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1.
J Phys Chem Lett ; 15(15): 4206-4211, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38598716

ABSTRACT

Understanding the nanoscale elastic-size-effects of atomically thin transition-metal dichalcogenides (TMDs) as a function of thickness underpins the avenue of flexible 2D electronics. In this work, we employed the atomic force acoustic microscopy (AFAM) technique to investigate the thickness-dependent elastic properties of CVD grown 2H-MoS2 films. The monolayer MoS2 exhibited a Young's modulus of 273 ± 27 GPa. Our systematic analysis from bulk to monolayer suggests that the 2H-MoS2 phase exhibits nanoscale elastic-stiffening behavior with decreasing number of layers (thickness). The Young's modulus increased by a factor of ∼2.7 for monolayer MoS2 when compared with the bulk. First-principle DFT calculations affirm the nanoscale elastic-stiffening behavior of MoS2 with decreasing number of layers. Our findings suggest that the observed elastic stiffening is due to the interlayer sliding, which may be facilitated by defects in MoS2 layers. The observed elastic stiffening may be of potential importance for understanding TMD based nanomechanical devices.

2.
Mater Horiz ; 10(12): 5942-5949, 2023 Nov 27.
Article in English | MEDLINE | ID: mdl-37880977

ABSTRACT

Hybrid improper ferroelectricity is a useful tool to design ABO3/A'BO3 polar superlattices from non polar building blocks. In this study, we have designed high polarization-low switching barrier hybrid improper ferroelectric superlattices with efficient polarization, and polarization-magnetization switching properties above room temperature, using density functional theory and ab initio molecular dynamics simulations. Superlattices with a chemical formula of (AAlO3)m/(A'AlO3)n, where m/n = 1/1, 1/3, 3/1, 1/5 and 5/1, A, A' = Lanthanide and Y cations are considered to outline the design principles behind polarization switching and (LaFeO3)3/(CeFeO3)1 is investigated for polarization-magnetization switching. We find that the unconventional switching paths via out-of-phase rotation QR- (a0a0c-) and tilt precession QTP always yield lower switching barrier compared to those via in-phase rotation QR+ (a0a0c+) and tilt QT (a-a-c0) of BO6 octahedra. Results from ab initio molecular dynamics simulations estimate the temperature at which the lowest energy barrier can be overcome. It is possible to tune the polarization switching barrier by tuning the tolerance factor, A,A' cation radius mismatch and super lattice periodicity. For switching via QR-, the switching barrier varies exponentially with rotation angle, indicating how high switching barrier is expected for systems, away from cubic symmetry. We provide a recipe to overcome such a bottleneck by tuning superlattice periodicity. Finally, we have proposed the multiferroic device application concept through a proposed polarization-temperature hysteresis loop and magnetization switching.

3.
J Am Chem Soc ; 145(33): 18549-18559, 2023 Aug 23.
Article in English | MEDLINE | ID: mdl-37579341

ABSTRACT

Organic-inorganic metal hybrids with their tailorable lattice dimensionality and intrinsic spin-splitting properties are interesting material platforms for spintronic applications. While the spin decoherence process is extensively studied in lead- and tin-based hybrids, these systems generally show short spin decoherence lifetimes, and their correlation with the lattice framework is still not well-understood. Herein, we synthesized magnetic manganese hybrid single crystals of (4-fluorobenzylamine)2MnCl4, ((R)-3-fluoropyrrolidinium)MnCl3, and (pyrrolidinium)2MnCl4, which represent a change in lattice dimensionality from 2D and 1D to 0D, and studied their spin decoherence processes using continuous-wave electron spin resonance spectroscopy. All manganese hybrids exhibit nanosecond-scale spin decoherence time τ2 dominated by the symmetry-directed spin exchange interaction strengths of Mn2+-Mn2+ pairs, which is much longer than lead- and tin-based metal hybrids. In contrast to the similar temperature variation laws of τ2 in 2D and 0D structures, which first increase and gradually drop afterward, the 1D structure presents a monotonous rise of τ2 with the temperatures, indicating the strong correlation of spin decoherence with the lattice rigidity of the inorganic framework. This is also rationalized on the basis that the spin decoherence is governed by the competitive contributions from motional narrowing (prolonging the τ2) and electron-phonon coupling interaction (shortening the τ2), both of which are thermally activated, with the difference that the former is more pronounced in rigid crystalline lattices.

