Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway

The CD28/B7 costimulatory pathway is generally considered dispensable for memory T cell responses, largely based on in vitro studies demonstrating memory T cell activation in the absence of CD28 engagement by B7 ligands. However, the susceptibility of memory CD4 T cells, including central (CD62L(high)) and effector memory (T(EM); CD62L(low)) subsets, to inhibition of CD28-derived costimulation has not been closely examined. In this study, we demonstrate that inhibition of CD28/B7 costimulation with the B7-binding fusion molecule CTLA4Ig has profound and specific effects on secondary responses mediated by memory CD4 T cells generated by priming with Ag or infection with influenza virus. In vitro, CTLA4Ig substantially inhibits IL-2, but not IFN-gamma production from heterogeneous memory CD4 T cells specific for influenza hemagglutinin or OVA in response to peptide challenge. Moreover, IL-2 production from polyclonal influenza-specific memory CD4 T cells in response to virus challenge was completely abrogated by CTLA4Ig with IFN-gamma production partially inhibited. When administered in vivo, CTLA4Ig significantly blocks Ag-driven memory CD4 T cell proliferation and expansion, without affecting early recall and activation. Importantly, CTLA4Ig treatment in vivo induced a striking shift in the phenotype of the responding population from predominantly T(EM) in control-treated mice to predominantly central memory T cells in CTLA4Ig-treated mice, suggesting biased effects of CTLA4Ig on T(EM) responses. Our results identify a novel role for CD28/B7 as a regulator of memory T cell responses, and have important clinical implications for using CTLA4Ig to abrogate the pathologic consequences of T(EM) cells in autoimmunity and chronic disease.     

DISCO is key to successful centriole maturation

Centriole maturation is essential for ciliogenesis, but which proteins and how they regulate ciliary assembly is unclear. In this issue, Kumar et al. (2021. J. Cell Biol. https://doi.org/10.1083/jcb.202011133) shed light on this process by identifying a ciliopathy complex at the distal mother centriole that restrains centriole length and supports the formation of distal appendages.

