The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation.

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.

Functional trait correlation network and proteomic analysis reveal multifactorial adaptation mechanisms to a climatic gradient associated with high altitude in the Himalayan region.

Globally occurring changes in environmental conditions necessitate extending our knowledge of the system-level mechanisms underlying plant adaptation to multifactorial stress conditions or stress combinations. This is crucial for designing new strategies to maintain plant performance under simultaneous abiotic pressure. Here, we conducted our study at Rohtang Pass and sampled Picrorhiza kurroa leaves along high-altitude gradient (3400, 3800 and 4100 meters above sea level) in the western Himalayas. The results showed the functional traits associated with morpho-anatomical structures and eco-physiological performances are highly variable. The air temperature and relative humidity represent dominant environmental factors among others that significantly regulate plant's physiological performance by adjusting the functional traits in altitude-specific manner. A trait coordination network is developed among significantly altered plant functional traits, which reveals high-altitude associated trait-based adaptation. Moreover, it reveals leaf area shows the highest degree, while photochemical quenching reflects the weighted degree of centrality in the network. Proteomic analysis reveals various stress-responsive proteins, including antioxidants were accumulated to deal with combined stress factors. Furthermore, a high-altitudinal protein interaction network unravels key players of alpine plant adaptation processes. Altogether, these systems demonstrate a complex molecular interaction web extending the current knowledge of high-altitudinal alpine plant adaptation, particularly in an endangered medicinal herb, P. kurroa.

Apolipoprotein E Is Upregulated in Blood and Circulating Monocytes of Indian Patients With Visceral Leishmaniasis.

Apolipoprotein E (ApoE) has been associated with several diseases including Parkinson's disease, Alzheimer's and multiple sclerosis. ApoE also has documented immunomodulatory functions. We investigated gene expression in circulating monocytes and in bone marrows of patients with visceral leishmaniasis (VL) living in an endemic area in Bihar, India, and contrasted these with control healthy subjects or other diagnostic bone marrows from individuals in the same region. Samples from VL patients were obtained prior to initiating treatment. Our study revealed significant upregulated expression of the apoE transcript in patients with VL. Furthermore, the levels of ApoE protein were elevated in serum samples of subjects with VL compared with healthy endemic controls. These observations may provide clues regarding the complex interactions between lipid metabolism and immunoregulation of infectious and inflammatory diseases.

Evaluation of blood based quantitative PCR as a molecular diagnostic tool for post kala-azar dermal leishmaniasis (PKDL).

BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL) is a consequential dermal manifestation of visceral leishmaniasis (VL), serving as a parasite reservoir. The traditional diagnostic approach, which requires an invasive skin biopsy is associated with inherent risks and necessitates skilled healthcare practitioners in sterile settings. There is a critical need for a rapid, less invasive method for Leishmania detection. The main objective of this study was to evaluate and compare the diagnostic efficacy of PCR and qPCR in detecting PKDL, utilizing both skin and blood samples and to assess the utility of blood samples for molecular diagnosis. METHODS AND RESULTS: 73 individuals exhibiting clinical symptoms of PKDL and who had tested positive for rK39 rapid diagnostic test (RDT) were enrolled in this study. For the diagnosis of PKDL, both PCR and real-time quantitative PCR (qPCR), employing SYBR Green and TaqMan assays, were performed on blood and skin matched samples. qPCR results using both TaqMan and SYBR Green assay, indicated higher parasite loads in the skin compared to blood, as evident by the Ct values. Importantly, when blood samples were used for PKDL diagnosis by qPCR, an encouraging sensitivity of 69.35% (TaqMan assay) and 79.36% (SYBR Green) were obtained, compared to 8.2% with conventional PCR. CONCLUSION: The findings of the study suggest the potential utility of blood for molecular diagnosis by qPCR, offering a less invasive alternative to skin biopsies in field setting for the early detection of parasitaemia in PKDL patients and effective management and control of the disease.

The regulation of CD4+ T cells during malaria.