4.
Life Sci ; 329: 121911, 2023 Sep 15.
Article in English | MEDLINE | ID: mdl-37429416

ABSTRACT

AIMS: Identification of the progress of non-alcoholic fatty liver disease (NAFLD) is crucial for their effective treatment. Circulating peripheral blood mononuclear cells (PBMC) could be a surrogate monitor instead of complicated and expensive biopsies. Changes in immuno-metabolic status in NAFLD patients may be reflected by an expression of different PBMC-specific molecular markers. It was hypothesized that impaired autophagy with enhanced inflammasome activation is a critical molecular event in PBMC that could contribute to systemic inflammation associated with NAFLD progression. MAIN METHODS: A cross-sectional study with a sample size of 50 subjects were undertaken from a governmental facility in Kolkata, India. Major anthropometric, biochemical, and dietary parameters were recorded. Cellular and serum samples of NAFLD patients were analyzed for oxidative stress, inflammation, inflammasome activation, and autophagic flux by western blot, flow cytometry, immunocytochemistry. KEY FINDINGS: Baseline anthropometric and clinical parameters were found associated with NAFLD severity. Elevated systemic inflammation was reflected by higher proinflammatory markers like iNOS, Cox-2, IL-6, TNF-α, IL-1ß, hsCRP in the serum of NAFLD subjects (p < 0.05). ROS-induced NLRP3 inflammasomes marker proteins were upregulated (p < 0.05) in PBMC along with NAFLD severity. Expression of autophagic markers such as LC3B, Beclin-1 and its regulator pAMPKα were found diminished (p < 0.05) with a concomitant rise of p62. Colocalization of NLRP3 with LC3B proteins in PBMC was found diminished along NAFLD severity. SIGNIFICANCE: Present data provide mechanistic evidence of impaired autophagy and intracellular ROS triggered inflammasome activation in PBMC, which could potentially exacerbate NAFLD severity.


Subject(s)
Inflammasomes , Non-alcoholic Fatty Liver Disease , Humans , Inflammasomes/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Leukocytes, Mononuclear/metabolism , Reactive Oxygen Species/pharmacology , Cross-Sectional Studies , Inflammation , Autophagy
5.
Indian Econ Rev ; : 1-23, 2023 May 31.
Article in English | MEDLINE | ID: mdl-37360998

ABSTRACT

In an emerging market economy (EME) that depends largely on bank-credit, it is important to decipher whether supply-side or demand-side factors are responsible for a sluggish credit growth phase. A formal empirical analysis using Indian data and a disequilibrium model suggests that demand side factors have majorly contributed to the credit slowdown during the post-GFC period and prior to the pandemic. This could be because of adequate supply of funds, and several concerted policy actions taken by the regulatory authorities to mitigate concerns over the asset quality risks. In contrast, lower investment demand and global supply side bottlenecks have often contributed to demand side weaknesses, suggesting the need for strong policy support to uphold credit demand.

6.
RSC Adv ; 12(48): 31046-31055, 2022 Oct 27.
Article in English | MEDLINE | ID: mdl-36349037

ABSTRACT

In this article, we have systematically investigated the structural, electronic, magnetic, and spin-based thermoelectric properties of K2W(Cl/Br)6 by first-principles calculation. The obtained negative formation energy confirmed the thermodynamic stability of K2W(Cl/Br)6, while the tolerance factor calculation showed their cubic phase stability. In addition, we have estimated the elastic constants which confirmed the mechanical stability of K2W(Cl/Br)6. Further, the spin-polarized band structure and density of states calculations revealed the half-metallic nature with high Curie temperature (T c) values of 613 K and 597 K for K2WCl6 and K2WBr6, respectively. Moreover, we have studied the temperature variation of thermoelectric properties such as k l, σ, k e, S, PF, and ZT. Such results showed that higher ZT values for spin-down channels are obtained from ultra-low k e, and high PF. Therefore, K2W(Cl/Br)6 are viable thermoelectric and spintronic materials.

