Repurposing of clinically proven bioactive compounds for targeted treatment of Alzheimer's disease using molecular docking approach.

Neurodegenerative diseases like Alzheimer's have become a growing concern as it is difficult to cure. Tau protein is found to be playing a major role in Alzheimer's disease, and the majority of drugs that are currently on the market are not only prohibitively expensive but also come packaged with side effects that the body cannot tolerate. Repurposing existing compounds is a successful and optimistic strategy that offers reduced risk and increased possibility. We aim to retrieve the existing drugs and analyze them using in-silico techniques. We have retrieved the compounds from the Selleckchem natural product library, and the ability of the drug to cross Blood Brain Barrier (BBB) and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties were examined using SwissADME. The structure of Tau protein (2MZ7) was then retrieved from PDB, and molecular docking of the compounds was performed using the PyRx-Virtual Screening Tool. Initially, 92 compounds passed the ADMET screening criteria, out of which the compound Ligustroflavone was found to have the most favourable binding affinity without violating Lipinski's rule of 5 of the compounds in the library.

Pictilisib-Induced Resistance Is Mediated through FOXO1-Dependent Activation of Receptor Tyrosine Kinases in Mucinous Colorectal Adenocarcinoma Cells.

The phosphatidylinositol (PI3K)/AKT/mTOR axis represents an important therapeutic target to treat human cancers. A well-described downstream target of the PI3K pathway is the forkhead box O (FOXO) transcription factor family. FOXOs have been implicated in many cellular responses, including drug-induced resistance in cancer cells. However, FOXO-dependent acute phase resistance mediated by pictilisib, a potent small molecule PI3K inhibitor (PI3Ki), has not been studied. Here, we report that pictilisib-induced adaptive resistance is regulated by the FOXO-dependent rebound activity of receptor tyrosine kinases (RTKs) in mucinous colorectal adenocarcinoma (MCA) cells. The resistance mediated by PI3K inhibition involves the nuclear localization of FOXO and the altered expression of RTKs, including ErbB2, ErbB3, EphA7, EphA10, IR, and IGF-R1 in MCA cells. Further, in the presence of FOXO siRNA, the pictilisib-induced feedback activation of RTK regulators (pERK and pAKT) was altered in MCA cells. Interestingly, the combinational treatment of pictilisib (Pi3Ki) and FOXO1i (AS1842856) synergistically reduced MCA cell viability and increased apoptosis. These results demonstrate that pictilisib used as a single agent induces acute resistance, partly through FOXO1 inhibition. Therefore, overcoming PI3Ki single-agent adaptive resistance by rational design of FOXO1 and PI3K inhibitor combinations could significantly enhance the therapeutic efficacy of PI3K-targeting drugs in MCA cells.

Andersen health care utilization model: A survey on factors affecting the utilization of dental health services among school children.

BACKGROUND: Children's quality of life, academic performance, and future achievement can all be negatively affected by poor dental health. The present study aimed to assess the need for dental health services and the factors influencing their utilization using the Andersen health care utilization model among school children. METHODS: The current cross-sectional study was conducted among schoolchildren aged 13 to 15 in Bangalore, India (n = 1100). A questionnaire was developed using the concepts of the Andersen healthcare usage model. The parents of the children filled out the questionnaire. The factors were investigated using bivariate analysis and multivariate logistic regression analysis. RESULTS: About 78.1% of the children did not utilize dental health services. Regarding the reasons for not visiting a dentist, 65.8% said they did not have a dental problem, and 22.2% said they could not afford it. Bivariate analysis showed that age, gender, education level, occupation of the family's head of household, monthly family income, socioeconomic status, perceived oral health problems, accessibility of dental health facilities, and parental attitudes toward their children's oral health were significantly associated with using dental health services (p<0.05). Multiple regression analysis showed dental health service utilization was directly related to age (OR = 2.206), education, family size (OR = 1.33), and brushing frequency twice a day (OR = 1.575) with no significant relationship between distance to reach the dental facility, the number of dental visits, and socioeconomic status. CONCLUSION: Dental health service utilization was low in the past year. The age, number of family members, parent's education level, travel time to the dental facility, the child's oral health behaviors, and positive parental attitude all play a role in a children's utilization of dental health service.

