.     

Herpetological diversity across intact and modified habitats of Nosy Komba Island,Madagascar

A six month herpetological survey was undertaken between March and September 2015 on Nosy Komba, an island off of the north-west coast of mainland Madagascar which has undergone considerable anthropogenic modification. A total of 14 species were found that have not been previously recorded on Nosy Komba, bringing the total island diversity to 52 (41 reptiles and 11 frogs). The species assemblage, richness and abundance of four distinct habitat types were compared: closed-canopy forest, disturbed-canopy forest, shade-grown coffee plantation and mixed open plantation. The anthropogenic habitats on Nosy Komba were found to be of high conservation value for reptile species, where species richness and abundance found during surveys was equal to or higher than closed-canopy forest. By contrast, the abundance and species richness for frogs was reduced in anthropogenic habitats, especially in sun-exposed plantations. The forested areas of Nosy Komba contain twelve IUCN threatened species (9 reptiles and 3 frogs). Of these, Uroplatus henkeli, Uroplatus ebenaui, Phelsuma seippi, Zonosaurus subuniclor, Stumpffia psologlossa and Stumpffia pygmaea were also found in shade-grown coffee plantations, demonstrating the conservation value of these anthropogenic environments. Five threatened species on Nosy Komba were found exclusively in forested areas: Brookesia minima, Brookesia ebenaui, Lygodactylus madagascariensis, Rhombophryne testudo and Thamnosophis stumpffi. Our surveys demonstrate the importance of Nosy Komba for conserving regionally endemic and threatened species, and the often under-appreciated value of anthropogenic environments in species conservation, when also coupled with the protection of primary forest.     

Activity-dependent homeostatic specification of transmitter expression in embryonic neurons

Neurotransmitters are essential for interneuronal signalling, and the specification of appropriate transmitters in differentiating neurons has been related to intrinsic neuronal identity and to extrinsic signalling proteins. Here we show that altering the distinct patterns of Ca2+ spike activity spontaneously generated by different classes of embryonic spinal neurons in vivo changes the transmitter that neurons express without affecting the expression of markers of cell identity. Regulation seems to be homeostatic: suppression of activity leads to an increased number of neurons expressing excitatory transmitters and a decreased number of neurons expressing inhibitory transmitters; the reverse occurs when activity is enhanced. The imposition of specific spike frequencies in vitro does not affect labels of cell identity but again specifies the expression of transmitters that are inappropriate for the markers they express, during an early critical period. The results identify a new role of patterned activity in development of the central nervous system.     

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.     

Reactive oxygen species produced by NADPH oxidase regulate plant cell growth

Cell expansion is a central process in plant morphogenesis, and the elongation of roots and root hairs is essential for uptake of minerals and water from the soil. Ca2+ influx from the extracellular store is required for (and sets the rates of) cell elongation in roots. Arabidopsis thaliana rhd2 mutants are defective in Ca2+ uptake and consequently cell expansion is compromised--rhd2 mutants have short root hairs and stunted roots. To determine the regulation of Ca2+ acquisition in growing root cells we show here that RHD2 is an NADPH oxidase, a protein that transfers electrons from NADPH to an electron acceptor leading to the formation of reactive oxygen species (ROS). We show that ROS accumulate in growing wild-type (WT) root hairs but their levels are markedly decreased in rhd2 mutants. Blocking the activity of the NADPH oxidase with diphenylene iodonium (DPI) inhibits ROS formation and phenocopies Rhd2-. Treatment of rhd2 roots with ROS partly suppresses the mutant phenotype and stimulates the activity of plasma membrane hyperpolarization-activated Ca2+ channels, the predominant root Ca2+ acquisition system. This indicates that NADPH oxidases control development by making ROS that regulate plant cell expansion through the activation of Ca2+ channels.     

Multi‐step forecasting for long‐memory processes

In this paper we present results of a simulation study to assess and compare the accuracy of forecasting techniques for long‐memory processes in small sample sizes. We analyse differences between adaptive ARMA(1,1) L‐step forecasts, where the parameters are estimated by minimizing the sum of squares of L‐step forecast errors, and forecasts obtained by using long‐memory models. We compare widths of the forecast intervals for both methods, and discuss some computational issues associated with the ARMA(1,1) method. Our results illustrate the importance and usefulness of long‐memory models for multi‐step forecasting. Copyright © 1999 John Wiley & Sons, Ltd.