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The corona virus disease (COVID 19) had upended medical education. This pandemic had risen the uncertainty over the start of normal routine of studies in medical universities. During this pandemic period educators had to find new alternatives for academic delivery. Various online platforms were used for educating various courses for the students. As COVID 19 is a new disease and was having devastation effect globally its emergence and its spared caused anxiety among students. The exams were postponed due to lockdown and students were under going stress and it further led to anxiety. Nursing education was also most affected by this pandemic. Nursing a practice based profession, apart from the theoretical knowledge they need to acquire clinical expertise. Due to the emergence of COVID 19 pandemic the Undergraduate nursing students had an anxiety of future due to lack of clinical practice. More over students are anxious regarding the course completion, exams, financial constraints of their family and hazards in their working place. This study was aimed at assessing the anxiety and its causes among the Undergraduate Nursing students during COVID 19 Pandemic.: Descriptive survey design was used. A total of 200 Nursing students were selected using convenient quota sampling method data was collected using semi structured questionnaire to assess causes of anxiety and rating scale to access the anxiety. Study results revealed that the 50% of students had mild anxiety, 49.5 % had moderate anxiety and 0.5% had severe anxiety. In the area of technical issues 60% had issues related heavy battery consumption of their devices and reduced storage space. Regarding academic issues 64.5% had issues regarding inability of understand the topic in online classes, 63.5% had concerns regarding the extension of course due to delaying of exam results and 50.5% of them had concerns regarding their skill acquisition since they had only completed 80% of practical requirements. It was found that 88.5% of students faced decreased interaction with teachers due to online classes as a communication issue and 59% of students experienced financial issues due to increase in the expense of PPE kits. Twenty nine percentage of students were having concerns regarding migration difficulties that might come across in their future career. Sixty one percentage of students were having fear of getting infection due to disease transmission. The rapid escalation in corona cases across the globe has created panic among people. Nursing students, being in direct contact with the patients in health care facilities, were always at risk to contact the deadly virus. This anxiety and worry poses a great mental turmoil and impacts the psychological health of the students. The study had generated baseline data with respect to the effect of the COVID-19 pandemic on causing the anxiety among nursing students. Students across the nursing institutes reported high levels of anxiety. Nurse educators should address such issues of students and use appropriate measures to allay their anxiety

With an increase in ageing population worldwide individuals with partial or complete edentulism are on the rise. Retaining a few natural teeth in the oral cavity to place a telescopic overdenture facilitates excellent prosthetic results. The present case report utilized three natural teeth in the mandibular arch to fabricate a telescopic overdenture with improved retention and stability.

Current Covid -19 pandemic has disrupted life in every corner of the world and will likely affect those children with preexisting disabilities. About 40% of differently-abled students are planning to drop out of schools because of difficulties they are facing in online education. The social distancing measures implemented by many countries have caused social isolation among children and had resulted in increased anxiety; stress and relapse of preexisting issues. This study aimed a) To Review the impact of the Covid-19 pandemic on differently-abled children and their parents b) Discuss alternative measures for delivering health services for differently-abled children A literature review through online sources of the database. Studies published from January 2020 up to October 2021 where included The review revealed that lack of socialization due to social distancing creates anxiety, stress, and depression among children and their parents. As schools have been suspended children with disabilities were not able to practice their learned skills which they attained through special education. Tele-medicine and Tele-rehabilitation activities may help to lower the prevalence of mental health issues among children and their parents Everyday life of individuals across the globe has been severely affected due to the covid 19 pandemic. Amidst this, it becomes important to keep children with physical and mental disabilities not only physically safe but also looks after their psychological and emotional well-being.

255 Background: During the COVID-19 pandemic, Twitter has been instrumental in accelerating knowledge dissemination and forging collaborations within the medical community and amongst patient advocates. Tweetchats within Twitter are scheduled conversations on a specific topic. In oncology, Tweetchats have been used by cancer advocates to spread awareness and for patient and caregiver education. A colorectal cancer (CRC) specific tweetchat did not previously exist. This abstract describes the creation, and experiences with a CRC specific tweetchat. Methods: The #CRCTrialsChat tweetchat was created by a patient advocate for colorectal cancer patients, caregivers and clinicians to meet and exchange clinical trial-related information. Two gastrointestinal (GI) medical oncologists and two radiation oncologists were enlisted as moderators. The topic for each session is chosen by the patient advocate, who creates an outline and divides the content, which is designed to last a one hour session. The idea is to create engaging, technical, but easy to understand content. Each moderator then works on the answers to their assigned section, which is edited to fit tweet character limit. Sessions may also have guest moderators with expertise on a specific topic. Through tweeting, moderators answer specific questions that come up during the session and later. Results: To date, we have had four sessions covering the following topics: Clinical trial basics, CRC Updates from ASCO22, ClinicalTrialFinders and BRAF-mutated tumors. The content created has been simple and engaging, the format has functioned smoothly, and the reach of #CRCTrialsChat has been steadily increasing. After the most recent session on BRAF in September 2022, the @CRCTrialsChat has 281 followers, 17K impressions and 14.6K profile visits, a reflection of its excellent content. From a clinician perspective, this is a great format to interact with colleagues, discuss enrolling trials and also become familiar with using Twitter. Conclusions: A CRC clinical trial focused tweetchat is an engaging way to deliver trial-related content to an audience of clinicians, patients and caregivers. The current format appears to be an effective way to create and disseminate information. Future sessions will focus on ctDNA, molecular markers such as KRAS and HER2, and rectal cancer trials. Our hope is that #CRCTrialsChat will stimulate continued patient and clinician engagement, increase awareness of clinical trials, enhance trial participation and initiate patient-centric research and collaborations.