Co-Variation of Serum Osteoprotegerin and Pigment-Epithelial Derived Factor as Biomarker of Pancreatic Cancer.

Pancreatic cancer is one the most lethal cancers. Currently, there are reliable predictive markers to assess cancer development. Widely used CA19-9 molecular marker has been less effective in the diagnosis of early stages of cancer. Objective: To study if the soluble Osteoprotegerin (OPG) and pigment-epithelial derived factor (PEDF) levels in serum will be an indicator of cancer progression. Methods: Soluble OPG and PEDF were measured from human pancreatic cancer patients by ELISA. Results: We show that while OPG has been less predictive features, PEDF is more sensitive than CA19-9 in cancer detection. More importantly, PEDF and CA19-9 as combined markers showed higher sensitivity in stratifying early stages of pancreatic cancer. Conclusion: Results from the pilot studies suggest that PEDF is useful biomarker for pancreatic cancer.

Evaluating the failure to bloom in dark-cutting and lactate-enhanced beef longissimus steaks.

Previous studies have noted lower L* (lightness) values for both dark-cutting beef and normal-pH beef enhanced with lactate. In the current study, absorption-coefficient, scattering-coefficient, CIE L*a*b* values, refractive index of sarcoplasm, and inter-muscle bundle space were evaluated for dark-cutting beef, normal-pH beef enhanced with lactate, normal-pH beef enhanced with water, and normal-pH beef not enhanced with either water or lactate. Compared with non-enhanced loins, lactate-enhancement had lower a*, chroma, oxymyoglobin, reflectance, scattering, and inter-muscle bundle space as well as greater absorption and refractive index. Dark-cutting steaks had lower a*, chroma, oxymyoglobin values, reflectance, and scattering as well as less inter-muscle bundle space compared with lactate-enhanced steaks. Sarcoplasm refractive index values were greater in lactate-enhanced steaks than dark-cutting steaks. The results suggest that changes in muscle structure and optical properties due to either pH or lactate addition can alter muscle darkening and blooming properties.

Role of cell-free network communication in alcohol-associated disorders and liver metastasis.

The aberrant use of alcohol is a major factor in cancer progression and metastasis. Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-cancerous cells along the brain-gut-liver axis. Such interplay leads to changes in molecular, cellular, and biological functions resulting in cancer progression. Recent investigations have examined the role of extracellular vesicles (EVs) in cancer mechanisms in addition to their contribution as diagnostic biomarkers. Also, EVs are emerging as novel cell-free mediators in pathophysiological scenarios including alcohol-mediated gut microbiome dysbiosis and the release of nanosized EVs into the circulatory system. Interestingly, EVs in cancer patients are enriched with oncogenes, miRNA, lipids, and glycoproteins whose delivery into the hepatic microenvironment may be enhanced by the detrimental effects of alcohol. Proof-of-concept studies indicate that alcohol-associated liver disease is impacted by the effects of exosomes, including altered immune responses, reprogramming of stromal cells, and remodeling of the extracellular matrix. Moreover, the culmination of alcohol-related changes in the liver likely contributes to enhanced hepatic metastases and poor outcomes for cancer patients. This review summarizes the numerous aspects of exosome communications between organs with emphasis on the relationship of EVs in alcohol-associated diseases and cancer metastasis. The potential impact of EV cargo and release along a multi-organ axis is highly relevant to the promotion of tumorigenic mechanisms and metastatic disease. It is hypothesized that EVs target recipient tissues to initiate the formation of prometastatic niches and cancer progression. The study of alcohol-associated mechanisms in metastatic cancers is expected to reveal a better understanding of factors involved in the growth of secondary malignancies as well as novel approaches for therapeutic interventions.

Impact of oral diseases on daily activities among 12- to 15-year-old institutionalized orphan and non-orphan children in Bengaluru city: A cross-sectional analytical study.