7.
Nano Lett ; 22(22): 9020-9026, 2022 Nov 23.
Article in English | MEDLINE | ID: mdl-36367392

ABSTRACT

Halide perovskites have been widely explored for numerous optoelectronic applications among which phototransistors have appeared as one of the most promising light signal detectors. However, it is still a great challenge to endow halide perovskites with both mobility and high photosensitivity because of their high sensitivity to moisture in ambient atmosphere. Here, we explore an FAPbBr3 perovskite quantum dot (QD) phototransistor with bandlike charge transport and measure a dark hole mobility of 14.2 cm2 V-1 s-1 at ambient atmosphere. Attaining both high mobility and good optical figures of merit, a detectivity of ∼1016 Jones is achieved, which is a record for halide perovskite nanocrystals. Simple A-site salt (FABr) treatments offer a mechanism for connecting between perovskite QDs for better charge transfer in high-quality devices. All of these important properties are superior to most advanced inorganic semiconductor phototransistors, indicating a promising future in optoelectronic applications.

8.
Orphanet J Rare Dis ; 17(1): 176, 2022 04 27.
Article in English | MEDLINE | ID: mdl-35477461

ABSTRACT

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma (chromophobe). Here, we comprehensively studied the mutational background of 31 clinically diagnosed BHDS patients and their 74 asymptomatic related members from 15 Indian families. RESULTS: Targeted amplicon next-generation sequencing (NGS) and Sanger sequencing of FLCN in patients and asymptomatic members revealed a total of 76 variants. Among these variants, six different types of pathogenic FLCN mutations were detected in 26 patients and some asymptomatic family members. Two of the variants were novel mutations: an 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and a splice acceptor mutation (c.1301-1G > A). Two variants were Clinvar reported pathogenic mutations: a stop-gain (c.634C > T) and a 4-nucleotide duplication (c.1329_1332dupAGCC). Two known variants were: hotspot deletion (c.1285delC) and a splice donor mutation (c.1300 + 1G > A). FLCN mutations could not be detected in patients and asymptomatic members from 5 families. All these mutations greatly affected the protein stability and FLCN-FNIP2 interaction as observed by molecular docking method. Family-based association study inferred pathogenic FLCN mutations are significantly associated with BHDS. CONCLUSION: Six pathogenic FLCN mutations were detected in patients from 10 families out of 15 families in the cohort. Therefore, genetic screening is necessary to validate the clinical diagnosis. The pathogenic mutations at FLCN affects the protein-protein interaction, which plays key roles in various metabolic pathways. Since, pathogenic mutations could not be detected in exonic regions of FLCN in 5 families, whole genome sequencing is necessary to detect all mutations at FLCN and/or any undescribed gene/s that may also be implicated in BHDS.


Subject(s)
Birt-Hogg-Dube Syndrome , Kidney Neoplasms , Birt-Hogg-Dube Syndrome/genetics , Female , Humans , Male , Molecular Docking Simulation , Mutation/genetics , Nucleotides , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
9.
J Genet ; 1012022.
Article in English | MEDLINE | ID: mdl-35129133

ABSTRACT

In genomewide association study (GWAS) of a complex phenotype, a large number of variants, many with small effect sizes, are found to contribute to the variability of the phenotype. Subsequent to the identification of such variants in a GWAS, it is of interest to estimate the risk jointly conferred by the variants. We propose three different strategies of combining the risk SNPs to calculate an allele dosage score. Using simulations, we evaluate the different measures of allele dosage score with respect to the risk prediction accuracy of a binary trait and the proportion of variance explained for a quantitative trait. For a binary trait, an allele dosage score defined based on log odds ratio performs marginally better than the other two measures. For a quantitative trait, the measure based on the standardized slope coefficient in linear regression of the trait on single-nucleotide polymorphism (SNP) genotypes performs better than the measures using the weights proportional to log P-value and the proportion of variance explained. We demonstrate the utility of these measures using a real data on type 2 diabetes and fasting blood sugar level in a south Indian population.


