Evolutionary trajectory of the enzyme activation-induced cytidine deaminase (AID) within the Gadiformes lineage

Activation-induced cytidine deaminase (AID) is a DNA-mutating enzyme that initiates secondary antibody diversification process upon immune stimulation. One outcome of this diversification is the generation of antibodies with higher affinity for the cognate antigen. In human and mouse models, functional deficiency of AID leads to hyper IgM syndrome type Ⅱ, exhibiting lack of secondary antibody diversification. Despite the central role of AID in instigating this diversification process, its off-targeting activity has been attributed to the initiation and progression of various type of cancers. The emergence of AID and, therefore, secondary antibody diversification process have been dated back to the common ancestor of jawed vertebrates. However, several studies investigating the Atlantic cod (Gadus morhua) immune responses revealed lack of high affinity antibodies and robust humoral response in this species. Moreover, genomic sequence of several Gadiformes species, including Atlantic cod, uncovered the loss of histocompatibility complex class II (mhc Ⅱ), cluster of differentiation 4 (cd4), and invariant chain (Ii) genes in their common ancestor. These genes are involved in B cell activation in the mammalian model of immune system. Since AID is responsible for generation of high affinity antibodies in other vertebrates, we sought to examine the genetics, expression, and function of Atlantic cod AID. We also investigated the evolutionary trajectory of AID within Gadiformes species to shed light on the extent of immune system remodeling in this lineage. In chapter two, we showed that the AID gene synteny and transcript expression were conserved in Atlantic cod in comparison with other studied vertebrates. Interestingly, we identified two distinct AID transcripts, one of which encoded a full-length AID, whilst the other one lacked the first exon. In chapter three, we synthesized, expressed, and purified Atlantic cod AID (Gm-AID) and examined its biochemical properties. Our results showed that despite having a similar DNA binding ability, Gm-AID exhibited extremely low catalytic efficiency compared with other studied vertebrates. In chapter four, we synthesized, expressed, and purified 36 AID homologs within and outside of the Gadiformes lineage. Previous studies have shown a drastic re-modeling of the Gadigormes’ immune system where the loss of genes involved in antibody responses has coincided with an expansion of innate and cell-mediated immune genes. Our biochemical analyses revealed a vast diversity in the enzymatic properties of AID homologs. Remarkably, two Gadifomes AID homologs examined here did not exhibit any cytidine deaminase activity. By predicting and resurrecting the ancestral AIDs within and outside of Gadiformes lineage, we showed that the functional impairment of AID most likely has happened in the ancestor of Gadidae group. Since Gadidae species have successfully populated their natural habitats, the functional impairment of their AID enzyme did not hamper their fitness. This is most likely duet to the compensatory mechanisms such as the expansion of innate and cell-mediated immune systems. Our findings of the first example of a vertebrate species with a dysfunctional AID and secondary antibody diversification challenge the long-standing immunological concept that the loss of AID activity leads to immunodeficiency

Diasporic Language and Identity in “Namesake”

The present paper attempts to indicate the way through which Lahiri investigates the issue of name and immigrant's identity and belongingness in The Namesake. In the ancient era an enormous number of Indians immigrated to Far East Asia to advertise Buddhism. But in the modern time the Indian Diaspora describes the people who emigrated from land of India. Nowadays, the condition is basically the story of success of the Indian Diasporas settled in America., U.K. and Europe. This study considers the term Diaspora: and its function and role in the contemporary world where the issues such as multiculturalism, identity and belongingness are observed among the Indian diasporas. The namesake by Jhumpa Lahiri have vividly depicted Gauguli family’s immigrate to American. Alienation and self-identity are main lines to connect the whole story. The most significant and debatable elements that the Jhumpa Lahiri covers in this novel is to depict the issue of multiculturalism and its influence on the person's identity very beautifully and utterly. Therefore, the theme of alienation, of being a stranger in a foreign land, isolation from a group or an activity to which one should belong or in which one should be involved. Main character Ashima’s feeling of isolated is prominent throughout the novel

Evolutionary Comparative Analyses of DNA-Editing Enzymes of the Immune System: From 5-Dimensional Description of Protein Structures to Immunological Insights and Applications to Protein Engineering

The immune system is unique among all biological sub-systems in its usage of DNA-editing enzymes to introduce targeted gene mutations and double-strand DNA breaks to diversify antigen receptor genes and combat viral infections. These processes, initiated by specific DNA-editing enzymes, often result in mistargeted induction of genome lesions that initiate and drive cancers. Like other molecules involved in human health and disease, the DNA-editing enzymes of the immune system have been intensively studied in humans and mice, with little attention paid (< 1% of published studies) to the same enzymes in evolutionarily distant species. Here, we present a systematic review of the literature on the characterization of one such DNA-editing enzyme, activation-induced cytidine deaminase (AID), from an evolutionary comparative perspective. The central thesis of this review is that although the evolutionary comparative approach represents a minuscule fraction of published works on this and other DNA-editing enzymes, this approach has made significant impacts across the fields of structural biology, immunology, and cancer research. Using AID as an example, we highlight the value of the evolutionary comparative approach in discoveries already made, and in the context of emerging directions in immunology and protein engineering. We introduce the concept of 5-dimensional (5D) description of protein structures, a more nuanced view of a structure that is made possible by evolutionary comparative studies. In this higher dimensional view of a protein’s structure, the classical 3-dimensional (3D) structure is integrated in the context of real-time conformations and evolutionary time shifts (4th dimension) and the relevance of these dynamics to its biological function (5th dimension)