BACKGROUND AND OBJECTIVE: As parents are the primary decision-makers of child's health, a study was conducted to assess and compare the oral health status and impact of oral diseases on daily activities among 12- to 15-year-old institutionalized orphan and non-orphan children in Bengaluru city. MATERIALS AND METHODS: This cross-sectional analytical study was conducted among 210 orphans and 210 government school children living with parents. Data with regard to the impact of oral diseases on daily activities were collected by means of Child Oral Impacts on Daily Performances (C-OIDP) index, and oral health status was determined using WHO Oral Health Assessment Form 1997. STATISTICAL ANALYSIS: Descriptive statistics of the key variables were reported and data were analyzed using Pearson's Chi-square test, Mann-Whitney U-test, One-way analysis of variance and Step-wise multiple linear regression analysis. Statistical significance was set at P < 0.05 for this study. RESULTS: Common oral health problems perceived by orphans and non-orphans were bleeding gums (16.8% and 12.4%) and toothache (12.7% and 13.7%), respectively. The daily performances most affected were cleaning mouth (33.3%; orphans 5.35 ± 4.22; non-orphans 7.05 ± 7.55; P = 0.000) and eating (33.1%; orphans 6.91 ± 6.09; non-orphans 7.07 ± 6.78; P = 0.003). Oral mucosal condition, dental fluorosis, dentofacial anomalies, and calculus showed significant difference among orphans and non-orphans (P = 0.000). CONCLUSION: C-OIDP score was high in orphans. Age, dental fluorosis, and decayed teeth were the significant factors for determining C-OIDP score. More than half of the study subjects were suffering from oral diseases which required treatment to improve their quality of life.

iPSC modeling of young-onset Parkinson's disease reveals a molecular signature of disease and novel therapeutic candidates.

Young-onset Parkinson's disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson's disease cases and, while some cases are associated with known genetic mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson's disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.

Progression of Gastric Acid Production in Preterm Neonates: Utilization of In-vitro Method.

Background: Limited studies are done regarding ability to produce gastric acid in preterm infants and most studies used in vivo method of assessing gastric pH. Objectives: To assess the feasibility of using an in vitro method of measuring gastric pH in babies ≤ 28 weeks gestational age (GA) and determine whether changes in gastric pH differ with gestational age, mode of delivery, and use of antenatal steroids. Design/Methods: Prospective study that enrolled extremely low birth weight (ELBW) babies. Gastric aspirate collected before feeding. In vitro testing of gastric aspirates for pH were done on days of life 1, 3, 5, 7, 14, and 28 by using pH electrode. The pH was measured on each sample in triplicate, mean calculated and used for data analysis. Stastical methods included descriptive statistics, t-tests and repeated measures ANOVA. Results: 29 subjects ≤ 28 weeks or birth weight ≤ 1,000 g were enrolled. No significant change was noted in pH measurements over time. Antenatal steroids and mode of delivery did not affect gastric acid pH. Conclusion: The in vitro method for gastric pH measurements is non-invasive and affords more frequent testing. It would be useful in studying various conditions that may affect gastric pH.

NF1 mutations in conjunctival melanoma.

BACKGROUND: Conjunctival melanoma is a potentially deadly eye tumour. Despite effective local therapies, tumour recurrence and metastasis remain frequent. The genetics of conjunctival melanomas remain incompletely understood. METHODS: A large cohort of 63 conjunctival melanomas was screened for gene mutations known to be important in other melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with patient prognosis. RESULTS: Frequent mutations in genes activating the MAP kinase pathway were identified. NF1 mutations were most frequent (n = 21, 33%). Recurrent activating mutations were also identified in BRAF (n = 16, 25%) and RAS genes (n = 12, 19%; 11 NRAS and 1 KRAS). CONCLUSIONS: Similar to cutaneous melanomas, conjunctival melanomas can be grouped genetically into four groups: BRAF-mutated, RAS-mutated, NF1-mutated and triple wild-type melanomas. This genetic classification may be useful for assessment of therapeutic options for patients with metastatic conjunctival melanoma.

The tobacco trade and trail in Karnataka.

