Contents: 1. Introduction 2. Neuroanatomy of the corneal nerves 2.1. Embryology and development of corneal innervation 2.2. Origin of corneal nerves 2.3. Corneal nerve architecture 3. Neurochemistry of the cornea (Neurotrophins, Neurotransmitters and Neuropeptides) 4. The role of corneal nerves 4.1. Sensory and reflex function 4.2. Axonal reflex and neurogenic inflammation 4.3. Trophic function 5. Manifestations of corneal nerve dysfunction 5.1. Definitions 5.2. Corneal pain in the absence of ocular surface disease "Pain without stain" 5.3. Anaesthetic cornea with intact corneal nerves (pre-ganglionic damage) 5.4. Anaesthetic/hypoesthetic cornea with absent nerves and abnormal ocular surface "neurotrophic keratopathy, stain without pain" 6. Visualisation of corneal nerves 6.1. In vitro/ex vivo techniques 6.2. In vivo techniques: In vivo confocal microscopy (IVCM) 7. Nerve affection in corneal pathology 7.1. Post-surgical conditions 7.2. Diabetic Keratopathy 7.3. Herpetic corneal disease 7.4. Dry eyes 7.5. Keratoconus 7.6. Contact lens wear 7.7. Bullous keratopathy 7.8. Neurotrophic keratopathy (NK) 7.9. Glaucoma 7.10. Corneal dystrophies 7.11. Limbal stem cell deficiency 7.12 Small-fibre sensory neuropathy (SFSN) 79 8. Future directions 9. Funding support 10. Acknowledgement 11. References 12. Figure legends

The golden era of antibiotics, heralded by the discovery of penicillin, has long been challenged by the emergence of antimicrobial resistance (AMR). Host defense peptides (HDPs), previously known as antimicrobial peptides, are emerging as a group of promising antimicrobial candidates for combatting AMR due to their rapid and unique antimicrobial action. Decades of research have advanced our understanding of the relationship between the physicochemical properties of HDPs and their underlying antimicrobial and non-antimicrobial functions, including immunomodulatory, anti-biofilm, and wound healing properties. However, the mission of translating novel HDP-derived molecules from bench to bedside has yet to be fully accomplished, primarily attributed to their intricate structure-activity relationship, toxicity, instability in host and microbial environment, lack of correlation between in vitro and in vivo efficacies, and dwindling interest from large pharmaceutical companies. Based on our previous experience and the expanding knowledge gleaned from the literature, this review aims to summarize the novel strategies that have been employed to enhance the antimicrobial efficacy, proteolytic stability, and cell selectivity, which are all crucial factors for bench-to-bedside translation of HDP-based treatment. Strategies such as residues substitution with natural and/or unnatural amino acids, hybridization, L-to-D heterochiral isomerization, C-and N-terminal modification, cyclization, incorporation with nanoparticles, and "smart design" using artificial intelligence technology, will be discussed. We also provide an overview of HDP-based treatment that are currently in the development pipeline.

Complement plays a key role in host defense, but its dysregulation can cause autologous tissue injury. Complement activation is normally controlled by regulatory proteins, including factor H (FH) in plasma and membrane cofactor protein (MCP) on the cell surface. Mutations in FH and MCP are linked to atypical hemolytic uremic syndrome, a type of thrombotic microangiopathy (TMA) that causes renal failure. We describe here that disruption of FH function on the cell surface can also lead to disseminated complement-dependent macrovascular thrombosis. By gene targeting, we introduced a point mutation (W1206R) into murine FH that impaired its interaction with host cells but did not affect its plasma complement-regulating activity. Homozygous mutant mice carrying this mutation developed renal TMA as well as systemic thrombophilia involving large blood vessels in multiple organs, including liver, lung, spleen, and kidney. Approximately 30% of mutant mice displayed symptoms of stroke and ischemic retinopathy, and 48% died prematurely. Genetic deficiency of complement C3 and factor D prevented both the systemic thrombophilia and renal TMA phenotypes. These results demonstrate a causal relationship between complement dysregulation and systemic angiopathy and suggest that complement activation may contribute to various human thrombotic disorders involving both the micro- and macrovasculature.

BackgroundThe Limbal epithelial crypt (LEC) is a solid cord of cells, approximately 120 microns long. It arises from the undersurface of interpalisade rete ridges of the limbal palisades of Vogt and extends deeper into the limbal stroma parallel or perpendicular to the palisade. There are up to 6 or 7 such LEC, variably distributed along the limbus in each human eye.Morphological and immunohistochemical studies on the limbal epithelial crypt (LEC) have demonstrated the presence of limbal stem cells in this region. The purpose of this microarray study was to characterise the transcriptional profile of the LEC and compare with other ocular surface epithelial regions to support our hypothesis that LEC preferentially harbours stem cells (SC).ResultsLEC was found to be enriched for SC related Gene Ontology (GO) terms including those identified in quiescent adult SC, however similar to cornea, limbus had significant GO terms related to proliferating SC, transient amplifying cells (TAC) and differentiated cells (DC). LEC and limbus were metabolically dormant with low protein synthesis and downregulated cell cycling. Cornea had upregulated genes for cell cycling and self renewal such as FZD7, BTG1, CCNG, and STAT3 which were identified from other SC populations. Upregulated gene expression for growth factors, cytokines, WNT, Notch, TGF-Beta pathways involved in cell proliferation and differentiation were noted in cornea. LEC had highest number of expressed sequence tags (ESTs), downregulated and unknown genes, compared to other regions. Genes expressed in LEC such as CDH1, SERPINF1, LEF1, FRZB1, KRT19, SOD2, EGR1 are known to be involved in SC maintenance. Genes of interest, in LEC belonging to the category of cell adhesion molecules, WNT and Notch signalling pathway were validated with real-time PCR and immunofluorescence.ConclusionsOur transcriptional profiling study identifies the LEC as a preferential site for limbal SC with some characteristics suggesting that it could function as a 'SC niche' supporting quiescent SC. It also strengthens the evidence for the presence of "transient cells" in the corneal epithelium. These cells are immediate progeny of SC with self-renewal capacity and could be responsible for maintaining epithelial turn over in normal healthy conditions of the ocular surface (OS). The limbus has mixed population of differentiated and undifferentiated cells.