Malaria is a major global health problem. Despite decades of research, there is still no effective vaccine to prevent disease in the majority of people living in malaria-endemic regions. Additionally, drug treatment options are continually threatened by the emergence of drug-resistant parasites. Immune responses generated against Plasmodium parasites that cause malaria are generally not sufficient to prevent the establishment of infection and can even contribute to the development of disease, unless individuals have survived multiple infections. Research conducted in experimental models, controlled human malaria infection studies, and with malaria patients from disease-endemic areas indicate the rapid development of immunoregulatory pathways in response to Plasmodium infection. These "imprinted" immune responses limit inflammation, and likely prevent progression to severe disease manifestations. However, they also cause slow acquisition of immunity and possibly hamper the development of vaccine-mediated protection against disease. A major target for and mediator of the immunoregulatory pathways established during malaria are CD4+ T cells that play critical roles in priming phagocytic cells to capture and kill malaria parasites, as well as helping B cells produce functional anti-parasitic antibodies. In this review, we describe mechanisms of CD4+ T cell activation during malaria and discuss the immunoregulatory mechanisms that develop to dampen their anti-parasitic and pathological functions. We also offer some ideas about how host-directed approaches might be applied to modulate CD4+ T cell functions to improve vaccine responses and enhance development of natural immunity.

Recognition of immune reactive proteins as a potential multiepitope vaccine candidate of Taenia solium cysticerci through proteomic approach.

Metacestode, the larva of Taenia solium, is the causative agent for neurocysticercosis (NCC), which causes epilepsy. The unavailability of a vaccine against human NCC is a major cause for its widespread prevalence across the globe. Therefore, the development of a reliable vaccine against NCC is the need of the hour. Employing a combination of proteomics and immunoinformatics, we endeavored to formulate a vaccine candidate. The immune reactive cyst fluid antigens of T. solium were identified by immune-blotting two-dimensional gels with NCC patient's sera, followed by Matrix-assisted laser desorption-ionization analysis. We performed a detailed proteomic study of these immune reactive proteins by utilizing immune-informatics tools, identified the nontoxic, nonallergic, B-cell epitopes, and collected epitopes with the least sequence homology with human and other Taenia species. These epitopes were joined through linkers to construct a multiepitope vaccine. Different physiochemical parameters such as molecular weight (23.82 kDa), instability (39.91), and aliphatic index (49.61) were calculated to ensure the stability of the linked peptides vaccine. The vaccine demonstrated stable interactions with different immune receptors like Toll-like receptor 4 and IgG confirming that it will effectively stimulate the host immune response. We anticipate that our designed B-cell linear epitope-based vaccine will show promising results in in vitro and in vivo assays. This study provides a platform that would be useful to develop other suitable vaccine candidates to prevent helminthic neglected tropical diseases in near future.

A randomised controlled trial of long NY-ESO-1 peptide-pulsed autologous dendritic cells with or without alpha-galactosylceramide in high-risk melanoma.

AIM: We have previously reported that polyfunctional T cell responses can be induced to the cancer testis antigen NY-ESO-1 in melanoma patients injected with mature autologous monocyte-derived dendritic cells (DCs) loaded with long NY-ESO-1-derived peptides together with α-galactosylceramide (α-GalCer), an agonist for type 1 Natural Killer T (NKT) cells. OBJECTIVE: To assess whether inclusion of α-GalCer in autologous NY-ESO-1 long peptide-pulsed DC vaccines (DCV + α-GalCer) improves T cell responses when compared to peptide-pulsed DC vaccines without α-GalCer (DCV). DESIGN, SETTING AND PARTICIPANTS: Single-centre blinded randomised controlled trial in patients ≥ 18 years old with histologically confirmed, fully resected stage II-IV malignant cutaneous melanoma, conducted between July 2015 and June 2018 at the Wellington Blood and Cancer Centre of the Capital and Coast District Health Board. INTERVENTIONS: Stage I. Patients were randomised to two cycles of DCV or DCV + α-GalCer (intravenous dose of 10 × 106 cells, interval of 28 days). Stage II. Patients assigned to DCV + α-GalCer were randomised to two further cycles of DCV + α-GalCer or observation, while patients initially assigned to DCV crossed over to two cycles of DCV + α-GalCer. OUTCOME MEASURES: Primary: Area under the curve (AUC) of mean NY-ESO-1-specific T cell count detected by ex vivo IFN-γ ELISpot in pre- and post-treatment blood samples, compared between treatment arms at Stage I. Secondary: Proportion of responders in each arm at Stage I; NKT cell count in each arm at Stage I; serum cytokine levels at Stage I; adverse events Stage I; T cell count for DCV + α-GalCer versus observation at Stage II, T cell count before versus after cross-over. RESULTS: Thirty-eight patients gave written informed consent; 5 were excluded before randomisation due to progressive disease or incomplete leukapheresis, 17 were assigned to DCV, and 16 to DCV + α-GalCer. The vaccines were well tolerated and associated with increases in mean total T cell count, predominantly CD4+ T cells, but the difference between the treatment arms was not statistically significant (difference - 6.85, 95% confidence interval, - 21.65 to 7.92; P = 0.36). No significant improvements in T cell response were associated with DCV + α-GalCer with increased dosing, or in the cross-over. However, the NKT cell response to α-GalCer-loaded vaccines was limited compared to previous studies, with mean circulating NKT cell levels not significantly increased in the DCV + α-GalCer arm and no significant differences in cytokine response between the treatment arms. CONCLUSIONS: A high population coverage of NY-ESO-1-specific T cell responses was achieved with a good safety profile, but we failed to demonstrate that loading with α-GalCer provided an additional advantage to the T cell response with this cellular vaccine design. CLINICAL TRIAL REGISTRATION: ACTRN12612001101875. Funded by the Health Research Council of New Zealand.

