다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

Pathogen Recognition and Innate Immunity

The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

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The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Pattern Recognition Receptors and Inflammation

Inflammation is the body’s natural response to injury or biotic and abiotic challenges to the host. Controlled inflammation is required in order to maintain tissue homeostasis and physiological processes under various intrinsic and extrinsic perturbations. However, uncontrolled inflammation leads to various degrees of immune-pathologies such as susceptibility to infection or autoimmune diseases. Various biotic and abiotic factors induce inflammation, including, pathogenic invasion, physical injury, stress, obesity, and chemical or radiation insult to the host. At the cellular or molecular level, inflammation is induced by complex signaling through innate immune sensors expressed on immune and non-immune cells, and through specialized adaptive immune cells. Inflammatory mediators can be amines (e.g. histamine), lipid derivatives (e.g. prostaglandins), the peptide, bradykinin or proteins (small fragments of complements and inflammatory cytokines). These inflammatory mediators can cause cell damage, can result in a cytokine storm, and can lead to damage to the vital organs. This special issue of International Reviews of Immunology focuses on inducers of inflammation and how inflammation shapes immunity and its dysregulation results in the development of diseases and disorders (Figure 1). In mammals, lactate is a metabolic by-product of anaerobic respiration, a glycolytic pathway that ensures quick energy replenishment in the form of adenosine triphosphate (ATP) for the cells and prevention of muscle fatigue. Lactate acts as a circulating fuel in the blood that goes to the liver and is converted into pyruvate by the enzyme lactate dehydrogenase. Pyruvate is then converted into glucose via a metabolic pathway known as gluconeogenesis in the liver. Notably, lactate production increases when demand for ATP increases. In the past three decades, lactate has also been proved to be a very important signaling molecule that regulates various signaling pathways including inflammation-associated immune pathways. In this special issue, Zhou et al. [1] and Luo et al. [2] shed light on how endogenous lactate regulates inflammation in various immunological events, such as via macrophage polarization, T-cell immune dysfunction and its link with infectious and noninfectious diseases such as tumors. These two articles will be of interest to a broad readership in the field of immunology, as well as researchers investigating metaflammation and immunometabolic disorders and those in associated fields (Figure 1). Extracellular vesicles (EVs) are cell-derived membranous structures generated from broad cell-types including hematopoetic and non-hematopoetic cells. They range in size from the smallest exosomes and medium-sized micro-vesicles to apoptotic bodies and large-sized macrolets. Extracellular vesicles carry several biomolecules such as proteins (enzymes, receptors, cytokines etc.), lipids, genetic materials (miRNA, RNA, DNA) in them. Hence, by virtue of carrying a variety of biomolecules, EVs qualify to participate in several cellular processes, namely, signaling pathways that regulate cell growth, metabolism, immunity and inflammation, and thereby help in intercellular communication. Depending on what biomolecules they carry, EVs either induce or suppress physiological processes. In this special issue, Kumar et al. [3] discuss how EVs secreted from adipose tissue initiate inflammation at target cells by carrying several adipokines (pro-inflammatory cytokines) in obese people. Obesity is the manifestation of an unwanted accumulation of fat (lipids) and a slow metabolic rate. Obesity predisposes individuals to many diseases such as cardiovascular diseases, diabetes mellitus, hypertension,

Dimensions of inflammation in host defense and diseases

Plasmacytoid dendritic cells (pDCs) are the key producers of type I interferons (IFNs), thus playing central role in initiating antiviral immune response. Besides robust type I IFN production, pDCs also act as antigen presenting cells post immunogenic stimulation. Transcription factor Irf8 is indispensable for development of both pDC and cDC1 subset. However, the mechanism underlying the differential regulation by IRF8 in cDC1 and pDC specific genomic architecture of developmental pathways still remains to be fully elucidated. Previous studies indicated that, the Irf8R294C mutation specifically abrogates development of cDC1 without affecting that of pDC. In present study using RNA-seq based approach, we have found that though the point mutation Irf8R294C does not affect pDC development, it leads to defective type I IFN production, thus resulting in inefficient antiviral response. This observation unravels the distinctive roles of IRF8 in these two subpopulations- regulating the development of cDC1 whereas modulating the functionality of pDCs without affecting development. We report here, Irf8R294C mutation also causes defect in production of ISGs, prevents pDC activation in response to NDV infection (or CpG stimulation). Through in vivo studies, we demonstrate that abrogation of type I IFN production was concomitant with absence of pDC activation and increased NDV burden in IRF8R294C mice in comparison with wild type indicating inefficient viral clearance. Further we have also shown that Irf8R294C mutation abolishes the activation of type I IFN promoter by IRF8 justifying the low level of type I IFN production. Taken together, our study signifies that the single point mutation in Irf8, Irf8R294C severely compromises type I IFN mediated immune response by pDCs, thereby causing impairment in antiviral immunity.

