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Structural basis of signalling by TIR domain containing proteins
The Toll/interleukin-1 receptor (TIR) domain is found in animal, plant and bacterial immune systems, and function through self-association and homotypic interactions with other TIR domains. [1]. It was first described as a protein-protein interaction module mediating signalling downstream of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families in animals. However, studies of the neurodegenerative disease therapeutic target SARM1, plant immune receptors, and many bacterial TIR domain-containing proteins revealed that TIR domains have self- association-dependent enzymatic activities [2] and can produce diverse signaling molecules using nicotinamide adenine dinucleotide (NAD+) as a substrate. We have reconstituted TIR domain signalosomes and characterised them using an integrative structural biology approach combining MicroED, cryoEM, NMR, site directed mutagenesis, cellular assays and chemical tools. Our results have provided structural insight into TLR signal transduction [3-4] and revealed mechanisms of SARM1 activation, NAD+ cleavage and inhibition [5-6] as well as chemical structures of novel immune signalling molecules and their role in bacterial antiphage defence systems [7-8]. Collectively, our studies have led to new models for signal transduction in response to infection and provided rational avenues for the design of new therapeutics to combat a range of neurodegenerative diseases.
Journal Article
Efficacy of blink software in improving the blink rate and dry eye symptoms in visual display terminal users - A single-blinded randomized control trial
Purpose:
Dry eye disease (DED) is a multifactorial disease, more prevalent among visual display terminal users. Reduced blink rate is a risk factor to dry eye disorder, innovative means to remind to blink while using computers can be helpful.
Methods:
Single-blinded Randomized Control Trial enrolled computer users with dry eye. Allocation concealment was done using opaque envelope and principal investigator was blinded. After baseline examination, eligible participants were randomized to intervention group (appearance of bars is 8 times/min) and control group (appearance of bars is 1 time/min). Participants from both groups used the software for 15 days, came for first follow up, and did not use the software for next 15 days until second follow-up examination. During each visit, detailed eye examination was done including blink rate, tear film break up time, and Ocular Surface Disease Index score.
Results:
Forty-six participants (women n = 31; men n = 15) with a mean age of 28.02 (±6.295) years completed the study. Four participants were excluded from analysis because of early dropout. In the intervention group (n = 23) and control group (n = 23), participants were allocated. At the end of first phase, there was statistically significant difference in OSDI score (P = 0.021). Statistically significant difference was noticed in OSDI (P = 0.014) and blink rate (P = 0.049) as baseline, and final visit data were compared.
Conclusion:
\"Blink-Blink\" software with 8 reminders/min improved DED-related symptoms by increasing the blink rate. The carry-over effect after cessation of Blink-Blink software in improving blink rate was maintained even after 1 month.
Trial Registration: Clinical Trials Registry-India (CTRI): CTRI/2018/08/015176
Journal Article
Glaucoma and its association with obstructive sleep apnea: A narrative review
Obstructive sleep apnea (OSA) is one of the systemic risk factors for glaucoma which causes irreversible visual field (VF) damage. We reviewed the published data of all types of studies on the association between these two conditions and papers regarding functional and structural changes related to glaucomatous damage using Scopus, web of science, and PubMed databases. There is evidence that the prevalence of glaucoma is higher in OSA patients, which independent of intraocular pressure (IOP). Studies have reported thinning of retinal nerve fiber layer (RNFL), alteration of optic nerve head, choroidal and macular thickness, and reduced VF sensitivity in patients of OSA with no history glaucoma. A negative correlation of apnea-hypopnea index with RNFL and VF indices has been described in some studies. Raised IOP was noted which is possibly related to obesity, supine position during sleep, and raised intracranial pressure. Diurnal fluctuations of IOP show more variations in OSA patients before and after continuous positive airway pressure (CPAP) therapy when compared with the normal cases. The vascular factors behind the pathogenesis include recurrent hypoxia with increased vascular resistance, oxidative stress damage to the optic nerve. In conclusion, comprehensive glaucoma evaluation should be recommended in patients with OSA and should also periodically monitor IOP during CPAP treatment which may trigger the progression of glaucomatous damage.
Journal Article
Development and validation of competency framework for teaching management of refractive errors: A participatory Delphi approach
Purpose:
Competency-based education and assessment are globally trending, also embraced by recently announced National education policy 2020, India. Medical programs are rapidly transforming to produce competent health professionals, to satisfy public health requirements. This paper describes Delphi study with a participatory approach, to develop a competency matrix required for training of eye care professionals.
Methods:
Scoping review of literature formulated the baseline architecture of competency framework identifying two core competencies for management of refractive error, namely, \"visual function assessment\" and \"optical technology management.\" The Delphi technique was employed for the development of a competency matrix with detailed knowledge, skills, and attitude (KSA) definitions for all competency elements. A heterogeneous group including optometry practitioners, academicians, researchers, association representatives, and industry representatives accomplished the objective in four rounds.
Results:
Delphi study resulted in defining two competency clusters (CC): \"CC1: Refraction\" with 10 units and 43 elements and \"CC2: Dispensing optics\" with 8 units and 54 elements. KSA components of each of competency elements were identified and mapped with applied optics curriculum in the optometry program.
Conclusion:
Participation of all stakeholders of the educational system is essential and beneficial for nurturing of the competent workforce in healthcare. It helps build a curriculum not only having theoretical knowledge and skills but also the attitude and behavioral component of measurable competencies that satisfies the needs of the local healthcare system. This study has evolved a comprehensive competency matrix highlighting essential competencies required for the effective management of refractive error.
Journal Article
Structure and function of Toll/interleukin-1 receptor/resistance protein (TIR) domains
The Toll/interleukin-1 receptor/resistance protein (TIR) domain is a protein–protein interaction domain consisting of 125–200 residues, widely distributed in animals, plants and bacteria but absent from fungi, archea and viruses. In plants and animals, these domains are found in proteins with functions in innate immune pathways, while in bacteria, some TIR domain-containing proteins interfere with the innate immune pathways in the host. TIR domains function as protein scaffolds, mostly involving self-association and homotypic interactions with other TIR domains. In the last 15 years, the three-dimensional structures of TIR domains from several mammalian, plant and bacterial proteins have been reported. These structures, jointly with functional data including the identification of interacting proteins, have started to provide insight into the molecular basis of the assembly of animal and plant immune signaling complexes, and for host immunosuppression by bacterial pathogens. This review focuses on the current knowledge of the structures of the TIR domains and how the structure relates to function.
Journal Article