Phosphatonins: From Discovery to Therapeutics.

OBJECTIVE: Phosphate is crucial for cell signaling, energy metabolism, nucleotide synthesis, and bone mineralization. The gut-bone-parathyroid-kidney axis is influenced by parathyroid hormone, 1,25-dihydroxyvitamin D, and phosphatonins, especially fibroblast growth factor 23 (FGF23). These hormones facilitate maintenance of phosphate homeostasis. This review summarizes current knowledge regarding the phosphate homeostasis, phosphatonin pathophysiology, and clinical implications of FGF23-related hypophosphatemic disorders, with specific focus on burosumab treatment. METHOD: A focused literature search of PubMed was conducted. RESULTS: Phosphatonins including FGF23, secreted frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 7 play a pathogenic role in several hypophosphatemic disorders. Excess FGF23 inhibits sodium-dependent phosphate cotransporters (NaPi-2a and NaPi-2c), resulting in hyperphosphaturia and hypophosphatemia. Additionally, FGF23 suppresses 1,25-dihydroxyvitamin D synthesis in the proximal renal tubule, and thus, it indirectly inhibits intestinal phosphate absorption. Disorders of FGF23-related hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia/McCune-Albright syndrome, and tumor-induced osteomalacia (TIO). Complications of conventional therapy with oral phosphate and vitamin D analogs comprise gastrointestinal distress, hypercalcemia, nephrocalcinosis, and secondary/tertiary hyperparathyroidism. In both children and adults with XLH and TIO, the anti-FGF23 antibody burosumab exhibits a favorable safety profile and is associated with healing of rickets in affected children and improvement of osteomalacia in both children and adults. CONCLUSION: The treatment paradigm for XLH and TIO is changing based on data from recent clinical trials. Research suggest that burosumab is effective and safe for pediatric and adult patients with XLH or TIO.

Population-wide genetic analysis of Ovar-DQA1 and DQA2 loci across sheep breeds in India revealed their evolutionary importance and fitness of sheep in a tropical climate.

Genetic variability at the major histocompatibility complex (MHC) is important in any species due to significant role played by MHC for antigen presentation. DQA locus has not been studied for its genetic variability across sheep population in India. In the present study, MHC of sheep at DQA1 and DQA2 loci were evaluated across 17 Indian sheep breeds. Results revealed high degree of heterozygosity (10.34% to 100% for DQA1 and 37.39 to 100% for DQA2). 18 DQA1 alleles and 22 DQA2 alleles were isolated in different breeds. Nucleotide content for DQA region revealed richness of AT content (54.85% for DQA1 and 53.89% for DQA2). DQA1 and DQA2 sequences clustered independently. We could see evidence of divergence of DQA as DQA1 and DQA2 across sheep breeds. Wu-Kabat variability index revealed vast genetic variation across DQA1 and DQA2, specifically at peptide binding sites (PBS) that consisted 21 residues for DQA1 and 17 residues for DQA2. Evolutionary analysis revealed the presence of positive and balancing selection for DQA1 locus, however DQA2 was under purifying selection across sheep breeds. Higher heterozygosity and large diversity at both loci especially at PBS indicated the fitness of the sheep population for evading pathogens and adapt to the harsh tropical climate.