Mutation in Irf8 Gene (Irf8R294C) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs

Isolation and evaluation of restorers and examining possibility of developing new version of CMS lines for upland rainfed rice hybrids.

Tinnitus is a phantom sound (ringing of the ears) that affects quality of life for millions around the world and is associated in most cases with hearing impairment. There are numerous Self-rated questionnaire in foreign languages used to assess the negative effects of tinnitus. India being multilingual country, these questionnaires are less effective on Indian population. Hence there is a great need to develop and standardize a self-assessment questionnaire in Indian languages. This study aims at transadapting and standardizing Tinnitus Functional Index (TFI-English) into Bengali language. Validity and reliability measures of the newly developed Tinnitus Functional Index-Bengali (B-TFI) was calculated statistically along with its assessment on sixty tinnitus participants (30 with hearing loss and 30 without hearing loss). A significantly good correlation was found when the results of the tool were compared with THI-Bengali and TFI-English for both the groups of participants. Test-retest reliability showed high correlation between the conditions on all the eight sub-scales of B-TFI. B-TFI is found to be a good tool with high internal consistency for detecting tinnitus related handicap. Study also provides information and need for further research.

/pdf/transadaptation-and-standardization-of-tinnitus-functional-4maoqe7txr.pdf

Transadaptation and Standardization of Tinnitus Functional Index in Bengali

Viruses are obligate intracellular entities that require a living host and its machinery for replication. During replication, viral components known as pathogen-associated molecular patterns (PAMPs) are sensed by a family of innate immune sensors or pattern recognition receptors (PRRs) and promote an antiviral state. Viral nucleic acids are one of the key PAMPs sensed by cytosolic RIG-I-like receptors (RLRs), Cyclic GMP-AMP Synthase (cGAS), Absent In Melanoma 2 (AIM2), Interferon Gamma Inducible Protein 16 (IFI16), and Z-DNA Binding Protein 1 (ZBP1 or DAI) and endosome-localized Toll-like receptors (TLR3, 7, 8, and 9). Recognition of viral RNA by Retinoic acid-inducible gene I (RIG-I), Melanoma differentiation associated gene 5 (MDA5), and TLR3, 7, and 8 or viral DNA by TLR9, cGAS, AIM2, IFI16, and DAI triggers a cascade of signaling events to recruit transcription factors, interferon regulatory factors and NF-κB. Activated IRF3/7 and NF-κB translocate to the nucleus and induce expression of type I and III interferons and proinflammatory cytokines, respectively. The production of these interferons is further enhanced in an autocrine and paracrine manner through the JAK-STAT signaling pathway. Type I and III interferons further induce interferoninducible genes, and together with proinflammatory cytokines, they develop an antiviral state. The antiviral state is characterized by by apoptosis of virally infected cells and inhibition of the cellular protein synthesis machinery, making the uninfected cells resistant to viral infection and initiates virus-specific adaptive immune responses (Fig. 1a). The cytosolic sensors RLRs consist of three members, (RIG-I, MDA5, and Laboratory of genetics and physiology 2 (LGP2), which recognize viral RNA. These sensors contain a DExD/H-box RNA helicase domain at the C-terminus with an ATP binding motif. RIG-I and MDA5 additionally possess two caspase activation and recruitment domains (CARDs) at the N-terminus, which are required for homotypic CARD-CARD interactions and downstream signaling. LGP2 lacks the CARD and therefore is considered to acts as a negative regulator of the RLR pathway by sequestering RNA away from RIG-I and MDA5. However, in vivo genetic studies revealed that LGP2 potentiates RIG-I and MDA5-mediated responses under physiological conditions. RIG-I and MDA5 are specialized to recognize viral