Subject(s)
Diabetes Mellitus, Type 2 , Polymorphism, Single Nucleotide , Genome-Wide Association Study/methods , Genotype , Humans , Phenotype
10.
Ocul Surf ; 21: 279-298, 2021 07.
Article in English | MEDLINE | ID: mdl-33865984

ABSTRACT

PURPOSE: Single cell (sc) analyses of key embryonic, fetal and adult stages were performed to generate a comprehensive single cell atlas of all the corneal and adjacent conjunctival cell types from development to adulthood. METHODS: Four human adult and seventeen embryonic and fetal corneas from 10 to 21 post conception week (PCW) specimens were dissociated to single cells and subjected to scRNA- and/or ATAC-Seq using the 10x Genomics platform. These were embedded using Uniform Manifold Approximation and Projection (UMAP) and clustered using Seurat graph-based clustering. Cluster identification was performed based on marker gene expression, bioinformatic data mining and immunofluorescence (IF) analysis. RNA interference, IF, colony forming efficiency and clonal assays were performed on cultured limbal epithelial cells (LECs). RESULTS: scRNA-Seq analysis of 21,343 cells from four adult human corneas and adjacent conjunctivas revealed the presence of 21 cell clusters, representing the progenitor and differentiated cells in all layers of cornea and conjunctiva as well as immune cells, melanocytes, fibroblasts, and blood/lymphatic vessels. A small cell cluster with high expression of limbal progenitor cell (LPC) markers was identified and shown via pseudotime analysis to give rise to five other cell types representing all the subtypes of differentiated limbal and corneal epithelial cells. A novel putative LPCs surface marker, GPHA2, expressed on the surface of 0.41% ± 0.21 of the cultured LECs, was identified, based on predominant expression in the limbal crypts of adult and developing cornea and RNAi validation in cultured LECs. Combining scRNA- and ATAC-Seq analyses, we identified multiple upstream regulators for LPCs and demonstrated a close interaction between the immune cells and limbal progenitor cells. RNA-Seq analysis indicated the loss of GPHA2 expression and acquisition of proliferative limbal basal epithelial cell markers during ex vivo LEC expansion, independently of the culture method used. Extending the single cell analyses to keratoconus, we were able to reveal activation of collagenase in the corneal stroma and a reduced pool of limbal suprabasal cells as two key changes underlying the disease phenotype. Single cell RNA-Seq of 89,897 cells obtained from embryonic and fetal cornea indicated that during development, the conjunctival epithelium is the first to be specified from the ocular surface epithelium, followed by the corneal epithelium and the establishment of LPCs, which predate the formation of limbal niche by a few weeks. CONCLUSIONS: Our scRNA-and ATAC-Seq data of developing and adult cornea in steady state and disease conditions provide a unique resource for defining genes/pathways that can lead to improvement in ex vivo LPCs expansion, stem cell differentiation methods and better understanding and treatment of ocular surface disorders.


Subject(s)
Epithelium, Corneal , Limbus Corneae , Adult , Cell Differentiation , Cells, Cultured , Cornea , Epithelial Cells , Humans , Stem Cells
11.
Mol Med ; 26(1): 59, 2020 06 17.
Article in English | MEDLINE | ID: mdl-32552660