Objective: Given the increasing risk of young-onset colorectal cancer (yCRC) among adults under 50 years, it is important to understand impacts on reproductive health. Our objective was to assess experiences with reproductive health after yCRC diagnosis among females. Methods: We conducted a cross-sectional study among females, 18 years or older, who have been diagnosed yCRC and are able to communicate in English. Data were gathered using an online survey involving both quantitative (e.g., multiple choice) and qualitative (e.g., open-ended text) questions on pregnancy history, influence of yCRC on reproductive decisions, and experiences with reproductive healthcare. Results: Altogether, 101 females with yCRC participated, including 23 who had never been pregnant and 78 who had been pregnant. yCRC influenced family planning goals for one-third of participants. Furthermore, compared to participants who completed treatment, those currently undergoing treatment had higher odds of indicating their yCRC diagnosis influenced family planning goals (adjusted odds ratio 4.93; 95% confidence interval 1.29 to 18.78). Although 53 (52.5%) participants indicated having discussions regarding reproductive health with healthcare provider(s), 44 (43.6%) did not. Content analysis of open-ended survey questions identified themes on the emotional impacts, experiences with reproductive healthcare, reproductive and family planning considerations, and the related issue of sexual health impacts of yCRC. Conclusions: Gaps in care, related to limited reproductive health discussions, influence of yCRC on family planning, and experiencing lasting reproductive health impacts highlight the need for improving reproductive healthcare, particularly for females diagnosed with yCRC.

Simple Summary Selection of appropriate stage II colon cancer patients for adjuvant chemotherapy (AC) is controversial. A novel immune response classifier has previously been validated to refine patient selection, but its impact on oncologist treatment planning had yet to be described. In this survey, all but one oncologist altered clinical practice recommendations, and recommendations for AC prescriptions were reduced by half (among the Immunoscore-high cases (low recurrence risk)). This study revealed that the Immunoscore results could significantly decrease AC use in patients with stage II colon cancer who may not benefit from it, thereby reducing the administration of nonvalue care. Abstract Background: Adjuvant chemotherapy use in stage II colon cancer is controversial. Current prognostic risk factors do not take the tumor immune microenvironment into account. Consideration of the Immunoscore, which measures the host immune response at the tumor site, may assist clinicians in reducing adjuvant chemotherapy use in patients who are unlikely to benefit from it. This study sought to determine the potential clinical utility of the Immunoscore, via its effect on medical oncologists’ recommendations for management of patients with stage II colon cancer. Methods: De-identified vignettes of 10 patients with stage II colon cancer were presented to 25 practicing medical oncologists. Each participant completed surveys indicating recommendations for adjuvant chemotherapy and surveillance strategies. An educational session was subsequently conducted, and the same patient profiles were re-presented but included immunoscore results. Participants were again asked to provide their recommendations. A participant was counted as influenced if their responses were altered after immunoscore test results were provided. Results: All but one participant (96%) altered a management recommendation for ≥1 case. For individual cases, a mean of 55% (range, 40–80%) of participants altered their recommendations for adjuvant chemotherapy and/or surveillance. For the immunoscore-high cases (low-risk of recurrence), recommendations for adjuvant chemotherapy use decreased from 60% to 31%. Conclusions: These results indicate a willingness by oncologists to integrate immunoscore information into clinical practice recommendations. Incorporation of immunoscore data resulted in the reduction of nonvalue care in the simulated population. Confirmation in prospective studies is planned.

Autism spectrum disorder (ASD) has emerged as a fairly common yet heterogeneous condition. More evidence towards a large number of specific genetic variations in ASD are now identified. Often we encounter difficulties in counselling the parents on the disease origin. We present a case series of 6 children including a pair of twin sibling who were diagnosed as ASD with a definite genetic aetiology. These children belonged to the age group of 3 to 15 years and were diagnosed as ASD as per DSM V criteria. Of the 6 children, two were otherwise clinically normal and remaining four children had associated medical conditions including hypocalcemia, severe hypotonia, seizures, cardiomyopathy, intellectual disability and neuroregression. In view of an unrecognised aetiology and children being first born in the family, parents were counselled for a genetic evaluation. Genetic test reports revealed gene variation pathogenic for ASD, of which 4 of them had known syndromic association. Though intervention would mostly remain the same, genetic aetiology helped us in prognosticating and improved the family’s outlook towards the disease. Hence it is desirable to identify genetic variations in all possible ASD cases as it has the potential to improve family planning, trigger screening for co-occurring medical problems, aid the prognosis, and start specific interventions.