CONTEXT: Tobacco use is a major public health challenge in India with 275 million adults consuming different tobacco products. Despite innumerable laws, the overall picture of the current system is not clear and the menace of tobacco persists. What does it take to stop this menace? The present study made an attempt to throw some light on the prevailing discrepancy in the current system. AIMS: The aim of the study was to explore the knowledge and attitude of people involved in growth and sales of tobacco. MATERIALS AND METHODS: This qualitative research was aimed at farmers growing tobacco in Mysore district and vendors selling tobacco in Bangalore. Snowball sampling technique was used to select the farmers. Simple random sampling technique was used to shortlist vendors selling tobacco products in Bangalore. Data were collected using semistructured questionnaire through interviews which were recorded using an audio recorder. RESULTS: Inductive analysis was conducted for the present study and the responses were divided into three categories, that is, awareness of laws, compliance to laws, and opinion regarding banning tobacco. Ninety percent of the growers and all the tobacco vendors (100%) were aware of the laws governing them; however, the compliance was poor in both the populations (32% and 20%, respectively). CONCLUSIONS: Implementation of law is an area that needs to be strengthened. Violations of these laws are not adequately reported; this matter should be dealt with. It was seen that the system which creates the laws itself promotes the growth and thereby the distribution of the tobacco products.

A prediction tool incorporating the biomarker S-100B for patient selection for completion lymph node dissection in stage III melanoma.

INTRODUCTION: Completion lymph node dissection (CLND) in sentinel node (SN)-positive melanoma patients is accompanied with morbidity, while about 80% yield no additional metastases in non-sentinel nodes (NSNs). A prediction tool for NSN involvement could be of assistance in patient selection for CLND. This study investigated which parameters predict NSN-positivity, and whether the biomarker S-100B improves the accuracy of a prediction model. METHODS: Recorded clinicopathologic factors were tested for their association with NSN-positivity in 110 SN-positive patients who underwent CLND. A prediction model was developed with multivariable logistic regression, incorporating all predictive factors. Five models were compared for their predictive power by calculating the Area Under the Curve (AUC). A weighted risk score, 'S-100B Non-Sentinel Node Risk Score' (SN-SNORS), was derived for the model with the highest AUC. Besides, a nomogram was developed as visual representation. RESULTS: NSN-positivity was present in 24 (21.8%) patients. Sex, ulceration, number of harvested SNs, number of positive SNs, and S-100B value were independently associated with NSN-positivity. The AUC for the model including all these factors was 0.78 (95%CI 0.69-0.88). SN-SNORS was the sum of scores for the five parameters. Scores of ≤9.5, 10-11.5, and ≥12 were associated with low (0%), intermediate (21.0%) and high (43.2%) risk of NSN involvement. CONCLUSIONS: A prediction tool based on five parameters, including the biomarker S-100B, showed accurate risk stratification for NSN-involvement in SN-positive melanoma patients. If validated in future studies, this tool could help to identify patients with low risk for NSN-involvement.

Bilateral blockade of MEK- and PI3K-mediated pathways downstream of mutant KRAS as a treatment approach for peritoneal mucinous malignancies.

Mucinous colorectal adenocarcinomas (MCAs) are clinically and morphologically distinct from nonmucinous colorectal cancers (CRCs), show a distinct spectrum of genetic alterations (higher KRAS mutations, lower p53, high MUC2), exhibit more aggressive behavior (more prone to peritoneal dissemination and lymph node involvement) and are associated with poorer response to chemotherapy with limited treatment options. Here, we report the effectiveness of combinatorial targeting of two KRAS-mediated parallel pathways in reducing MUC2 production and mucinous tumor growth in vitro and in vivo. By knockdown of mutant KRAS we show that, mutant KRAS (a) is necessary for MUC2 production in vitro and (b) synergistically engages PI3K/AKT and MEK/ERK pathways to maintain MUC2 expression in MCA cells. These results define a novel and a previously undescribed role for oncogenic KRAS in mucinous cancers. MCA cells were sensitive to MEK inhibition suggesting cellular dependence ('addiction') of KRAS-mutant MCA cells on hyperactivation of the MEK-driven pathway. Interestingly, MCA cells, though initially sensitive, were later resistant to PI3K single agent inhibition. Our studies suggest that this resistance involves dynamic rewiring of signaling circuits mediated through relief of RTK inhibition and MEK-ERK rebound activation. This resistance however, could be overcome by co-targeting of PI3K and MEK. Our studies thus provide a rational basis for MEK- and PI3K-targeted combination therapy for not only KRAS mutant MCA but also for other related mucinous neoplasms that overproduce MUC2 and have a high rate of KRAS mutations such as pseudomyxoma peritonei.