ABSTRACT

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is a cancer of the exocrine pancreas and 5-year survival rates remain constant at 7%. Along with PDAC, Periampullary Adenocarcinoma (PAC) accounts for 0.5-2% of all gastrointestinal malignancies. Genomic observations were well concluded for PDAC and PACs in western countries but no reports are available from India till now. METHODS: Targeted Next Generation Sequencing were performed in 8 (5 PDAC and 3 PAC) tumour normal pairs, using a panel of 412 cancer related genes. Primary findings were replicated in 85 tumour samples (31 PDAC and 54 PAC) using the Sanger sequencing. Mutations were also validated by ASPCR, RFLP, and Ion Torrent sequencing. IHC along with molecular dynamics and docking studies were performed for the p.A138V mutant of TP53. Key polymorphisms at TP53 and its associated genes were genotyped by PCR-RFLP method and association with somatic mutations were evaluated. All survival analysis was done using the Kaplan-Meier survival method which revealed that the survival rates varied significantly depending on the somatic mutations the patients harboured. RESULTS: Among the total 114 detected somatic mutations, TP53 was the most frequently mutated (41%) gene, followed by KRAS, SMAD4, CTNNB1, and ERBB3. We identified a novel hotspot TP53 mutation (p.A138V, in 17% of all patients). Low frequency of KRAS mutation (33%) was detected in these samples compared to patients from Western counties. Molecular Dynamics (MD) simulation and DNA-protein docking analysis predicted p.A138V to have oncogenic characteristics. Patients with p.A138V mutation showed poorer overall survival (p = 0.01). So, our finding highlights elevated prevalence of the p53p.A138V somatic mutation in PDAC and pancreatobiliary PAC patients. CONCLUSION: Detection of p.A138V somatic variant in TP53 might serve as a prognostic marker to classify patients. It might also have a role in determining treatment regimes. In addition, low frequency of KRAS hotspot mutation mostly in Indian PDAC patient cohort indicates presence of other early drivers in malignant transformation.


Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Mutation , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , Tumor Suppressor Protein p53/genetics , Alleles , Ampulla of Vater/pathology , Biomarkers, Tumor , Carcinoma, Pancreatic Ductal/diagnosis , Female , Genotype , Germ-Line Mutation , Humans , Kaplan-Meier Estimate , Male , Neoplasm Grading , Neoplasm Staging , Pancreatic Neoplasms/diagnosis , Prognosis , Pancreatic Neoplasms
12.
Nat Commun ; 10(1): 5248, 2019 11 20.
Article in English | MEDLINE | ID: mdl-31748526

ABSTRACT

Polar metals are commonly defined as metals with polar structural distortions. Strict symmetry restrictions make them an extremely rare breed as the structural constraints favor insulating over metallic phase. Moreover, no polar metals are known to be magnetic. Here we report on the realization of a magnetic polar metal phase in a BaTiO3/SrRuO3/BaTiO3 heterostructure. Electron microscopy reveals polar lattice distortions in three-unit-cells thick SrRuO3 between BaTiO3 layers. Electrical transport and magnetization measurements reveal that this heterostructure possesses a metallic phase with high conductivity and ferromagnetic ordering with high saturation moment. The high conductivity in the SrRuO3 layer can be attributed to the effect of electrostatic carrier accumulation induced by the BaTiO3 layers. Density-functional-theory calculations provide insights into the origin of the observed properties of the thin SrRuO3 film. The present results pave a way to design materials with desired functionalities at oxide interfaces.

13.
Sci Rep ; 9(1): 13652, 2019 09 20.
Article in English | MEDLINE | ID: mdl-31541143

ABSTRACT

The current investigation has identified the biomarkers associated with severity of disability and correlation among plethora of systemic, cellular and molecular parameters of intellectual disability (ID) in a rehabilitation home. The background of study lies with the recent clinical evidences which identified complications in ID. Various indicators from blood and peripheral system serve as potential surrogates for disability related changes in brain functions. ID subjects (Male, age 10 ± 5 yrs, N = 45) were classified as mild, moderate and severe according to the severity of disability using standard psychometric analysis. Clinical parameters including stress biomarkers, neurotransmitters, RBC morphology, expressions of inflammatory proteins and neurotrophic factor were estimated from PBMC, RBC and serum. The lipid peroxidation of PBMC and RBC membranes, levels of serum glutamate, serotonin, homocysteine, ROS, lactate and LDH-A expression increased significantly with severity of ID whereas changes in RBC membrane ß-actin, serum BDNF, TNF-α and IL-6 was found non-significant. Structural abnormalities of RBC were more in severely disabled children compared to mildly affected ones. The oxidative stress remained a crucial factor with severity of disability. This is confirmed not only by RBC alterations but also with other cellular dysregulations. The present article extends unique insights of how severity of disability is correlated with various clinical, cellular and molecular markers of blood. This unique study primarily focuses on the strong predictors of severity of disability and their associations via brain-blood axis.