e24129 Background: Clinical trials are increasingly part of the continuum of care for colorectal cancer patients, particularly those with metastatic disease. Yet most patients have limited knowledge about clinical trials, and many struggle to navigate the myriad barriers to enrollment. To bridge this gap, PALTOWN supports a broad array of activities in its COLONTOWN online community to help patients and caregivers interested in pursuing clinical trials. The function and impact of these activities is examined here. Methods: A comprehensive inventory of all clinical trial-related activity was conducted across three main sources: 1) resources and activity in COLONTOWN’s nine clinical trial-focused groups; 2) clinical trial materials posted in COLONTOWN UNIVERSITY, an online disease education center; and 3) patient feedback on clinical trial programming. Results: The MSS and MSI-High clinical trial groups in COLONTOWN serve more than 2,200 members, and more than 1,000 members are served by mutation- and location-specific trial groups. These groups have helped at least 187 members enroll in a clinical trial between 2019 and 2022. Among 10 trial-related activities, a majority (6/10) focused on sharing biomedical information, including : 1) patient-friendly descriptions of new trials; 2) explanations of trial results; 3) abstracts, articles, and videos from professional outlets such as ASCO Daily Post and OncLive; 4) patient-created resources on clinical trial basics in COLONTOWN UNIVERSITY; 5) “Doc Talks” by prominent CRC oncologists; and 6) patient advocates serving as information liaisons between patients and NCI Task Forces. A smaller number of activities (3/10) focused on psycho-social support from peers, including 1) accounts of patient experiences while seeking and participating in trials; 2) strategy discussions about how and when to pursue trials; and 3) “Alanna Project” database of members on a trial. COLONTOWN’s Clinical Trial Workshop (1/10) offers a novel approach to integrating biomedical education with psycho-social support via a four-week, peer-led clinical trial navigation program. Assessment of the cognitive and behavioral outcomes of the workshop demonstrate improvements in all four dimensions of health literacy: the ability to access, understand, appraise, and apply relevant information in the search for clinical trials. Conclusions: COLONTOWN's clinical trial programming offers comprehensive clinical trial education to patients and caregivers that leads to enrollment in trials. By embedding that education within a supportive community of peers, it enhances patients' capacity to collaborate with health care professionals in making informed decisions about clinical trials.

This paper mainly deals with the prevention of flutter instability in fin with shroud of a typical Rocket body through parametric studies. Flutter is an aeroelastic instability which occurs when aerodynamic loads cause deformation of the body which in turn initiates an oscillation in the body and further interacts with aerodynamics. The crew escape system is an emergency escape structure designed to swiftly pull the crew module along with the astronauts to a secure distance from the launch vehicle during launch abort. For the control of crew escape system during the ascent phase of trajectory, sweep back fins are used at the bottom of the vehicle. Finite element modelling of the fin was done using MSC/PATRAN software. Flutter analysis is carried out in MSC/NASTRAN using in-built aerodynamics. MSC/NASTRAN uses plate theories such as Doublet Lattice Method for subsonic Mach number, ZONA51 for transonic and low supersonic Mach numbers and Piston theory for high supersonic Mach numbers to generate the aerodynamic force within NASTRAN. MSC/PATRAN is a software developed to provide a systematic approach towards making finite element modeling fast and accurate; MSC/NASTRAN is a general purpose finite element analysis computer program that addresses a wide range of engineering problem and is also capable to focus on particular types of analysis. In this work, initially normal mode analysis was carried out for the modeled fin and flutter analysis was performed. It was observed that flutter instability occurred in most of the Mach numbers. In order to prevent flutter, the method of mass redistribution is adopted. Mass addition is carried out on leading edge and trailing edge to see the effect of movement of C.G with respect to the shaft axis. By carrying out various mass redistribution studies, the flutter instability in the fin is alleviated. This effort will be helpful for flutter prevention in control surfaces of upcoming vehicles also.

Modern aircraft structures uses more lightweight materials such as composites for their design. This makes the aeroelastic study an extremely important aspect of aircraft design. By having more light weight control surfaces, the control effectiveness study becomes vital in today’s scenario. Control effectiveness is the ability of a control surface such as an aileron or a rudder to produce aerodynamic forces and moments to change the airplane orientation and manoeuvre it along the intended flight path. This paper presents the static aeroelastic analysis of a typical reusable launch vehicle focusing on control effectiveness of elevon. A Reusable Launch Vehicle (RLV) is the space analogy of an aircraft. Ideally it takes off vertically on the back of a dispensable rocket and then glides back down like an aircraft. MSC PATRAN and MSC NASTRAN were the software’s used for Finite Element Modeling and Analysis. The main aim of the analysis is to compute the control effectiveness of launch vehicle along its trajectory to determine whether it is efficient to control the vehicle. The objectives of this work are, to study the control surface effectiveness of elevon by carrying out static aeroelastic analysis using NASTRAN inbuilt aerodynamics, for a typical Reusable Launch Vehicle (RLV).

205 Background: PALTOWN’s Facebook community, COLONTOWN, serves over 6,000 colorectal cancer (CRC) patients and caregivers. 81% of members are late stage patients (or late stage caregivers), and 85% are under the age of 60. They are highly motivated to find reliable information about treatment options as quickly as possible. Many arrive with little prior CRC education. Here we illustrate the creation of a patient-centric disease education program, COLONTOWN University (CTU), developed from the conversations and information journeys in COLONTOWN. Methods: CTU is a unique model for disseminating patient-facing disease education. CTU’s patient and caregiver staff develop original resources from a patient perspective, and work with principal investigators, testing companies, and other partners to create content specifically designed for the Learning Centers. Each Center provides resources to address the information needs of patients across both the spectrum of disease education and of CRC disease experience. Within the University’s online platform, self-contained Learning Centers offer structured resource libraries on topics of high interest to patients. Results: CTU creates patient-centric disease education that is accessible and more sophisticated than typical patient education materials. The discussions in COLONTOWN, in groups focused on specific biomarkers, metastases locations, and treatment modalities, provide members with the framework for understanding their disease. CTU gives them the resources they need to have informed discussions with their care teams. The CTU platform provides insight into what resources are most utilized. Survey tools facilitate an understanding of whether patients feel they have access to more treatment options, and have more productive interactions with their care teams, as a result of the education provided by CTU and the conversations with their peers in COLONTOWN. Conclusions: In its first year, CTU has become the education resource of choice for the thousands of members of COLONTOWN. Clinicians, principal investigators, and industry have all been enthusiastic partners in the development of resources. The positive response to CTU demonstrates the value of this model of patient-driven disease education.[Table: see text]