Cross-population genetic analysis revealed genetic variation and selection in the Ovar-DRB1 gene of Indian sheep breeds.

In sheep, MHC variability is studied widely to explore disease association. The aim of the current study was to explore the genetic diversity of Ovar-DRB diversity across sheep breeds of India. Here, Ovar-DRB1 locus was studied across 20 sheep breeds. DRB1 was amplified (301 bp) and sequenced using a PCR-sequence-based typing approach. Results revealed a high degree of heterozygosity across breeds (mean: 73.99%). Overall mean distance for DRB1 was highest in Sangamneri (0.18) and lowest in Madgyal sheep (0.10). There was a higher rate of transition, across breeds. Further, 39 alleles were isolated in different breeds, out of which 10 were new. To allow easy access and use of the immune-polymorphic database, an online database management system was launched (http://www.mhcdbms.in/). Nucleotide content across breeds for the DRB1 region revealed the richness of GC content (59.26%). Wu-Kabat index revealed vast genetic variation across peptide binding sites (PBS) of DRB1. Residues 6, 66, 69, 52, and 81, were polymorphic showing utility for antigen presentation. All breeds were under positive selection for DRB1 locus (dN > dS). Study revealed the importance of DRB locus diversity for beta chain specifically at PBS across sheep breeds of the Indian subcontinent and presented evidence of positive selection for DRB owing to its evolutionary significance.

High-Resolution Mass Spectrometry for the Measurement of PTH and PTH Fragments: Insights into PTH Physiology and Bioactivity.

Full-length parathyroid hormone (PTH 1-84) is crucial for the regulation of calcium and phosphate homeostasis and bone remodeling. PTH 1-84 is metabolized into various PTH fragments, which are measured with varying levels of efficiency by PTH immunoassays. These PTH fragments, which increase in serum as CKD progresses, could potentially modulate the effects of PTH 1-84 and contribute to CKD-associated bone disorders. To obtain a true biologic representation of total PTH bioactivity, it is necessary to measure not only PTH 1-84 but also PTH fragments that are present in circulation. Traditional second-generation PTH immunoassays collectively measure PTH 1-84, PTH fragments, and post-translationally modified PTH 1-84, making it difficult to accurately predict the character of underlying renal osteodystrophy. This review highlights current advances in methods available for PTH measurement and the clinical relevance of PTH fragments in CKD. We emphasize the usefulness of mass spectrometry as a potential reference method for PTH measurement.

Benzenesulfonamides with trisubstituted triazole motif as selective carbonic anhydrase I, II, IV, and IX inhibitors.

Twenty novel 1,2,3-triazole benzenesulfonamides featuring nitrile 8a-g, carbothioamide 9a-f, and N'-hydroxycarboximidamide 10a-g functionalities were designed and synthesized to improve potency and selectivity as carbonic anhydrase inhibitors (CAIs). The synthesized 1,2,3-triazole compounds were tested in vitro as CAIs against four physiologically and pharmacologically relevant isoforms of human carbonic anhydrase (hCA I, II, IV, and IX). Compounds 8a-g, 9a-f, and 10a-g displayed variable inhibition constants ranging from 8.1 nM to 3.22 µM for hCA I, 4.7 nM to 0.50 µM for hCA II, 15.0 nM to 3.7 µM for hCA IV, and 29.6 nM to 0.27 µM for hCA IX. As per the inhibition data profile, compounds 9a-e exhibited strong efficacy for hCA IV, whereas the inhibition was found to be somewhat diminished in the case of hCA IX by nearly all the compounds. A computational protocol based on docking and MM-GBSA was conducted to reveal the plausible interactions of the targeted sulfonamides within the hCA II and IX binding sites. The outcomes of appending various functionalities at the C-4 position of the 1,2,3-triazole motif over the inhibition potential and selectivity of the designed sulfonamides were examined with a potential for the discovery of new isoform selective CAIs. The CAI and SAR data established the significance of the synthesized 1,2,3-triazoles as building blocks for developing CAI drugs.