Subject(s)
Biomarkers/blood , Disabled Children/rehabilitation , Erythrocytes/pathology , Intellectual Disability/diagnosis , Adolescent , Child , Child, Preschool , Humans , India , Intellectual Disability/blood , Intellectual Disability/pathology , Lipid Peroxidation , Male , Severity of Illness Index
14.
Ther Adv Ophthalmol ; 11: 2515841419869508, 2019.
Article in English | MEDLINE | ID: mdl-31448362

ABSTRACT

Dry eye disease is a common ocular surface disease in patients who are undergoing cataract surgery. The significance of dry eye disease is often underestimated or overlooked during preoperative assessment of cataract. We report an 80-year-old patient, with a background of seropositive rheumatoid arthritis and diabetes, who presented with an acute corneal melt and perforation associated with undiagnosed dry eye disease and use of topical ketorolac 1 week following an uncomplicated cataract surgery. The patient underwent repeated corneal gluing for corneal perforation and was subsequently diagnosed and treated for bilateral moderate-severe dry eye disease. This case highlights the importance of meticulous preoperative assessment and management of the ocular surface, especially in patients with systemic diseases such as rheumatoid arthritis and diabetes prior to cataract surgery. The implication of the use of topical nonsteroidal anti-inflammatory drugs following cataract surgery - which might have contributed to the process of corneal melt in our case - is also discussed.

15.
Eye Contact Lens ; 45(4): e15-e23, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31241605

ABSTRACT

OBJECTIVES: To highlight the clinical characteristics, and visual and corneal tomographic outcomes of central toxic keratopathy (CTK) after contact lens (CL) wear and mechanical debridement. METHODS: A retrospective observational case series with literature review. RESULTS: Four patients (4 eyes) were included in this study; 3 (75%) females, mean age 29.3±8.1 years. The mean follow-up was 13.5±7.5 months. Early central or paracentral stromal opacification, assuming an inverse dome-shaped pattern observed under anterior-segment optical coherence tomography, with corneal flattening (Kmean 40.4±1.3 D) and thinning (mean thinnest pachymetry=404.8±29.4 microns) were observed in all cases. All patients had a recent use of CL wear, with three after mechanical debridement for recurrent corneal erosion syndrome. None of them had any previous laser refractive surgery (LRS). The mean corrected distance visual acuity improved from 20/40 (ranged 20/25-20/50) initially to 20/30 (ranged 20/20-20/40) at final follow-up, and the outcome was not influenced by the use of topical steroids. A mean improvement of corneal flattening (+Kmean 1.2±1.2 D), thinning (+123.5±23.8 microns), and astigmatism (-3.0±2.7 D), via epithelial and stromal remodeling, was observed up to 15 months after CTK. Persisting reduced corneal sensation was noted in all patients at the final follow-up. CONCLUSIONS: Central toxic keratopathy is not an exclusive complication of LRS, and it may occur after CL wear and mechanical debridement. Our findings are similar to those of LRS-related CTK and toxic peripheral keratopathy. Awareness of the clinical associations and understanding of the clinical course and tomographic characteristics of CTK helps obviate unnecessary investigation and overtreatment. Further studies are required to elucidate the underlying pathogenesis of this rare clinical entity.