The primary cilium plays a crucial role in embryonic development by allowing the integration of a variety of inputs, including chemical and mechanical signals. Primary cilia are found on most cell types; thereby, mutations in genes encoding cilia components may perturb many cellular functions, including airway mucus clearance, mechanosensation, and cell signaling, which are central regulators of organ function and homeostasis. Numerous mutations leading to ciliary dysfunction have been identified in recent years and thus linked to human cilia-related diseases, called ciliopathies (1, 2). Some of these mutations affect components of the centrioles, which are cytoplasmic cylindrical structures composed by triplets of microtubules arranged in a ninefold symmetry.Cilia originate from centrioles and are anchored to the cell surface. In most mammalian cells, centrioles are present within the centrosome, the main organizing center of microtubules. During G1 phase, cells have one centrosome containing two centrioles of different ages. The older mother centriole is distinguished from the younger daughter centriole by the presence of two sets of appendages organized around its circumference. The centrosome duplicates in S phase and, as a result, a new centriole is formed orthogonally to each parent centriole. The new centrioles subsequently elongate during S and G2 phases, and each daughter cell inherits a parent and a newly formed centriole after mitosis. During this transition, new centrioles become daughter centrioles, and the daughter centriole from the previous cycle acquires appendages to mature into a mother centriole. Distal appendages (DAs) are essential for anchoring the mother centriole to the plasma membrane and for the formation of a cilium (2). The formation of a mature centriole competent for ciliogenesis is therefore a complex process taking place over three successive cell cycles.Different molecular factors required for the progressive maturation of centrioles and the assembly of DAs have been identified in the past, and perturbation of their function has been linked to ciliopathies (2, 3). However, the precise mechanism by which DAs are assembled onto centrioles remains elusive. In this issue, Kumar et al. focused their attention on CEP90, a poorly characterized protein whose mutations have been implicated in several ciliopathies (4). CEP90 is a component of centriolar satellites, which are proteinaceous granules located at the periphery of the centrosome (5, 6). Using a combination of expansion microscopy and structured illumination super-resolution microscopy techniques, the authors found that CEP90 also localized to centrioles, where it formed a discontinuous ring with a ninefold symmetry. CEP90 localized near a well-characterized DA component, CEP164, which was consistent with CEP90 being present at the base of these appendages. Then, they searched for CEP90 interactors. For that, the researchers first had to circumvent the shortcoming of discriminating between interactions that may take place at the centrosome from those occurring within centriolar satellites. To get around this, Kumar et al. used a cell line in which satellite assembly is inhibited. Among the candidates they found interacting with CEP90 at the centrosome were OFD1 and Moonraker (MNR), which are two proteins previously associated with multiple ciliopathies. OFD1 is a centriole component required to restrict centriole elongation and assemble DAs (7). MNR, also called OFIP or KIAA073, is a satellite component necessary for cilia formation (8). Making again use of super-resolution microscopy, the authors showed that all three proteins colocalized at the centriole distal end, with the MNR protein being the closest to the centriole wall, so they named this newly identified complex after DISCO (distal centriole complex).Next, Kumar et al. elegantly demonstrated that, as previously shown for OFD1 (7), inactivating either CEP90 or MNR led to the absence of cilia in cells. In mice, deficiency of any of these proteins resulted in Hedgehog signaling inhibition and early arrest of embryonic development. As reported for OFD1-deficient cells, loss of MNR in human cells resulted in overly long centrioles. However, centriole length was normal in CEP90-deficient cells, suggesting partially distinct functions between members of the DISCO complex. The authors noted that ciliogenesis was blocked at an early stage in CEP90^−/− and MNR^−/− cells and, given that DAs are essential for centriole anchoring and ciliogenesis, they decided to examine DA organization in these cells (4). Indeed, they found that DA components, such as CEP83, were not recruited during centriole maturation in MNR^−/− or CEP90^−/− cells, and DAs were not detected by electron microscopy. These findings pointed out that CEP90 and MNR, like OFD1, were required for the assembly of DAs.Since CEP90 is required for satellite accumulation around the centrosome, and satellites are, in turn, essential for ciliogenesis (6), one possible explanation to their results is that CEP90 might affect DA assembly indirectly via its role in satellite localization. To answer this question, the authors again used cells lacking centriolar satellites. CEP90 was correctly localized at centriole distal ends in these cells, and DAs were formed, supporting a direct requirement for the centriolar pool of CEP90 in DA assembly. Putting all their data together, Kumar et al. proposed the following model: First, MNR is recruited to elongating centrioles, which, in turn, triggers the recruitment of OFD1 to arrest elongation at the end of the first cell cycle. MNR and OFD1 then recruit CEP90, which initiates the recruitment of DA components, including CEP83, at the end of the following cell cycle (Fig. 1). Thus, the DISCO complex allows for coupling the arrest of centriole elongation to centriole maturation across successive cell cycles.Open in a separate windowFigure 1.The DISCO complex restrains centriole elongation and initiates DA assembly. (1) The DISCO complex member MNR is recruited first at the distal end of assembling centrioles. MNR then recruits other members of the complex, including OFD1, which inhibits centriole elongation at the end of the first cell cycle, i.e., when newly formed centrioles become daughter centrioles (DCs). Other members of the complex include CEP90 and possibly also FOPNL. (2) At the end of the following cell cycle, as the daughter centriole matures into a mother centriole (MC), CEP90 initiates the recruitment of CEP83, the most upstream component in DA assembly. A previously identified interaction between OFD1 and another DA component, CEP89, might also contribute to DA organization (10). Proteins are drawn in contact with each other when an interaction or hierarchical recruitment was described (3, 4, 8, 11).Besides OFD1 and MNR proteins, Kumar et al. also identified a protein called FGFR1OP N-Terminal Like (FOPNL or FOR20) as a potential CEP90 interactor (4). Interestingly, this interaction was confirmed in a recent study describing that a complex containing CEP90, OFD1, and FOPNL localizes at the distal end of Paramecium centrioles and is necessary for the recruitment of DA components and centriole docking in Paramecium and human cells (9). FOPNL was previously found in complex with MNR and OFD1 and shown to facilitate their interaction (8). Together, these data suggest that the DISCO complex could also include FOPNL. The functional similarities of some of the components of the DISCO complex between Paramecium and humans strongly suggest that the role of DISCO in centriole maturation and ciliogenesis is broadly conserved across species.Previous studies in different organisms have underpinned the relevance of ciliopathy-associated proteins to ensure normal organism development and tissue function (1, 2). Overall, the findings by Kumar et al. highlight the critical role of a ciliopathy-associated protein complex at distal centrioles in building distal appendages, thus supporting centriole maturation and ciliogenesis in rodents and human cells (4).     

