Potential of mesenchymal stem cells as topical immunomodulatory cell therapies for ocular surface inflammatory disorders

Ocular surface inflammatory disorders (OSIDs) are a group of highly prevalent, heterogeneous diseases which display a variety of aetiologies and symptoms and are risk factors for serious complications including ocular and cornea impairment. Corneal inflammation is a common factor of all OSIDs, regardless of their cause or symptoms. Current medications include over‐the‐counter lubricating eye drops, corticosteroids, and ciclosporin, which either do not treat the corneal inflammation or have been associated with multiple side effects leading to alternative treatments being sought. Regenerative medicine cell therapies, particularly mesenchymal stem cells (MSCs), have shown great promise for immunosuppression and disease amelioration across multiple tissues, including the cornea. However, for successful development and clinical translation of MSC therapy for OSIDs, significant problems must be addressed. This review aims to highlight considerations, including whether the source of MSC isolation impacts the efficacy and safety of the therapy, in addition to assessing the feasibility of MSC topical application to the cornea and ocular surface through analysis of potential scaffolds and cell carriers for application to the eye. The literature contains limited data assessing MSCs incorporated into scaffolds for corneal administration, thus here we highlight the necessity of further investigations to truly exploit the potential of an MSC‐based cell therapy for the treatment of OSIDs

Host Defence Peptides: A Potent Alternative to Combat Antimicrobial Resistance in the Era of the COVID-19 Pandemic

One of the greatest challenges facing the medical community today is the ever-increasing trajectory of antimicrobial resistance (AMR), which is being compounded by the decrease in our antimicrobial armamentarium. From their initial discovery to the current day, antibiotics have seen an exponential increase in their usage, from medical to agricultural use. Benefits aside, this has led to an exponential increase in AMR, with the fear that over 10 million lives are predicted to be lost by 2050, according to the World Health Organisation (WHO). As such, medical researchers are turning their focus to discovering novel alternatives to antimicrobials, one being Host Defence Peptides (HDPs). These small cationic peptides have shown great efficacy in being used as an antimicrobial therapy for currently resistant microbial variants. With the sudden emergence of the SARS-CoV-2 variant and the subsequent global pandemic, the great versatility and potential use of HDPs as an alternative to conventional antibiotics in treating as well as preventing the spread of COVID-19 has been reviewed. Thus, to allow the reader to have a full understanding of the multifaceted therapeutic use of HDPs, this literature review shall cover the association between COVID-19 and AMR whilst discussing and evaluating the use of HDPs as an answer to antimicrobial resistance (AMR)

A 7-year review of clinical characteristics, predisposing factors and outcomes of post-keratoplasty infectious keratitis: the Nottingham infectious keratitis study

Background/objectives: Post-keratoplasty infectious keratitis (PKIK) is a unique sight-threatening clinical entity which often poses significant therapeutic challenges. This study aimed to examine the clinical presentation, risk factors, management, and clinical outcomes of PKIK. Methods: This was a retrospective study of all patients who presented to the Queen’s Medical Centre, Nottingham, with PKIK between September 2015 and August 2022 (a 7-year period). Relevant data on types of keratoplasty, clinical presentations, causative microorganisms, management, and outcome were analyzed. Results: Forty-nine PKIK cases, including four cases of interface infectious keratitis, were identified during the study period. The most common graft indications for PKP, DALK and EK were failed grafts (9, 37.5%), keratoconus (6, 54.5%) and Fuchs endothelial corneal dystrophy (FECD; 8, 57.1%), respectively. Staphylococcus spp. were the most commonly identified organisms (15, 50.0%). Bullous keratopathy (18, 36.7%), ocular surface disease (18, 36.7%), and broken/loose sutures (15, 30.6%) were the most common risk factors. Concurrent use of topical steroids was identified in 25 (51.0%) cases. Of 31 functioning grafts at presentation, 12 (38.7%) grafts failed at final follow-up with 15 (48.4%) patients retaining a CDVA of ≥1.0 logMAR. The overall estimated 5-year survival rate post-PKIK was 55.9% (95% CI, 35.9%-75.9%), with DALK having the highest survival rate [63.6% (95% CI, 28.9%-98.3%)], followed by EK [57.1% (95% CI, 20.4%-93.8%)] and PKP [52.7% (95% CI, 25.1%-80.3%)], though no statistical difference was observed (p=0.48). Conclusions: PKIK represents an important cause of IK and graft failure. Bullous keratopathy, OSD and suture-related complications are the commonest risk factors, highlighting the potential benefit of prophylactic topical antibiotics (for unhealthy ocular surface) and early suture removal (where possible) in reducing the risk of PKIK. Graft survival may be higher in lamellar keratoplasty following PKIK but larger studies are required to elucidate this observation