74 Background: Patients with colorectal cancer often require a caregiver’s assistance with daily activities, medical care, social needs, and navigating treatment options. In providing this assistance, caregivers may be at an increased risk for psychological distress. Direct support to manage a caregiver’s stress and maintain their well-being is essential. More research is needed to fully understand the challenges caregivers face and to provide solutions. Previous studies have found that caregivers experience high levels of depression and anxiety, and many lack access to resources despite the evidenced need for support. Methods: A survey was disseminated via the Colorectal Cancer Alliance’s Blue Hope Nation community for two weeks and by email. Forty caregivers of colorectal cancer patients of varying stages and diverse demographic backgrounds completed the survey. Results: Half of the respondents have been providing care for 1-3 years, and 63% indicated they were a patient’s spouse or partner. Most caregivers were in the 35-40 age group, and 30% were full-time caregivers. A majority reported experiencing anxiety/stress (97.5%), fatigue (80%), poor sleep (77.5%), depression (75%), and feelings of isolation (72.5%). Primary caregiver activities included providing moral support, completing household chores, and researching treatment options. Only 32.5% of caregivers received help or advice from their patient’s doctors or medical team on the tasks listed. The survey results suggest the need for a comprehensive resource with information on medications, side effects and treatments; a guide for medical discussions; organization for medical forms and documents; and a tool to connect with peer caregivers. Conclusions: Survey themes indicate that caregivers often feel unprepared to provide care, have inadequate knowledge, and receive little guidance from health care providers, so there is continued need to place both the patient and caregiver at the center of care. A comprehensive centralized resource given at diagnosis with vital information and a method for document organization would help reduce caregivers’ stress and allow them to share information easily. Such patient and caregiver-directed resources would enable a better quality of care experience, and potentially better mental health outcomes, for patients and their caregivers.

Context and Aims: Dysfunction of cognition and emotion is known in alcohol dependence; however, their relationship in alcohol dependence is unknown. Thus, this study aimed to know the level of emotional dysregulation and cognitive functions and their correlation in patients with alcohol dependence. Materials and Methods: In this hospital-based cross-sectional study, 120 patients with alcohol dependence were consecutively recruited and assessed with sociodemographic and clinical pro forma, Montreal Cognitive Assessment (MoCA), and Difficulty in Emotional Regulation Scale–Short Form (DERS-SF). Statistical Analysis: Descriptive statistical, Kruskal–Wallis H, and regression analysis. Results: Results revealed a mild level of cognitive impairment (mean MoCA score = 0 23.76) and high levels of emotional dysregulation (mean DERS-SF score = 0 26.90). On linear regression analysis (R2 = 0.266, df = 0 1, F = 0 42.782, P =0.000), the score on MoCA had statistically significant negative association with score on DERS-SF (P = 0.001). Conclusions: Cognitive impairment and emotional dysregulation are inversely related in patients with alcohol dependence. Improving the dysfunction may improve the outcome of alcohol dependence.

Addiction is the term employed not only for excess consumption of substances, but also for problem behaviours like eating disorders, pathological gambling, computer addiction and pathological preoccupation with video games and sexual acts. No clear diagnostic criterion has been established with validity for behavioral addictions. Sexual addiction, including addiction to pornography is not included as a separate entity because of a lack of strong empirical evidence in this area. Different scales can be used for assessment of sexual addiction. Since there is an absence of established diagnostic criteria, the significance of validity of these scales is doubted. Several of the questions in these scales do not yield information about whether the diagnostic criteria are met or not. Pharmacotherapy, together with psychotherapy proves to have a better outcome in such patients as it helps to synthesize the role of developmental antecedents, reduce current anxiety, depression, guilt and to improve social adjustment.

In this work, graphene oxide (GO) is prepared by modified Hummer's method. Nanocomposite of lanthana/graphene oxide (La2O3/GO) is obtained by solution mixing method and characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), differential thermal gravimetry (DTG) and differential thermal analysis (DTA). DTG analysis of La2O3/GO nanocomposite shows the stability of the nanocomposite up to 400°C. XRD and FT-IR verified the formation of crystalline GO and La2O3/GO nanocomposite. From TEM analysis, it is found that loading of La2O3 prevents the aggregation of GO sheets.