Clinico-laboratory Profile and Outcomes of Megaloblastic Anemia presenting as Severe Pyrexial Illness mimicking Tropical Infection.

BACKGROUND: Anemia-causing fever has been described in patients with megaloblastic anemia. Although the exact mechanism of this is unknown, high-grade fever is relatively less reported. MATERIALS AND METHODS: This prospective observational study included all new cases of megaloblastic anemia presenting with febrile illness (>101°F) during a 3-year period. Patients with existing anemia, comorbidities, and other causes of macrocytosis were excluded. A detailed evaluation for megaloblastic anemia and workup for excluding tropical infections was done. The patients were treated with parenteral vitamin B12, folic acid, and other hematinics. RESULTS: Around 24 cases of megaloblastic anemia presenting with high-grade fever were included, with 14 (58.3%) males, mean duration of fever 7.7 days (4-18 days), and 09 (37.5%) having temperature >103°F. The mean hemoglobin (Hb) was 8.15 g/dL (3.7-11.1 g/dL), the mean corpuscular volume (MCV) was 111 ± 7.8 fL, 18 (75%) had unconjugated hyperbilirubinemia, the mean lactate dehydrogenase (LDH) was 814 ± 24 IU/L, and 21 (87.5%) had low B12 or folate levels. Most showed good therapeutic response to B12 or folic acid with defervescence in 1-5 days (mean 2.6 days) and improvement in lab parameters in 1 week. The study population was divided into those with temperature ≥103°F, and temperature <103°F it was seen that there was a significant association (p < 0.05) with leucocyte count of ≤3000/cumm, and MCV ≥110 fL, in patients with temperature ≥103°F Conclusion: Megaloblastic anemia should be considered in the differentials of a patient presenting with a febrile illness with no clinical localization and a negative initial fever workup. Early identification and prompt therapy of this easily treatable disorder are very essential.

Preclinical Investigation of Transdermal Route for Enhanced Bio-performance of Duloxetine HCl.

The aim of the study was to develop and optimise drug-in-adhesive (DIA) transdermal patch of duloxetine HCl for enhanced drug delivery. DIA patch so developed reduced the dose and dosing frequency by enhancing bio-performance of the drug. A transdermal DIA patch having Duro-Tak 87-2287 as DIA polymer and Transcutol P as permeation enhancer loaded with 40% drug previously complexed with MeßCD duly characterised (FTIR, DSC, and SEM) was developed for in vivo study. Pharmacokinetic parameters of developed formulation were assessed and compared with oral route of administration. Among various permeation enhancers (PEs), Transcutol P exhibited most enhanced permeation (ER ≈ 1.99) in terms of flux and Q24 compared to control group having. Mean of maximum plasma concentration (Cmax) and area under time-concentration curve (AUC0-72) in Wistar rats (n = 6) for transdermal patch (10 mg/kg) was found to be 70.31 ± 11.2 ng/ml and 2997.29 ± 387.4 ng/ml*h, respectively, and were considerably higher than oral dose of DLX (20 mg/kg and 10 mg/kg). Albeit, T1/2 was higher in case of transdermal delivery, but this was due to sustained behaviour of delivery system. These findings highlight the significance of both inclusion complexation and transdermal delivery of DLX using DIA patch for efficient drug absorption.

Preventing Risks of Infections and Medication Errors in IV therapy (PRIME): a patient safety initiative.

BACKGROUND: Two major avoidable reasons for adverse events in hospital are medication errors and intravenous therapy-induced infections or complications. Training for clinical staff and compliance to patient safety principles could address these. METHODS: Joint Commission International (JCI) consultants created a standardised, 6-month training programme for clinical staff in hospitals. Twenty-one tertiary care hospitals from across south-east Asia took part. JCI trained the clinical consultants, who trained hospital safety champions, who trained nursing staff. Compliance and knowledge were assessed, and monthly audits were conducted. RESULTS: There was an overall increase of 29% in compliance with parameters around medication preparation and vascular access device management. CONCLUSION: The programme improved safe practice around preparing medications management and managing vascular access devices. The approach could be employed as a continuous quality improvement initiative for the prevention of medication errors and infusion-associated complications.

Successful T replete haploidentical HSCT with post-transplant cyclophosphamide in two patients with Wiskott-Aldrich syndrome.

