Reiterative FGF signaling determines the identity and morphology of the lacrimal gland

Indiana University-Purdue University Indianapolis (IUPUI)The lacrimal gland plays an essential role in protection of the ocular surface by secreting the aqueous component of the tear film. Deficiency in the lacrimal gland is the main cause of dry eye disease, but existing treatments only alleviate the symptoms without curing the underlying disease. To develop curative measures, a thorough understanding of lacrimal gland development is needed. Lacrimal gland is formed as a result of interaction between the neural crest-derived mesenchyme and the conjunctival epithelium. The mesenchyme secretes the chemo-attractive signal of Fgf10, which binds to epithelial Fgfr2b and co-receptor heparan sulphate proteoglycans, to promote budding and branching morphogenesis of the lacrimal gland. However, the mechanism by which Fgf10 expression is regulated within the neural crest and the direct downstream targets of Fgf signaling in the epithelium are currently unknown. In this study, we show that FGF signaling mediated by protein phosphatase Shp2 is required for the proper patterning and differentiation of the neural crest-derived mesenchyme to produce Fgf10. Genetic evidence further demonstrates that Shp2 is recruited by Frs2α to activate Ras-MAPK signaling downstream to Fgfr1 and Fgfr2 but not to Pdgfrα in the neural crest. By differential gene expression analysis, we identified homeodomain transcription factor Alx4 as the key effector of Shp2 signaling to control expression of Fgf10 in the periocular mesenchyme. Loss of function ALX4/Alx4 mutation disrupted lacrimal gland development in both human and mouse. Our results reveal a FGF-Shp2-Alx4-Fgf10 axis in regulating neural crests during lacrimal gland development. In addition, we also show that Fgf signaling cascade mediated by Pea3 family of transcription factors are critical for lacrimal gland duct elongation and branching. High-throughput gene expression analysis revealed that Pea3 genes were important for establishing the tissue identity of the lacrimal gland. Loss of Pea3 resulted in upregulation of Notch signaling with the concomitant loss in the expression of the members of Six family of transcription factors and a switch of cell fate to the epidermal skin-like cells. These findings show that Fgf signaling is used reiteratively to establish the identity of both the epithelium and mesenchyme of the lacrimal gland.2 year

Lacrimal gland development: From signaling interactions to regenerative medicine

The lacrimal gland plays a pivotal role in keeping the ocular surface lubricated, and protecting it from environmental exposure and insult. Dysfunction of the lacrimal gland results in deficiency of the aqueous component of the tear film, which can cause dryness of the ocular surface, also known as the aqueous-deficient dry eye disease. Left untreated, this disease can lead to significant morbidity, including frequent eye infections, corneal ulcerations, and vision loss. Current therapies do not treat the underlying deficiency of the lacrimal gland, but merely provide symptomatic relief. To develop more sustainable and physiological therapies, such as in vivo lacrimal gland regeneration or bioengineered lacrimal gland implants, a thorough understanding of lacrimal gland development at the molecular level is of paramount importance. Based on the structural and functional similarities between rodent and human eye development, extensive studies have been undertaken to investigate the signaling and transcriptional mechanisms of lacrimal gland development using mouse as a model system. In this review, we describe the current understanding of the extrinsic signaling interactions and the intrinsic transcriptional network governing lacrimal gland morphogenesis, as well as recent advances in the field of regenerative medicine aimed at treating dry eye disease

A Stochastic Linear Programming Model for Asset Liability Management: The Case of an Indian Insurance Company

Asset - Liability management is one of the most critical tasks for any financial institution for determining its cushion against the risk and the net returns. The problem of asset liability management for an insurance company requires matching the cash inflows from premium collections and investment income with the cash outflows due to casualty and maturity claims. Thus, what is required is a prudent investment strategy such that the returns earned on the assets match the liability claims at all points of time in future. Conventionally, the asset allocation has been done using the Mean Variance approach due to Markowitz (1952, 1959). While such a strategy ensures that the asset value always match or are greater than the liability for the next year, it does not maximise the net worth of the firm nor does it take care of all the cash inflows and outflows over a long term period. A stochastic linear programming model (on the lines of Pirbhai, 2004) maximises the net worth of the firm and also takes care of the uncertainties. While there are instances of stochastic linear programming being applied for ALM in financial institutions in developed markets, no such practical application has been reported in this area in Indian context as yet. In this paper, we describe the development of a multi stage stochastic linear programming model for insurance companies. The multi-stage stochastic linear programming model was developed on the modelling language AMPL (Fourer, 2002).