140 Background: Online cancer patient and caregiver support groups have burgeoned in the recent years; many provide critical emotional support and experiential wisdom to newly diagnosed patients. We outline below our experience engaging patients in clinical trial design working with COLONTOWN, a 5000+ member, online colorectal cancer (CRC) patient and caregiver support and educational community. Effective trial design is a complicated and lengthy process that requires input from multiple sources. Complex trial design can be particularly challenging, where opinions are mixed and a clear path forward may not be visible. Informed patient perspectives from support groups can be invaluable in such situations. Methods: Principal Investigators (PIs) for the oligometastatic CRC ERASure trial and the Janus rectal cancer trial worked with the lead author, a patient who is the Scientific Director of COLONTOWN. An interactive survey strategy was adopted and followed to solicit group feedback. COLONTOWN members (n = 70-120) were enthusiastic to participate and share the logic behind poll choices, and their personal experiences. Poll participation led to additional scientific discussion and improved community engagement around the survey questions. Poll data and highlights of the discussion were collected and passed on to study PIs in a de-identified manner. Results: Feedback from COLONTOWN helped PIs gauge patient enthusiasm for trial concepts and provide patient perspective and clarity to controversial questions in study design. This was particularly useful where data to support more than one option was available and the guidance from the NCI Task Force or cooperative group was split. The perspective from COLONTOWN was invaluable and used alongside NCI Task Force and cooperative group feedback to make decisions to move the trial concept forward. Conclusions: Support groups such as COLONTOWN are a versatile, valuable, underutilized and available resource that can be used to tap into patient perspectives during any clinical trial design process. Ideally, when utilized early, structured patient input can provide unique insights to PIs developing clinical trial concepts that could eliminate barriers and shorten the inception part of trial design. Increased awareness and knowledge of trial design support provided by such cancer communities could facilitate the development of patient-friendly trials to promote better accrual.

e16140 Background: Oxaliplatin continues to be the standard of care in the adjuvant and palliative setting in colorectal cancer (CRC). Although effective in CRC treatment, it is associated with a high risk of chemotherapy induced peripheral neuropathy (CIPN), which can debilitate the patient, prevent completion of care, and deteriorate their quality of life. Methods: Colontown is a Facebook-based CRC patient and caregiver support, education and advocacy group. Live Wire, a Colontown neighborhood that was formed in 2018 to help members manage CIPN, consists of over 700 CRC patients. One member of this group applied ice on hands and feet (‘icing’) during oxaliplatin infusion to limit exposure to chemotherapy via cold-induced vasoconstriction. The member was able to prevent CIPN, gaining the attention of the entire group. Results: Subsequently, popularization of icing occurred, as administrators communicated patient experiences and relayed published results on the effect of oral icing to patients. Several Colontown members voluntarily tried it during their chemotherapy, and reported successful outcomes. Live Wire created an “icing protocol” and distributed it to patients, oncologists, and care teams, both in-person and on social media (sm). Conclusions: This real-world example highlights the role of educated patient advocates on sm. Working with these groups directly can provide insights for the medical community on measures patients can do to prevent chemotherapy-associated side effects. The limited publications on icing to prevent CIPN, although promising, have not been enough to make it a recommended standard practice. Meanwhile, voluntary participation using icing for CIPN is growing in Colontown. At this time, Colontown is discussing with oncologists and cancer centers the potential of creating a clinical trial to verify the efficacy icing has during oxaliplatin infusion as a strategy to counter CIPN. Our hope is that this patient-informed icing protocol will be able to guide the design of a clinical trial on icing. Furthermore, with this “experiment”, we hope to illustrate the advantages of serious engagement with a large patient population through the modern use of social media.

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.

Members of the four-member C-terminal EPS15-Homology Domain-containing (EHD) protein family play crucial roles in endocytic recycling of cell surface receptors from endosomes to the plasma membrane. In this study, we show that Ehd1 gene knockout in mice on a predominantly B6 background is embryonic lethal. Ehd1-null embryos die at mid-gestation with a failure to complete key developmental processes including neural tube closure, axial turning and patterning of the neural tube. We found that Ehd1-null embryos display short and stubby cilia on the developing neuroepithelium at embryonic day 9.5 (E9.5). Loss of EHD1 also deregulates the ciliary SHH signaling with Ehd1-null embryos displaying features indicative of increased SHH signaling, including a significant downregulation in the formation of the GLI3 repressor and increase in the ventral neuronal markers specified by SHH. Using Ehd1-null MEFS we found that EHD1 protein co-localizes with the SHH receptor Smoothened in the primary cilia upon ligand stimulation. Under the same conditions, EHD1 was shown to co-traffic with Smoothened into the developing primary cilia and we identify EHD1 as a direct binding partner of Smoothened. Overall, our studies identify the endocytic recycling regulator EHD1 as a novel regulator of the primary cilium-associated trafficking of Smoothened and Hedgehog signaling.

ErbB2 overexpression drives oncogenesis in 20-30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca(2+)-dependent PKCs (α, β1, βII, and γ). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-α and PKC-δ together with the endocytic recycling regulator Arf6. PKC-α knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-δ knockdown. PMA-induced Erk phosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-δ but not that of PKC-α. Our results suggest that activation of PKC-α and -δ mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling.

Sexual dysfunction is one of the common symptoms seen in depression. Presentations include decreased libido, erectile dysfunction, arousal difficulties and orgasm related dysfunctions. The probable causes of sexual dysfunction in such patients are complex and biological, psychological as well as psychosocial factors are likely to play an important role. Sexual dysfunction could also occur as an adverse effect of anti-depressants although it is difficult to establish whether the dysfunction is due to the illness or the medication. Awareness among professionals about sexual dysfunction is essential as it can have a profound impact in terms of relationship conflict, marital satisfaction, quality of life and compliance with treatment in patients with depression.