Association of mitochondrial nitric oxide synthase activity with respiratory chain complex I

The present study shows that rat liver and brain mitochondrial nitric oxide synthase (mtNOS) are functionally associated with mitochondrial respiratory chain complex I. When complex I is activated, mtNOS exerts high activity and generates nitric oxide, whereas inactivation of complex I leads mtNOS to abandon its NOS activity. Functional association of mtNOS with complex I is potentially important in regulating mtNOS activity and mitochondrial functions.     

<Emphasis Type="Italic">Longidorus</Emphasis><Emphasis Type="Italic">kheirii</Emphasis> n. sp. (Nematoda: Longidoridae) from Iran

Longidorus kheirii n. sp., a parthenogenetic species, was found in soil samples collected from the rhizosphere of Rosa sp. growing in a natural mountainous region close to Maragheh city, northwestern Iran. It is characterised by having a long body (6.7-9 mm), a 19.5-23 mum wide head continuous with the body contour, a truncate and slightly concave lip region with convex sides between the anterior end and the guide-ring, an odontostyle 113-130 mum long, an odontophore 69-97.5 mum long, a body width of 90.5-117.5 mum at the mid-body, a long, wide oesophageal bulb (149.5-193.5 x 39.5-48 mum), a tail length of 47-72 mum, a male with 11 ventromedian supplements and spicules of 85 mum in length, and four juvenile stages. The ribosomal 18S rDNA gene of L. kheirii n. sp., L. leptocephalus Hooper, 1961, L. profundorum Hooper, 1966 L. euonymus Mali & Hooper, 1973 and two unidentified species listed as Longidorus sp. 1 and Longidorus sp. 2, all recovered from northwestern Iran in the same survey, and the ITS1 of L. kheirii n. sp. and Longidorus sp. 1 were sequenced in order to investigate the phylogenetic relationships with other previously sequenced Longidorus species.     

Antibody affinity measurements

The use of antibodies in immunoaffinity separations represents one of the most specific methods for purifying substances of biological interest. Since the binding affinity of antibody greatly influences its behavior in such separations, it is often important to know the value of the antibody affinity expressed as an equilibrium constant K. The present review discusses the equations used in the quantitative analysis of antigen/antibody interactions and describes currently used experimental methods for measuring K values. Advantages and shortcomings of the solution phase and solid phase approaches used for measuring antibody affinity are discussed.     

Lack of association between LXRα and LXRβ gene polymorphisms and prevalence of metabolic syndrome: A case–control study of an Iranian population

The metabolic syndrome (MetS) is considered to be a major risk factor for type 2 diabetes mellitus and cardiovascular diseases. It is characterized by central adiposity, high blood pressure, glucose intolerance and abnormalities of lipoprotein metabolism. The cause of MetS is likely to be due to a complex interaction between genetic and environmental factors. Liver X receptors alpha (NR1H3) and beta (NR1H2) play a key role in lipid and carbohydrate metabolism. The aim of this study was to investigate the contribution of genetic polymorphisms in the LXRs to risk of MetS and related traits. Two common SNPs in NR1H3 (rs11039155 and rs2279238) and in NR1H2 (rs17373080 and rs2695121) were genotyped using TaqMan assays in MetS patients (n = 265) and controls (n = 219). Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotypes with the presence of MetS and related phenotypes. Although The NR1H2 polymorphism rs2695121 was nominally associated with MetS but correction for multiple-testing and adjustment for age, sex and number of MetS criteria, failed to identify any significant interactions associated with prevalence of MetS. However in the haplotype analysis, a LXRα haplotype AC, was more common in controls and was associated with a significant protective effect for MetS (OR [95% CI] = 0.25 [0.07–0.88], p = 0.031). In conclusion, this study suggests that the above-named variants in LXRα and LXRβ genes are not potential contributors to the risk of MetS and related traits in an Iranian population.     