Diagnostic values of bronchodilator response versus 9-question questionnaire for asthma

Introduction: Several studies have investigated different tools for asthma diagnosis in order to reduce the cost and improve its early recognition. The goal of this study is to establish a short questionnaire to be used in practice for asthma screening and compare diagnostic values between this method and spirometric response to bronchodilators.Material and method: 208 patients presenting with chronic stable dyspnea (&gt; 6 months) and definite clinical diagnosis of chronic obstructive pulmonary disease, bronchiectasis, pulmonary fibrosis or asthma, were enrolled. 9 questions out of 43 based on the literature search were selected by regression analysis. Patients were asked to complete the questionnaire and then their spirometric responses to bronchodilators were evaluated. Results: Of all, 53.8% of cases were diagnosed clinically to have asthma. For establishing diagnosis of asthma, the bronchodilator test had 48.2% sensitivity, 78.1% specificity, 72% positive, 56.4% negative predictive values, 2.2 positive, 0.66 negative likeli-hood ratios, and false positive, false negative and accuracy of 21.9%, 51.8% and 62.01%, respectively. The revised 9 questions from the questionnaire had 97.3% sensitivity, 77.1% specificity, 83.2% positive, 96.1% negative predictive values, 4.24 positive,  0.03 negative likelihood ratios, 22.9% false positive, 2.7% false negative and 87.98% accuracy.Conclusions: The 9-question questionnaire had better diagnostic values in defining asthma in patients with chronic dyspnea than reversibility of airway obstruction to salbutamol and can be used as a useful screening test for diagnosis of asthma in clinical practice and for investigational purposes

Characterization and Transcript Expression Analyses of Atlantic Cod Viperin

Viperin is a key antiviral effector in immune responses of vertebrates including the Atlantic cod (Gadus morhua). Using cloning, sequencing and gene expression analyses, we characterized the Atlantic cod viperin at the nucleotide and hypothetical amino acid levels, and its regulating factors were investigated. Atlantic cod viperin cDNA is 1,342 bp long, and its predicted protein contains 347 amino acids. Using in silico analyses, we showed that Atlantic cod viperin is composed of 5 exons, as in other vertebrate orthologs. In addition, the radical SAM domain and C-terminal sequences of the predicted Viperin protein are highly conserved among various species. As expected, Atlantic cod Viperin was most closely related to other teleost orthologs. Using computational modeling, we show that the Atlantic cod Viperin forms similar overall protein architecture compared to mammalian Viperins. qPCR revealed that viperin is a weakly expressed transcript during embryonic development of Atlantic cod. In adults, the highest constitutive expression of viperin transcript was found in blood compared with 18 other tissues. Using isolated macrophages and synthetic dsRNA (pIC) stimulation, we tested various immune inhibitors to determine the possible regulating pathways of Atlantic cod viperin. Atlantic cod viperin showed a comparable pIC induction to other well-known antiviral genes (e.g., interferon gamma and interferon-stimulated gene 15-1) in response to various immune inhibitors. The pIC induction of Atlantic cod viperin was significantly inhibited with 2-Aminopurine, Chloroquine, SB202190, and Ruxolitinib. Therefore, endosomal-TLR-mediated pIC recognition and signal transducers (i.e., PKR and p38 MAPK) downstream of the TLR-dependent pathway may activate the gene expression response of Atlantic cod viperin. Also, these results suggest that antiviral responses of Atlantic cod viperin may be transcriptionally regulated through the interferon-activated pathway

Histopathologic Findings of Olfactory Mucosa in COVID-19 Patients

Background: Olfactory manifestations are common findings during the course of COVID-19, while exact physiopathology is not known Aim: We review histological changes of the nasal olfactory mucosa in COVID-19 non-survivors who died in the ICU. Methods: Sampling was done within 1 hour of death under direct vision. Specimens were taken medial to the middle turbinate in the cribriform area and embedded in paraffin blocks and stained by haematoxylin and eosin. Results: The most frequent histologic finding was the infiltration of inflammatory cells mostly comprised of lymphocytes. Inflammatory infiltration of mucosa was seen in all 11 patients with ulceration in 9 cases and neuritis in 3 cases.&nbsp; Conclusion: Inflammatory infiltration of olfactory mucosa may be associated with smell manifestations. Further histological studies will clarify the role of the nasal mucosa in the physiopathology of COVID-19 especially olfactory involvement