Members of the four-member C-terminal EPS15-Homology Domain-containing (EHD) protein family play crucial roles in endocytic recycling of cell surface receptors from endosomes to the plasma membrane. In this study, we show that Ehd1 gene knockout in mice on a predominantly B6 background is embryonic lethal. Ehd1-null embryos die at mid-gestation with a failure to complete key developmental processes including neural tube closure, axial turning and patterning of the neural tube. We found that Ehd1-null embryos display short and stubby cilia on the developing neuroepithelium at embryonic day 9.5 (E9.5). Loss of EHD1 also deregulates the ciliary SHH signaling with Ehd1-null embryos displaying features indicative of increased SHH signaling, including a significant downregulation in the formation of the GLI3 repressor and increase in the ventral neuronal markers specified by SHH. Using Ehd1-null MEFS we found that EHD1 protein co-localizes with the SHH receptor Smoothened in the primary cilia upon ligand stimulation. Under the same conditions, EHD1 was shown to co-traffic with Smoothened into the developing primary cilia and we identify EHD1 as a direct binding partner of Smoothened. Overall, our studies identify the endocytic recycling regulator EHD1 as a novel regulator of the primary cilium-associated trafficking of Smoothened and Hedgehog signaling.

The mammalian ferlins are calcium-sensing, C2 domain-containing proteins involved in vesicle trafficking. Myoferlin and dysferlin regulate myoblast fusion and muscle membrane resealing, respectively. Correspondingly, myoferlin is most highly expressed in singly nucleated myoblasts, whereas dysferlin expression is increased in mature, multinucleated myotubes. Myoferlin also mediates endocytic recycling and participates in trafficking the insulin-like growth factor receptor. We have now characterized a novel member of the ferlin family, Fer1L5, because of its high homology to dysferlin and myoferlin. We found that Fer1L5 protein is expressed in small myotubes that contain only two to four nuclei. We also found that Fer1L5 protein binds directly to the endocytic recycling proteins EHD1 and EHD2 and that the second C2 domain in Fer1L5 mediates this interaction. Reduction of EHD1 and/or EHD2 inhibits myoblast fusion, and EHD2 is required for normal translocation of Fer1L5 to the plasma membrane. The characterization of Fer1L5 and its interaction with EHD1 and EHD2 underscores the complex requirement of ferlin proteins and mediators of endocytic recycling for membrane trafficking events during myotube formation.

Rationale : Cardiac membrane excitability is tightly regulated by an integrated network of membrane-associated ion channels, transporters, receptors, and signaling molecules. Membrane protein dynamics in health and disease are maintained by a complex ensemble of intracellular targeting, scaffolding, recycling, and degradation pathways. Surprisingly, despite decades of research linking dysfunction in membrane protein trafficking with human cardiovascular disease, essentially nothing is known regarding the molecular identity or function of these intracellular targeting pathways in excitable cardiomyocytes. Objective : We sought to discover novel pathways for membrane protein targeting in primary cardiomyocytes. Methods and Results : We report the initial characterization of a large family of membrane trafficking proteins in human heart. We used a tissue-wide screen for novel ankyrin-associated trafficking proteins and identified 4 members of a unique Eps15 homology (EH) domain–containing protein family (EHD1, EHD2, EHD3, EHD4) that serve critical roles in endosome-based membrane protein targeting in other cell types. We show that EHD1-4 directly associate with ankyrin, provide the first information on the expression and localization of these molecules in primary cardiomyocytes, and demonstrate that EHD1-4 are coexpressed with ankyrin-B in the myocyte perinuclear region. Notably, the expression of multiple EHD proteins is increased in animal models lacking ankyrin-B, and EHD3-deficient cardiomyocytes display aberrant ankyrin-B localization and selective loss of Na/Ca exchanger expression and function. Finally, we report significant modulation of EHD expression following myocardial infarction, suggesting that these proteins may play a key role in regulating membrane excitability in normal and diseased heart. Conclusions : Our findings identify and characterize a new class of cardiac trafficking proteins, define the first group of proteins associated with the ankyrin-based targeting network, and identify potential new targets to modulate membrane excitability in disease. Notably, these data provide the first link between EHD proteins and a human disease model.

Cadherin 23 (CDH23), a transmembrane protein localized near the tips of hair cell stereocilia in the mammalian inner ear, is important for delivering mechanical signals to the mechano-electric transducer channels. To identify CDH23-interacting proteins, a membrane-based yeast two-hybrid screen of an outer hair cell (OHC) cDNA library was performed. EHD4, a member of the C-terminal EH domain containing a protein family involved in endocytic recycling, was identified as a potential interactor. To confirm the interaction, we first demonstrated the EHD4 mRNA expression in hair cells using in situ hybridization. Next, we showed that EHD4 co-localizes and co-immunoprecipitates with CDH23 in mammalian cells. Interestingly, the co-immunoprecipitation was found to be calcium-sensitive. To investigate the role of EHD4 in hearing, compound action potentials were measured in EHD4 knock-out (KO) mice. Although EHD4 KO mice have normal hearing sensitivity, analysis of mouse cochlear lysates revealed a 2-fold increase in EHD1, but no increase in EHD2 or EHD3, in EHD4 KO cochleae compared with wild type, suggesting that a compensatory increase in EHD1 levels may account for the absence of a hearing defect in EHD4 KO mice. Taken together, these data indicate that EHD4 is a novel CDH23-interacting protein that could regulate CDH23 trafficking/localization in a calcium-sensitive manner.