Anaesthetic Considerations in the Perioperative Management of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy has emerged as one of the primary modalities of treatment of diffuse peritoneal malignancies. It is a complex surgical procedure with the patients facing major and potentially life threatening alterations of haemodynamic, respiratory, metabolic and thermal balance with significant fluid losses and the perioperative management is challenging for anaesthesiologists and intensive care physicians. Though the alterations are short lived, these patients require advanced organ function monitoring and support perioperatively. The anaesthesiologist is involved in the management of haemodynamics, respiratory function, coagulation, haematologic parameters, fluid balance, thermal variations, and metabolic and nutritional support perioperatively. The chemotherapy instillate used are known to cause nephrotoxicity, cardiotoxicity, dyselectrolytemia and lactic acidosis. The preoperative polypharmacy for pain control, previous surgery and/or chemotherapy, malnourished status secondary to feeding problems and tumour wasting syndrome make the task all the more challenging. The anaesthesiologist also needs to consider the perioperative care from a quality of life perspective and proper preoperative counselling is important. The present overview summarizes the challenges faced by the anaesthesiologist regarding the pathophysiological alterations during the Cytoreductive surgery and Hyperthermic intraperitoneal chemotherapy in the preoperative, intraoperative and postoperative periods.

Delivery of RANKL-Binding Peptide OP3-4 Promotes BMP-2-Induced Maxillary Bone Regeneration.

Although bone morphogenetic protein 2 (BMP-2) is known to stimulate osteogenesis, there is evidence that high doses of BMP-2 can lead to side effects, including inflammation and carcinogenesis. The supplementation of other bone-augmenting agents is considered helpful in preventing such side effects by reducing the amount of BMP-2 required to obtain a sufficient amount of bone. We recently showed that a receptor activator of nuclear factor κB ligand (RANKL)-binding peptide promotes osteoblast differentiation. In the present study, we aimed to investigate whether OP3-4, a RANKL-binding peptide, promotes BMP-2-induced bone formation in the murine maxilla using an injectable gelatin hydrogel (GH) carrier. A GH carrier containing OP3-4 with BMP-2 was subperiosteally injected into the murine maxillary right diastema between the incisor and the first molar. The mice were sacrificed 28 d after the injections. The local bone formation in the OP3-4-BMP-2-injected group was analyzed in comparison to the carrier-injected, BMP-2-injected, and control-peptide-BMP-2-injected groups. The GH carrier containing OP3-4 with BMP-2 enlarged the radio-opaque area and increased the bone mineral content and density in the radiological analyses in comparison to the other experimental groups. Interestingly, fluorescence-based histological analyses revealed that the mineralization had started from the outside, then proceeded inward, suggesting that the size of the newly formed bone had already been set before calcification started and that the effects of OP3-4 might be involved in accelerating the early steps of osteogenesis. Actually, OP3-4 enhanced the BMP-2-induced 5-bromo-2'-deoxyuridine (BrdU)-positive cell numbers at the injected site on day 7 and the expression of Runx2 and Col1a1, which are early osteogenic cell markers, on day 10 after the subperiosteal injections. In summary, we demonstrated, for the first time, that the application of OP3-4 by subperiosteal injection promoted BMP-2-induced bone formation, which could lead to the development of an easy and noninvasive means of promoting alveolar ridge formation.

Patient-derived xenograft mouse models of pseudomyxoma peritonei recapitulate the human inflammatory tumor microenvironment.