New data on Longidorus aetnaeus Roca, Lamberti, Agostinelli & Vinciguerra, 1986 (Nematoda: Longidoridae) from Iran and Ajaria (Georgia)

Longidorus aetnaeus Roca, Lamberti, Agostinelli & Vinciguerra, 1986 is reported for the first time from Iran and Ajaria (Georgia). Morphological and morphometric data are provided for two Iranian and one Ajarian populations. The D2–D3 region of 28S rDNA for both Iranian populations was sequenced for the first time and the data reported. A detailed study of juveniles of L. aetnaeus from Iran, Georgia and Bulgaria demonstrated that this species develops through three juvenile stages. Furthermore, phylogenetic studies inferred from sequences for the D2–D3 region of 28S rRNA gene revealed that L. aetnaeus is most closely related to L. leptocephalus.     

Proteomics in radiation research: present status and future perspectives

Rapidly developing postgenome research has made proteins an attractive target for biological analysis. The well-established term of proteome is defined as the complete set of proteins expressed in a given cell, tissue or organism. Unlike the genome, a proteome is rapidly changing as it tends to adapt to microenvironmental signals. The systematic analysis of the proteome at a given time and state is referred to as proteomics. This technique provides information on the molecular and cellular mechanisms that regulate physiology and pathophysiology of the cell. Applications of proteome profiling in radiation research are increasing. However, the large-scale proteomics data sets generated need to be integrated into other fields of radiation biology to facilitate the interpretation of radiation-induced cellular and tissue effects. The aim of this review is to introduce the most recent developments in the field of radiation proteomics.     

Plasmonics Optoelectronics Nanobiosensors for Detection of Alzheimer’s Disease Biomarker via Amyloid-Beta (Aβ) in Near-Infrared

The development of diagnostic factors for such neurodegenerative disorders as Alzheimer’s disease is hindered by several limitations that are often witnessed in the early detection of biomarkers in cerebrospinal fluid (CSF) and bio-fluids in clinical contexts. Therefore, here, we suggest a highly sensitive plasmonics nanobiosensor for detection of Alzheimer on one nanodevice through the excitation of surface plasmon resonance (SPR) depending on graphene chemical potential, called a nanobiosensor. This plasmonic nanobiosensor consists of only graphene metasurfaces and samples but does not need extra approaches for the exact analysis of the sample refractive index. Under FDTD simulation, we analyze the sensitivity of 3900 l/RIU for amyloid-beta (Aβ) and figure of merit of 138. This is the first high-performance plasmonics nanobiosensor to monitoring of Alzheimer samples which can be used to detect Alzheimer easily in the future.

     

Metabolic variation in natural populations of wild yeast

Ecological diversification depends on the extent of genetic variation and on the pattern of covariation with respect to ecological opportunities. We investigated the pattern of utilization of carbon substrates in wild populations of budding yeast Saccharomyces paradoxus. All isolates grew well on a core diet of about 10 substrates, and most were also able to grow on a much larger ancillary diet comprising most of the 190 substrates we tested. There was substantial genetic variation within each population for some substrates. We found geographical variation of substrate use at continental, regional, and local scales. Isolates from Europe and North America could be distinguished on the basis of the pattern of yield across substrates. Two geographical races at the North American sites also differed in the pattern of substrate utilization. Substrate utilization patterns were also geographically correlated at local spatial scales. Pairwise genetic correlations between substrates were predominantly positive, reflecting overall variation in metabolic performance, but there was a consistent negative correlation between categories of substrates in two cases: between the core diet and the ancillary diet, and between pentose and hexose sugars. Such negative correlations in the utilization of substrate from different categories may indicate either intrinsic physiological trade‐offs for the uptake and utilization of substrates from different categories, or the accumulation of conditionally neutral mutations. Divergence in substrate use accompanies genetic divergence at all spatial scales in S. paradoxus and may contribute to race formation and speciation.