Stability analysis and control of nonlinear, symmetrically coupled systems, with applications to paralleled power converters

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1998.Includes bibliographical references (p. 93-94).by Ankur Garg.M.S

Placement of the Internal Pulse Generator for Deep Brain Stimulation in the Upper Back to Prevent Fracture of the Extension Wire due to Generator Rotation: Case Report

Deep brain stimulation (DBS) is a common surgical procedure used for the treatment of Parkinson's disease (PD) and essential tremor. A potential complication of this procedure is hardware failure. The authors report a case of DBS hardware failure in which repeated fractures of the extension wire were caused by abnormal rotational movements of the IPG placed in the loose subclavicular tissue of an overweight female. Implantation of the IPG in the suprascapular area prevented further extension wire fractures. This strategy may be especially relevant in overweight females with loose subclavicular tissue

ANAGEMENT OF PROXIMAL HUMERUS FRACTURE IN ADULTS WITH PHILOS PLATE FIXATION IN NEER TYPE 2 AND TYPE 3

Objective: One of the most frequent bone fractures is a fracture of the proximal humerus. They make up between 4% and 5% of all fracture. With less invasive soft-tissue injury and a lower risk of iatrogenic avascular necrosis, closed reduction and percutaneous fixation have become more popular in recent years as opposed to open reduction (OR) and extensive internal fixation (IF) (by plates and screws). The aim of this study was to compare the functional results of proximal humerous locking osteosynthesis (PHILOS) fixation against OR and IF of proximal humerus fractures (2 and 3 Neer’s classification).  Methodology: This study involved 40 patients, with a mean age of 53 and a range of ages from 18 to 55, with 2 and 3 part fractures according to Neer’s classification. Patients were randomized to either group, with Group I type 2 fractures receiving OR and IF for 22 patients, and Group II (type 3 fractures) with 18 patients receiving PHILOS plate fixation, with function assessed using the CMS score.  Results: At 1 month, 3 months, and 6 months of follow-up, Group I’s mean Visual analog scale (VAS) score decreased to 2.52, 2.10, and 1.22 and in Group II, 3.86, 2.64, and 2.41. The VAS score was reduced and function CMS score were significantly increased in Group I (80% VAS score, 65% CMS score) as compared to Group II (64% VAS score, and 58%CMS score). At 1, 3, and 6 months, there was a statistically significant difference between the two groups. Conclusion: Both groups saw satisfactory results, with each method having benefits and drawbacks. We discovered that plate fixation provided stable fixation with few implant problems and early range-of-motion exercise to achieve acceptable functional results

Effect of Multiple Rounds of Mass Drug Administration under Lymphatic Filariasis Elimination Program on Prevalence of Soil-Transmitted Helminthiasis in One of the Co-endemic Districts of India

Both soil-transmitted helminthiasis and lymphatic filariasis are co-endemic in some districts of India. The study was aimed at comparing the prevalence of soil-transmitted helminthiasis (STH) infection before and after mass drug administration (MDA) given for lymphatic filariasis at Alappuzha.We examined stool samples of 219 children aged between 9 and 10 years from nine schools at Alappuzha, Kerala, in June 2015. The current STH situation was compared with that in the year 1999 (before the institution of MDA) in the same age group in the same district. WHO-recommended Kato-Katz technique was used for STH prevalence estimation. Information regarding socio-demographic variables, sanitation, personal hygiene practices was also recorded. Chi-square test was used to study association of risk factors with STH infection.A total of 79 (36.07%) children were found to be positive for STH infection. Out of all samples positive for Ascaris lumbricoides, 4 (5%) were found co-infected with Trichuris trichiura and none with hookworm. Factors like absence of household latrine, lack of hand washing before meals and practice of consumingunwashed fruits were found to be significantly associated with occurrence of STH infection.Over the years, consecutive rounds of MDA for LF have led to a decline in intestinal worm burden but with little effect on the overall prevalence of STH. Thus, STH control activities working synergistically with the Filarial Elimination Strategy can yield better results in the co-endemic areas with optimum resourceutilization

FGF-induced Pea3 transcription factors program the genetic landscape for cell fate determination

FGF signaling is a potent inducer of lacrimal gland development in the eye, capable of transforming the corneal epithelium into glandular tissues. Here, we show that genetic ablation of the Pea3 family of transcription factors not only disrupted the ductal elongation and branching of the lacrimal gland, but also biased the lacrimal gland epithelium toward an epidermal cell fate. Analysis of high-throughput gene expression and chromatin immunoprecipitation data revealed that the Pea3 genes directly control both the positive and negative feedback loops of FGF signaling. Importantly, Pea3 genes are also required to suppress aberrant Notch signaling which, if gone unchecked, can compromise lacrimal gland development by preventing the expression of both Sox and Six family genes. These results demonstrate that Pea3 genes are key FGF early response transcriptional factors, programing the genetic landscape for cell fate determination