Pseudomyxoma peritonei (PMP) is a neoplastic syndrome characterized by peritoneal tumor implants with copious mucinous ascites. The standard of care for PMP patients is aggressive cytoreductive surgery performed in conjunction with heated intraperitoneal chemotherapy. Not all patients are candidates for these procedures and a majority of the patients will have recurrent disease. In addition to secreted mucin, inflammation and fibrosis are central to PMP pathogenesis but the molecular processes that regulate tumor-stromal interactions within the peritoneal tumor microenvironment remain largely unknown. This knowledge is critical not only to elucidate PMP pathobiology but also to identify novel targets for therapy. Here, we report the generation of patient-derived xenograft (PDX) mouse models for PMP and assess the ability of these models to replicate the inflammatory peritoneal microenvironment of human PMP patients. PDX mouse models of low- and high-grade PMP were generated and were of a similar histopathology as human PMP. Cytokines previously shown to be elevated in human PMP were also elevated in PDX ascites. Significant differences in IL-6 and IL-8/KC/MIP2 were seen between human and PDX ascites. Interestingly, these cytokines were mostly secreted by mouse-derived, tumor-associated stromal cells rather than by human-derived PMP tumor cells. Our data suggest that the PMP PDX mouse models are especially suited to the study of tumor-stromal interactions that regulate the peritoneal inflammatory environment in PMP as the tumor and stromal cells in these mouse models are of human and murine origins, respectively. These mouse models are therefore, likely to be useful in vivo surrogates for testing and developing novel therapeutic treatment interventions for PMP.

Knowledge, attitude, and practice of needle stick and sharps injuries among dental professionals of Bangalore, India.

BACKGROUND: A needle stick injury (NSI) is an accidental skin-penetrating stab wound from a hollow-bore needle containing another person's blood or body fluid. Healthcare workers (HCWs) including dental professionals are at an occupational risk of exposure to blood-borne pathogens following NSIs and sharps injuries (SIs). A thorough understanding of the safe practices while handling needles and sharps is crucial for HCWs to create a risk-free work place environment. AIMS AND OBJECTIVES: To assess the knowledge, attitude, practice, and prevalence of NSIs and SIs among dental professionals in a dental college at Bangalore. MATERIALS AND METHODS: A cross-sectional survey was conducted in September 2012 using a structured, pretested, guided interview-based questionnaire that was administered to 200 dental professionals in a dental college at Bangalore to assess the knowledge, attitude, practices, and self-report information of NSIs. RESULTS: In the present study, 81.5% of dental professionals were vaccinated against hepatitis B. A total of 27.5% participants had an NSI during the previous 12 months. About 41.80% of NSIs occurred during device recapping. Most common reason for failure to report the incidents of NSIs, as declared by 29.09% of the participants, included the fear of being blamed or getting into trouble for having an NSI. CONCLUSION: The knowledge of dental professionals on NSIs and their preventive measures are inadequate; however, training on Universal Precaution Guidelines, protocols regarding post-exposure prophylaxis, and safety devices has to be provided to prevent such injuries in future among the dental professionals.

The endocytic recycling regulatory protein EHD1 Is required for ocular lens development.

The C-terminal Eps15 homology domain-containing (EHD) proteins play a key role in endocytic recycling, a fundamental cellular process that ensures the return of endocytosed membrane components and receptors back to the cell surface. To define the in vivo biological functions of EHD1, we have generated Ehd1 knockout mice and previously reported a requirement of EHD1 for spermatogenesis. Here, we show that approximately 56% of the Ehd1-null mice displayed gross ocular abnormalities, including anophthalmia, aphakia, microphthalmia and congenital cataracts. Histological characterization of ocular abnormalities showed pleiotropic defects that include a smaller or absent lens, persistence of lens stalk and hyaloid vasculature, and deformed optic cups. To test whether these profound ocular defects resulted from the loss of EHD1 in the lens or in non-lenticular tissues, we deleted the Ehd1 gene selectively in the presumptive lens ectoderm using Le-Cre. Conditional Ehd1 deletion in the lens resulted in developmental defects that included thin epithelial layers, small lenses and absence of corneal endothelium. Ehd1 deletion in the lens also resulted in reduced lens epithelial proliferation, survival and expression of junctional proteins E-cadherin and ZO-1. Finally, Le-Cre-mediated deletion of Ehd1 in the lens led to defects in corneal endothelial differentiation. Taken together, these data reveal a unique role for EHD1 in early lens development and suggest a previously unknown link between the endocytic recycling pathway and regulation of key developmental processes including proliferation, differentiation and morphogenesis.