Subject(s)
Contact Lenses, Hydrophilic/adverse effects , Corneal Opacity/etiology , Corneal Stroma/pathology , Debridement , Visual Acuity/physiology , Adult , Corneal Opacity/physiopathology , Corneal Opacity/surgery , Corneal Pachymetry , Corneal Stroma/surgery , Female , Follow-Up Studies , Humans , Male , Retrospective Studies , Slit Lamp Microscopy , Tomography, Optical Coherence , Vision Disorders/etiology , Vision Disorders/physiopathology , Vision Disorders/surgery , Young Adult
16.
Aliment Pharmacol Ther ; 49(10): 1346-1359, 2019 05.
Article in English | MEDLINE | ID: mdl-30982998

ABSTRACT

BACKGROUND: CD4+ regulatory T-cells (Tregs) expand during chronic hepatitis B virus (HBV) infection and inhibit antiviral immunity, although the underlying mechanism remains largely elusive. Myeloid-derived suppressor cells (MDSC) have been linked with T-cell dysfunction but questions remain regarding their persistence/profile/function in chronically HBV infected patients. AIM: To characterise MDSC in different phases of chronic HBV infection namely, immune-tolerant (IT), hepatitis B e-antigen-positive chronic hepatitis B (EP-CHB), inactive carriers (IC) and hepatitis B e-antigen-negative chronic hepatitis B (EN-CHB), to investigate their role in Treg induction and evaluate the effect of anti-viral therapy on these cells. METHODS: Multiparametric flow cytometry, cell-sorting and co-culture assays were performed along with longitudinal immune monitoring of CHB patients receiving tenofovir. RESULTS: HLA-DR- CD11b+ CD33hi -Monocytic-MDSC (M-MDSC) were enhanced in IT, EP-CHB and EN-CHB compared with IC, and this was related to increasing hepatitis B surface antigen (HBsAg) concentration. IT and EP-/EN-CHB displayed elevated frequency of CD4+ CD25+ FOXP3+ Treg that positively correlated with that of M-MDSC. However, both M-MDSC and HLA-DR- CD11b+ CD33low -granulocytic-MDSC from IT and EP-/EN-CHB expressed high transforming growth factor beta (TGF-ß) and interleukin-10 (IL-10). Co-culture of sorted HLA-DR- CD33+ -MDSC with autologous MDSC depleted-PBMC from IT and CHB but not from IC, increased CD4+ CD25+ FOXP3+ -iTreg and CD4+ FOXP3- IL-10+ -Tr1-cells through a cell-contact independent mechanism. While MDSC-derived TGF-ß and IL-10 promoted development of iTreg, only IL-10 appeared to be crucial for Tr1 induction. One year of tenofovir treatment failed to normalise MDSC frequency/function or reduce Treg percentage and serum HBsAg levels, despite reduction in viral load. CONCLUSIONS: We established a previously unrecognised role of MDSC in Treg development in IT and EP-/EN-CHB via TGF-ß/IL-10-dependent pathways and both cell-types persisted after anti-viral therapy. Hence, therapeutic targeting of MDSC or reducing circulating HBsAg level together with tenofovir-therapy might be more effective in restricting HBV persistence and disease progression.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis B Surface Antigens/blood , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/immunology , Myeloid-Derived Suppressor Cells/immunology , T-Lymphocytes, Regulatory/immunology , Adolescent , Adult , Child , Disease Progression , Female , Hepatitis B e Antigens/blood , Hepatitis B virus/immunology , Hepatitis B, Chronic/blood , Humans , Interleukin-10/blood , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Young Adult
19.
Eye (Lond) ; 33(5): 812-818, 2019 05.
Article in English | MEDLINE | ID: mdl-30610230