Expression of the rolC gene in plants has been shown to cause pleiotropic effects, including decreased height. The effects of differential rolC gene expression on plant height, leaf color, root growth, leaf size, corolla length, and stem diameter were determined. Differential expression of rolC in Nicotiana tabacum L. `Samsun' plants was achieved using the 35S promoter, the light-inducible rbcS promoter, or the native rolC promoter. Sixteen plants from the T1 generation—six with the 35S promoter, six with the rbcS promoter, and four with the native rolC promoter—and non-transformed controls were measured for height, internode length, branch number, bud size, corolla length and diameter, root growth, and the number of days to flowering. Steady state mRNA levels of rolC were measured in roots, stems, and leaves to assess relationships between rolC expression level in specific tissues and phenotypes. Plants expressing rolC showed a wide range of phenotypes, with the largest changes in plants expressing rolC using the 35S promoter, which also had the highest rolC mRNA levels. Plants expressing rolC with the rolC or rbcS promoter had significant changes for many measured traits, despite rolC mRNA levels that were not significantly different from non-transformed controls. In general, as rolC mRNA levels increased, so did the severity of the rolC phenotype observed. Three plants, A4, A7, and B9, had unique combinations of traits that did not follow this general trend. Transformation with rolC can be useful in ornamental crops where smaller cultivars are desired.

Substance abuse and addictive disorders are very common in the community. Patients with addictive disorders frequently experience sexual dysfunctions and chronic use of substances tends to adversely affect all stages of sexual response, in both male and female abusers. An important aspect in the management of sexual dysfunction is psychosocial intervention. In addictive disorders, sexual dysfunction is of high clinical relevance, as it often leads to treatment non adherence and sexual or marital disharmony. Instead of a disease-centred approach, a couple and relationship centred approach of management is desirable. A detailed history about the sexual dysfunction, the addictive disorder and enquiry into various psychosocial aspects is mandatory for adequate management of the same. Sexual therapy, behavioural techniques, systematic sensitization and desensitization are some of the techniques used in the management of sexual dysfunction in addictive disorders. The assessment and treatment need to be tailored depending upon the various psychosocial aspects of the individual.

Aphthoviruses are unique among picornaviruses in that they alone encode a functional L proteinase as the first component of the viral polyprotein. The L genes of a few Indian foot-and-mouth disease viruses were sequenced and compared with those available to study the extent of variation in this gene. Besides the two in-frame start codons present in all FMDV L genes, the Asia-I vaccine virus had an additional in-frame AUG (start) codon, at codon position 3. Amino acid sequence comparison revealed that 39.8% of positions were capable of accepting replacements, yet the residues of the catalytic dyad were totally conserved. Sequence comparison at the C-terminus of the protein indicated that K/R decreasing GAGQS is sufficient for L/P1 cleavage. Phylogenetic analysis based on the L gene sequences did not reveal any serotype-specific clustering. The probable implications of the observed high variability in this non-structural gene is briefly discussed.

Proteolytic processing of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase generates Aβ peptides. APP is constitutively trafficked through the secretory and endocytic pathways in cultured cells and neurons. The identities of cellular organelles and sorting pathways involved in amyloidogenic processing of APP have been extensively investigated. Although a consensus has not yet emerged, there is a general agreement from biochemical and genetic studies on the importance of endocytic APP trafficking for Aβ production. In neurons, APP is trafficked anterogradely along peripheral and central axons, and proteolytically processed during transit. Recent in vivo studies estimated that ~70% of Aβ released in the brain requires ongoing endocytosis, and synaptic activity regulates the vast majority of this endocytosis-dependent Aβ. BACE1 cleavage is thought to be the rate-limiting step in amyloidogenic processing of APP. Little, however, is known about endocytic BACE1 sorting and dynamic transport in neurons. We investigated BACE1 trafficking in cultured hippocampal neurons using live-cell imaging and selective labeling. This approach revealed dynamic neuronal transport of internalized BACE1 in dendrites and axons. BACE1 was transported in vesicles that were positive for markers of recycling endosomes. Dominant-negative expression and siRNA knock-down of proteins involved in endocytic transit revealed that BACE1 is dynamically transported in recycling endosomes and this process significantly contributes to amyloidogenic APP processing. Our results suggest that BACE1 trafficking in neuronal recycling endosomes is likely relevant for presynaptic Aβ production and contributes to Alzheimer’s disease pathogenesis.

The combination of propranolol and pulsed dye laser for the treatment of infantile hemangiomas may be superior to either alone. This case report illustrates the additive effect of propranolol and pulsed dye laser for an infantile hemangioma in a high-risk location. Although thorough clinical trials are needed, combination therapy for infantile hemangiomas may prove to be optimal for efficacy.

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3(-/-) mice and assessed renal development and pathology. Ehd3(-/-) animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3(-/-) mice and suggested functional compensation, we generated and analyzed Ehd3(-/-); Ehd4(-/-) mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between 3-24 weeks of age. Detailed analyses of Ehd3(-/-); Ehd4(-/-) kidneys demonstrated thrombotic microangiopathy (TMA)-like glomerular lesions including thickening and duplication of glomerular basement membrane, endothelial swelling and loss of fenestrations. Other changes included segmental podocyte foot process effacement, mesangial interposition, and abnormal podocytic and mesangial marker expression. The glomerular lesions observed were strikingly similar to those seen in human pre-eclampsia and mouse models of reduced VEGF expression. As altered glomerular endothelial VEGFR2 expression and localization and increased apoptosis was observed in the absence of EHD3 and EHD4, we propose that EHD-mediated endocytic traffic of key surface receptors such as VEGFR2 is essential for physiological control of glomerular function. Furthermore, Ehd3(-/-); Ehd4(-/-) mice provide a unique model to elucidate mechanisms of glomerular endothelial injury which is observed in a wide variety of human renal and extra-renal diseases.