Clinical Applications of Anterior Segment Optical Coherence Tomography:An Updated Review

Since its introduction, optical coherence tomography (OCT) has revolutionized the field of ophthalmology and has now become an indispensable, noninvasive tool in daily practice. Most ophthalmologists are familiar with its use in the assessment and monitoring of retinal and optic nerve diseases. However, it also has important applications in the assessment of anterior segment structures, including the cornea, conjunctiva, sclera, anterior chamber, and iris, and has the potential to transform the clinical examination of these structures. In this review, we aim to provide a comprehensive overview of the potential clinical utility of anterior segment OCT (AS-OCT) for a wide range of anterior segment pathologies, such as conjunctival neoplasia, pterygium, scleritis, keratoconus, corneal dystrophies, and infectious/noninfectious keratitis. In addition, the clinical applications of AS-OCT (including epithelial mapping) in preoperative planning and postoperative monitoring for corneal and refractive surgeries are discussed

Krein support vector machine classification of antimicrobial peptides

Antimicrobial peptides (AMPs) represent a potential solution to the growing problem of antimicrobial resistance, yet their identification through wet-lab experiments is a costly and time-consuming process. Accurate computational predictions would allow rapid in silico screening of candidate AMPs, thereby accelerating the discovery process. Kernel methods are a class of machine learning algorithms that utilise a kernel function to transform input data into a new representation. When appropriately normalised, the kernel function can be regarded as a notion of similarity between instances. However, many expressive notions of similarity are not valid kernel functions, meaning they cannot be used with standard kernel methods such as the support-vector machine (SVM). The Kreĭn-SVM represents generalisation of the standard SVM that admits a much larger class of similarity functions. In this study, we propose and develop Kreĭn-SVM models for AMP classification and prediction by employing the Levenshtein distance and local alignment score as sequence similarity functions. Utilising two datasets from the literature, each containing more than 3000 peptides, we train models to predict general antimicrobial activity. Our best models achieve an AUC of 0.967 and 0.863 on the test sets of each respective dataset, outperforming the in-house and literature baselines in both cases. We also curate a dataset of experimentally validated peptides, measured against Staphylococcus aureus and Pseudomonas aeruginosa, in order to evaluate the applicability of our methodology in predicting microbe-specific activity. In this case, our best models achieve an AUC of 0.982 and 0.891, respectively. Models to predict both general and microbe-specific activities are made available as web applications

Diagnostic Armamentarium of Infectious Keratitis: A Comprehensive Review

Infectious keratitis (IK) represents the leading cause of corneal blindness worldwide, particularly in developing countries. A good outcome of IK is contingent upon timely and accurate diagnosis followed by appropriate interventions. Currently, IK is primarily diagnosed on clinical grounds supplemented by microbiological investigations such as microscopic examination with stains, and culture and sensitivity testing. Although this is the most widely accepted practice adopted in most regions, such an approach is challenged by several factors, including indistinguishable clinical features shared among different causative organisms, polymicrobial infection, long diagnostic turnaround time, and variably low culture positivity rate. In this review, we aim to provide a comprehensive overview of the current diagnostic armamentarium of IK, encompassing conventional microbiological investigations, molecular diagnostics (including polymerase chain reaction and mass spectrometry), and imaging modalities (including anterior segment optical coherence tomography and in vivo confocal microscopy). We also highlight the potential roles of emerging technologies such as next-generation sequencing, artificial intelligence-assisted platforms. and tele-medicine in shaping the future diagnostic landscape of IK

Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse

Cranial neural tube defects (NTDs) occur in mice carrying mutant alleles of many different genes, whereas isolated spinal NTDs (spina bifida) occur in fewer models, despite being common human birth defects. Spina bifida occurs at high frequency in the Axial defects (Axd) mouse mutant but the causative gene is not known. In the current study, the Axd mutation was mapped by linkage analysis. Within the critical genomic region, sequencing did not reveal a coding mutation whereas expression analysis demonstrated significant up-regulation of grainyhead-like 2 (Grhl2) in Axd mutant embryos. Expression of other candidate genes did not differ between genotypes. In order to test the hypothesis that over-expression of Grhl2 causes Axd NTDs, we performed a genetic cross to reduce Grhl2 function in Axd heterozygotes. Grhl2 loss of function mutant mice were generated and displayed both cranial and spinal NTDs. Compound heterozygotes carrying both loss (Grhl2 null) and putative gain of function (Axd) alleles exhibited normalization of spinal neural tube closure compared with Axd/+ littermates, which exhibit delayed closure. Grhl2 is expressed in the surface ectoderm and hindgut endoderm in the spinal region, overlapping with grainyhead-like 3 (Grhl3). Axd mutants display delayed eyelid closure, as reported in Grhl3 null embryos. Moreover, Axd mutant embryos exhibited increased ventral curvature of the spinal region and reduced proliferation in the hindgut, reminiscent of curly tail embryos, which carry a hypomorphic allele of Grhl3. Overall, our data suggest that defects in Axd mutant embryos result from over-expression of Grhl2

CANDELS: The progenitors of compact quiescent galaxies at z~2

We combine high-resolution HST/WFC3 images with multi-wavelength photometry to track the evolution of structure and activity of massive (log(M*) > 10) galaxies at redshifts z = 1.4 - 3 in two fields of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS). We detect compact, star-forming galaxies (cSFGs) whose number densities, masses, sizes, and star formation rates qualify them as likely progenitors of compact, quiescent, massive galaxies (cQGs) at z = 1.5 - 3. At z > 2 most cSFGs have specific star-formation rates (sSFR = 10^-9 yr^-1) half that of typical, massive SFGs at the same epoch, and host X-ray luminous AGN 30 times (~30%) more frequently. These properties suggest that cSFGs are formed by gas-rich processes (mergers or disk-instabilities) that induce a compact starburst and feed an AGN, which, in turn, quench the star formation on dynamical timescales (few 10^8 yr). The cSFGs are continuously being formed at z = 2 - 3 and fade to cQGs by z = 1.5. After this epoch, cSFGs are rare, thereby truncating the formation of new cQGs. Meanwhile, down to z = 1, existing cQGs continue to enlarge to match local QGs in size, while less-gas-rich mergers and other secular mechanisms shepherd (larger) SFGs as later arrivals to the red sequence. In summary, we propose two evolutionary scenarios of QG formation: an early (z > 2), fast-formation path of rapidly-quenched cSFGs that evolve into cQGs that later enlarge within the quiescent phase, and a slow, late-arrival (z < 2) path for SFGs to form QGs without passing through a compact state.Comment: Submitted to the Astrophysical Journal Letters, 6 pages, 4 figure

Interaction Analysis between HLA-DRB1 Shared Epitope Alleles and MHC Class II Transactivator CIITA Gene with Regard to Risk of Rheumatoid Arthritis

HLA-DRB1 shared epitope (SE) alleles are the strongest genetic determinants for autoantibody positive rheumatoid arthritis (RA). One of the key regulators in expression of HLA class II receptors is MHC class II transactivator (CIITA). A variant of the CIITA gene has been found to associate with inflammatory diseases