RNAs with different molecular weights, and MDA5 preferentially binds to long (>1 kb) dsRNA molecules. In contrast, RIG-I participates in the recognition of short (<300 bp) RNA molecules, 5′ppp dsRNA, 5′pp dsRNA or ssRNA. In the inactive state, RIG-I and MDA5 adopt a closed structure with the CARDs concealed by its C-terminal domain (CTD). The interaction of RNA with CTD activates RIG-I by exposing the CARDs, promoting oligomerization and finally interacting with a mitochondrial membrane-associated CARD containing adapter protein interferon-β promoter stimulator-1 (IPS-1), also known as mitochondrial antiviral signaling protein, virusinduced signaling adapter or CARD adapter inducing interferon-β. Activation of IPS-1 leads to the recruitment of signaling proteins such as TRAF2, TRAF6, and TRADD. These changes recruit TRAF3 and TANK to induce the activation of TBK1 and IKKε and finally leads to the production of type I and III interferons and proinflammatory cytokines through the transcription factors IRF3/IRF7 and NF-κB, respectively (Fig. 1a). The RLR pathway is vital for viral defense, and its dysregulation can cause autoimmune diseases; therefore, the RLR signaling pathway is tightly regulated at the posttranslational level. Regulation of the RLR pathway by ubiquitination is pivotal for antiviral responses and immune homeostasis and occurs at various levels, such as sensing, signaling and transcription factor activation. Ubiquitin is a small peptide consisting of 76 amino acids, and multiple ubiquitin molecules can be sequentially added to one of the seven lysine (K) residues of ubiquitin (K6, K11, K27, K29, K33, K48, and K63), resulting in a variety of ubiquitin chains that can then be covalently linked to a target protein by E3 ubiquitin ligase. This posttranslational modification called ubiquitination can alter the function or stability of a protein depending on the type of ubiquitination. RIG-I is regulated by a number of E3 ubiquitin ligases, K27 and K48-linked ubiquitination by TRIM40 and K48-linked ubiquitination by RNF122, and STUB1 promotes proteasomal degradation, while K63-linked ubiquitination promotes oligomerization and RIG-I stabilization. In addition, multiple ubiquitin chains can be added to different lysine residues of RIG-I, and this multisite RIG-I ubiquitination is essential for its activation and helps in fine-tuning of type-I interferon production during virus infection. Binding of RNA ligands by RIG-I CTD exposes its CARDs for K63-linked ubiquitination at distinct sites by TRIM25, TRIM4, MEX3c and Riplet. Ubiquitination stabilizes RIG-I oligomerization and promotes the interaction with the CARD of IPS-1, resulting in IPS-1 aggregation and dimerization in the mitochondrial membrane, required for downstream signaling. TRIM25 is an interferon-inducible E3 ubiquitin ligase that interacts with RIG-I through its C-terminal SPla and the RYanodine receptor (SPRY) domain and ubiquitinates the second CARD of RIG-I at the lysine residues K99, K169, K172, K181, K190, and K193. The K172R mutation severely reduced RIG-I ubiquitination, suggesting that K172 is essential for TRIM25-mediated RIG-I ubiquitination and subsequent binding to IPS-1. Being a pivotal molecule in antiviral signaling, TRIM25 is tightly regulated through several different mechanisms. Linear ubiquitin assembly complex adds K48-linked ubiquitin molecules and marks TRIM25 for degradation, while USP15 removes these marks and prevents proteasomal degradation during viral infection. Noncoding RNAs

/pdf/long-noncoding-rna-trimming-the-viral-load-57ny3xl8bs.pdf

Himanshu Kumar

Papers

Dimensions of inflammation in host defense and diseases

Mutation in Irf8 Gene (Irf8R294C) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs

Isolation and evaluation of restorers and examining possibility of developing new version of CMS lines for upland rainfed rice hybrids.

Transadaptation and Standardization of Tinnitus Functional Index in Bengali

Long noncoding RNA: TRIMming the viral load.