We describe two young patients with Wiskott-Aldrich Syndrome (WAS) who were treated by T-replete hematopoietic stem cell transplantation (HSCT) from the HLA haploidentical father according to a modified Baltimore protocol. Whereas similar protocols have been successfully used in various malignant and non-malignant diseases, this is the first report for this particular disease. The data being presented pertains to the report about two successful haploidentical transplants with post transplant cyclophosphamide (PTCY) after busulfan-based conditioning.

Bone marrow transplant: A two-decade single centre hematology experience.

Background: Bone Marrow Transplant (BMT) is a curative form of therapy for many hematological disorders in both the adult and pediatric patients. The availability of BMT in the AFMS at AHRR for the last 02 decades has been a game changer for the patients. Methods: We reviewed our BMT data since the inception of the program till Feb 2023. Results: Over 700 patients with more than 23 different types of hematological disorders have undergone this procedure 58%% patients underwent an Autologous BMT and 42% an allogenic BMT. Autologous BMT for Multiple Myeloma and Allogenic BMT for Aplastic Anemia and Acute Leukemias have been the most common indications. 73% patients were adults, and 27% patients were of the pediatric age group. The male: female ratio was 2:1. The spectrum of allogenic Hematopoietic Stem Cell Transplant (HSCT) has expanded from Matched Sibling Donor (MSD) transplants to Matched Unrelated Donor (MUD) Transplants and Haploidentical Donor Transplants. 93% of our Allogenic BMT patients underwent a MSD BMT, 1% MUD BMT and 06% Haploidentical BMT. Today no patient with a malignant hematological disorder requiring a BMT is denied the procedure due to the lack of an HLA donor due to the availability of haploidentical BMT. Conclusion: The evolution of a BMT program has a long learning curve and the expanded pool of eligible donors has led to a situation of "transplant for all". Haploidentical HSCT for nonmalignant hematological disorders is an unmet need. CART cell therapy and Cellular therapies need to be prioritized for future inclusion.

Cryo-EM reveals conformational flexibility in apo DNA polymerase ζ.

The translesion synthesis (TLS) DNA polymerases Rev1 and Polζ function together in DNA lesion bypass during DNA replication, acting as nucleotide inserter and extender polymerases, respectively. While the structural characterization of the Saccharomyces cerevisiae Polζ in its DNA-bound state has illuminated how this enzyme synthesizes DNA, a mechanistic understanding of TLS also requires probing conformational changes associated with DNA- and Rev1 binding. Here, we used single-particle cryo-electron microscopy to determine the structure of the apo Polζ holoenzyme. We show that compared with its DNA-bound state, apo Polζ displays enhanced flexibility that correlates with concerted motions associated with expansion of the Polζ DNA-binding channel upon DNA binding. We also identified a lysine residue that obstructs the DNA-binding channel in apo Polζ, suggesting a gating mechanism. The Polζ subunit Rev7 is a hub protein that directly binds Rev1 and is a component of several other protein complexes such as the shieldin DNA double-strand break repair complex. We analyzed the molecular interactions of budding yeast Rev7 in the context of Polζ and those of human Rev7 in the context of shieldin using a crystal structure of Rev7 bound to a fragment of the shieldin-3 protein. Overall, our study provides new insights into Polζ mechanism of action and the manner in which Rev7 recognizes partner proteins.

Amphiregulin in cellular physiology, health, and disease: Potential use as a biomarker and therapeutic target.

Amphiregulin (AREG), which acts as one of the ligands for epidermal receptor growth factor receptor (EGFR), plays a crucial role in tissue repair, inflammation, and immunity. AREG is synthesized as membrane-anchored pre-protein, and is excreted after proteolytic cleavage, and serves as an autocrine or paracrine factor. After engagement with the EGFR, AREG triggers a cascade of signaling events required for many cellular physiological processes including metabolism, cell cycle, and proliferation. Under different inflammatory and pathogenic conditions, AREG is expressed by various activated immune cells that orchestrate both tolerance and host resistance mechanisms. Several factors including xenobiotics, cytokines, and inflammatory lipids have been shown to trigger AREG gene expression and release. In this review, we discuss the structure, function, and regulation of AREG, its role in tissue repair, inflammation, and homeostasis as well as the potential of AREG as a biomarker and therapeutic target.