ABSTRACT

OBJECTIVES: To examine the effectiveness and safety of accelerated corneal collagen cross-linking (CXL) for keratoconus over a 24-month period and to explore potential prognostic factors for post-treatment visual outcome and progression. METHODS: A retrospective, non-comparative, interventional case series. All patients who underwent accelerated epithelium-off CXL, using 9 mW/cm2 ultraviolet-A irradiation for 10 min, for progressive keratoconus in Sunderland Eye Infirmary, UK, between May 2014 and July 2016 were included. All patients completed 24 months' post-CXL follow-up. Significant post-CXL progression of keratoconus was defined as >1 D increase in Kmax from preoperative to 24-month visit. RESULTS: Fifty-two eyes of 48 patients were included. At 24-month post-CXL, there was a significant improvement in corrected-distance visual acuity (CDVA; -0.05 LogMAR; p = 0.026), Kmax (-1.68 D; p < 0.001), K1 (-0.64 D; p = 0.002) and Kmean (-0.50 D; p = 0.009). The proportion of eyes with CDVA ≥ 0.3 LogMAR significantly improved from 43 (82.7%) eyes preoperatively to 50 (96.2%) eyes at 24 months (p = 0.026). Corneal haze (12, 23.1%) was the only postoperative complication and no adverse event was noted. Final CDVA was associated with lower CDVA (p = 0.002) and greater Kmax (p = 0.018) at baseline. Post-CXL progression of keratoconus was associated with greater preoperative Kmax (p = 0.12) and Kmean (p = 0.11), though statistical significances were not achieved. CONCLUSIONS: Accelerated CXL (9 mW/cm2) serves as an effective and safe treatment for halting the progression of keratoconus and stabilising the vision over a 24-month period. Our observation suggests that accelerated CXL might be more effective in stabilising keratoconus of milder severity; however further larger studies are required to elucidate this finding.


Subject(s)
Collagen/metabolism , Corneal Stroma/drug effects , Cross-Linking Reagents , Keratoconus/drug therapy , Photosensitizing Agents/therapeutic use , Ultraviolet Rays , Adolescent , Adult , Corneal Pachymetry , Corneal Stroma/metabolism , Corneal Topography , Female , Follow-Up Studies , Humans , Keratoconus/metabolism , Keratoconus/physiopathology , Male , Refraction, Ocular/physiology , Retrospective Studies , Riboflavin/therapeutic use , Treatment Outcome , Visual Acuity/physiology , Young Adult
20.
Cornea ; 38(1): 8-12, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30199398

ABSTRACT

PURPOSE: To analyze the incidence, nature, outcomes, and complications of acute chemical eye injuries, including the incidence of limbal stem cell deficiency (LSCD) and to compare the 2 main classifications for ocular chemical injuries: Roper-Hall (RH) and Dua. METHODS: This is a prospective, consecutive, interventional single-center study between April and October 2009 of all new patients with acute chemical eye injury presenting to the Royal Victoria Infirmary eye emergency department (EED). RESULTS: Of 11,683 patients who attended the EED, 98 patients (110 eyes) presented with acute chemical eye injury (60% male). This represents an estimated annual incidence of 5.6 new cases per 100,000 population. Mean age was 36.5 years (1-78; SD 17.1 years), including 7 children (age <10 years). Fifty-one patients (52%) had work-related injuries. The most common chemical agent was alkali (78%). All 4 RH grade IV cases were unilateral, assault with ammonia, and required early amniotic membrane transplantation as per the protocol, but despite full treatment, they developed total LSCD in the affected eye. CONCLUSIONS: Acute chemical eye injuries are rare. Male patients in the working age group are more prone to work-related chemical injuries, whereas young children tend to have domestic injuries. Grade I, II, and III RH and Dua chemical injuries had a very good prognosis with topical treatment only, whereas RH grade IV (Dua grade IV-VI), mainly assaults with ammonia, progressed to total/severe LSCD despite appropriate management including early amniotic membrane transplantation. The Dua classification includes conjunctival involvement, having a greater value in predicting the final clinical outcome when grading chemical eye injuries.


Subject(s)
Burns, Chemical/epidemiology , Corneal Diseases/epidemiology , Eye Burns/epidemiology , Limbus Corneae/pathology , Stem Cells/pathology , Visual Acuity , Acute Disease , Adolescent , Adult , Aged , Alkalies , Burns, Chemical/pathology , Child , Child, Preschool , Corneal Diseases/pathology , Eye Burns/pathology , Female , Follow-Up Studies , Humans , Incidence , Infant , Male , Middle Aged , Prospective Studies , United Kingdom/epidemiology , Young Adult
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