The four highly homologous members of the C-terminal EH domain-containing (EHD) protein family (EHD1-4) regulate endocytic recycling. To delineate the role of EHD4 in normal physiology and development, mice with a conditional knockout of the Ehd4 gene were generated. PCR of genomic DNA and Western blotting of organ lysates from Ehd4−/− mice confirmed EHD4 deletion. Ehd4−/− mice were viable and born at expected Mendelian ratios; however, males showed a 50% reduction in testis weight, obvious from postnatal day 31. An early (Day 10) increase in germ cell proliferation and apoptosis and a later increase in apoptosis (Day 31) were seen in the Ehd4−/− testis. Other defects included a progressive reduction in seminiferous tubule diameter, dysregulation of seminiferous epithelium, and head abnormalities in elongated spermatids. As a consequence, lower sperm counts and reduced fertility were observed in Ehd4−/− males. Interestingly, EHD protein expression was seen to be temporally regulated in the testis and EHD4 levels peaked between days 10 and 15. In the adult testis, EHD4 was highly expressed in primary spermatocytes and EHD4 deletion altered the levels of other EHD proteins in an age-dependent manner. We conclude that high levels of EHD1 in the adult Ehd4−/− testis functionally compensate for lack of EHD4 and prevents the development of severe fertility defects. Our results suggest a role for EHD4 in the proper development of postmitotic and postmeiotic germ cells and implicate EHD protein-mediated endocytic recycling as an important process in germ cell development and testis function. genesis 48:328–342, 2010. © 2010 Wiley-Liss, Inc.

Background Epidermal growth factor receptor (EGFR) controls a wide range of cellular processes, and altered EGFR signaling contributes to human cancer. EGFR kinase domain mutants found in non-small cell lung cancer (NSCLC) are constitutively active, a trait critical for cell transformation through activation of downstream pathways. Endocytic trafficking of EGFR is a major regulatory mechanism as ligand-induced lysosomal degradation results in termination of signaling. While numerous studies have examined mutant EGFR signaling, the endocytic traffic of mutant EGFR within the NSCLC milieu remains less clear. Results This study shows that mutant EGFRs in NSCLC cell lines are constitutively endocytosed as shown by their colocalization with the early/recycling endosomal marker transferrin and the late endosomal/lysosomal marker LAMP1. Notably, mutant EGFRs, but not the wild-type EGFR, show a perinuclear accumulation and colocalization with recycling endosomal markers such as Rab11 and EHD1 upon treatment of cells with endocytic recycling inhibitor monensin, suggesting that mutant EGFRs preferentially traffic through the endocytic recycling compartments. Importantly, monensin treatment enhanced the mutant EGFR association and colocalization with Src, indicating that aberrant transit through the endocytic recycling compartment promotes mutant EGFR-Src association. Conclusion The findings presented in this study show that mutant EGFRs undergo aberrant traffic into the endocytic recycling compartment which allows mutant EGFRs to engage in a preferential interaction with Src, a critical partner for EGFR-mediated oncogenesis.

We followed 55 high risk newborns from birth till one year using Trivandrum Development Screening Chart (TDSC) and Denver Development Screening Test (DDST). We also assessed their muscle tone, vision and hearing. Babies were classified into mild, moderate, and severe risk groups using a scoring system. Babies with developmental delay were categorized as having mild, moderate, or severe delay. The risk score was significantly associated with the severity of developmental delay (Plt; 0.001). Abnormalities of tone were also associated with development delay (P0.001).

Background The four highly homologous human EHD proteins (EHD1-4) form a distinct subfamily of the Eps15 homology domain-containing protein family and are thought to regulate endocytic recycling. Certain members of this family have been studied in different cellular contexts; however, a lack of concurrent analyses of all four proteins has impeded an appreciation of their redundant versus distinct functions. Results Here, we analyzed the four EHD proteins both in mammalian cells and in a cross-species complementation assay using a C. elegans mutant lacking the EHD ortholog RME-1. We show that all human EHD proteins rescue the vacuolated intestinal phenotype of C. elegans rme-1 mutant, are simultaneously expressed in a panel of mammalian cell lines and tissues tested, and variably homo- and hetero-oligomerize and colocalize with each other and Rab11, a recycling endosome marker. Small interfering RNA (siRNA) knock-down of EHD1, 2 and 4, and expression of dominant-negative EH domain deletion mutants showed that loss of EHD1 and 3 (and to a lesser extent EHD4) but not EHD2 function retarded transferrin exit from the endocytic recycling compartment. EH domain deletion mutants of EHD1 and 3 but not 2 or 4, induced a striking perinuclear clustering of co-transfected Rab11. Knock-down analyses indicated that EHD1 and 2 regulate the exit of cargo from the recycling endosome while EHD4, similar to that reported for EHD3 (Naslavsky et al. (2006) Mol. Biol. Cell 17, 163), regulates transport from the early endosome to the recycling endosome. Conclusion Altogether, our studies suggest that concurrently expressed human EHD proteins perform shared as well as discrete functions in the endocytic recycling pathway and lay a foundation for future studies to identify and characterize the molecular pathways involved.