A machine learning based exploration of COVID-19 mortality risk

Early prediction of patient mortality risks during a pandemic can decrease mortality by assuring efficient resource allocation and treatment planning. This study aimed to develop and compare prognosis prediction machine learning models based on invasive laboratory and noninvasive clinical and demographic data from patients’ day of admission. Three Support Vector Machine (SVM) models were developed and compared using invasive, noninvasive, and both groups. The results suggested that non-invasive features could provide mortality predictions that are similar to the invasive and roughly on par with the joint model. Feature inspection results from SVM-RFE and sparsity analysis displayed that, compared with the invasive model, the non-invasive model can provide better performances with a fewer number of features, pointing to the presence of high predictive information contents in several non-invasive features, including SPO2, age, and cardiovascular disorders. Furthermore, while the invasive model was able to provide better mortality predictions for the imminent future, non-invasive features displayed better performance for more distant expiration intervals. Early mortality prediction using non-invasive models can give us insights as to where and with whom to intervene. Combined with novel technologies, such as wireless wearable devices, these models can create powerful frameworks for various medical assignments and patient triage

Patients with severe COVID-19 do not have elevated autoantibodies against common diagnostic autoantigens

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19) presents occasionally with an aberrant autoinflammatory response, including the presence of elevated circulating autoantibodies in some individuals. Whether the development of autoantibodies against self-antigens affects COVID-19 outcomes remains unclear. To better understand the prognostic role of autoantibodies in COVID-19, we quantified autoantibodies against 23 markers that are used for diagnosis of autoimmune disease. To this end, we used serum samples from patients with severe [intensive care unit (ICU)] and moderate (ward) COVID-19, across two to six consecutive time points, and compared autoantibody levels to uninfected healthy and ICU controls. Acute and post-acute serum (from 1 to 26 ICU days) was collected from 18 ICU COVID-19-positive patients at three to six time points; 18 ICU COVID-19-negative patients (sampled on ICU day 1 and 3); 21 ward COVID-19-positive patients (sampled on hospital day 1 and 3); and from 59 healthy uninfected controls deriving from two cohorts. Levels of IgG autoantibodies against 23 autoantigens, commonly used for autoimmune disease diagnosis, were measured in serum samples using MSD® U-PLEX electrochemiluminescence technology (MSD division Meso Scale Discovery®), and results were compared between groups. There were no significant elevations of autoantibodies for any of the markers tested in patients with severe COVID-19. Sample collections at longer time points should be considered in future studies, for assessing the possible development of autoantibody responses following infection with SARS-CoV-2

Impact of interferential current on recovery of pressure ulcers grade 1 and 2

Abstract Background: Pressure ulcers’ treatment imposes a considerable cost on health system and patients. Electrical stimulation has\ud already been introduced as an effective method for promoting wound healing. This study was conducted to determine the impact of interferential current (IF) on healing of pressure ulcers (grade1 and 2). Materials and Methods: In this clinical trial, 23 patients (12 as cases and 11 as controls) were recruited. The study group was treated with IF daily for 10 days. IF current was applied via isoplanar current with a sweep frequency of 30–99 Hz and with tolerable intensity for 15–20 min. Before intervention, condition of the wounds was assessed and recorded. Routine characteristics of the ulcers in both groups were recorded before intervention (first day) and on the fifth and tenth days after intervention. SPSS (ver. 13) with paired t‑test and Fisher’s exact test was also used to analyze the data. A P-value of 0.05 was considered significant. Results: According to one‑sample Kolmogorov–Smirnov test, demographic characteristics, features of ulcer, as well as the intensity of pain were not significantly different between the study and control groups. All patients in the control and study groups were complaining of pain (7.25 ± 1.21 in the intervention group vs. 6.35 ± 1.28 in the control group). Ulcer size decreased significantly in the study group (P = 0.012) with a significant reduction in pain intensity (P = 0.000), amount of discharge (P = 0.008), and level of edema (P = 0.000), compared to controls. Conclusion: As a first study in this field, the results showed that the use of IF current can accelerate pressure ulcer healing and reduce its size. As IF current can be considered as a deeper form of Transcutaneous Electrical Nerve Stimulation (TENS), it seems to be a safe method with no side effects. Key words: Healing, interferential current, pressure ulce

The Impact of Economic Policy Uncertainty on Exchange Rate Fluctuations with using the Nonlinear Autoregressive distributed lags Model (NARDL)

The purpose of this paper is to investigate the effect of economic policy uncertainty on exchange rate fluctuations in Iran. For this purpose, the data of the period 1368-1398 based on the frequency of quarterly data and the nonlinear autoregressive distributed lags have been used. The use of nonlinear models will lead to more realistic results than the response of the exchange rate variable to policy shocks. In this study, first, the exchange rate fluctuations index was modeled using the GARCH method, and in the second step, the effects of economic policy uncertainty in the form of positive and negative shocks on exchange rate fluctuations were estimated using the NARDL method. The results of the estimated model show that uncertainty in economic policies in the form of monetary and fiscal policy shocks has led to increased instability in the exchange rate in the country. The analysis of shocks showed that the impact of negative shocks on the exchange rate was more severe than positive monetary and financial shocks