Appetite regulation by leptin

Obesity is a prevalent problem in modern society, which requires the upmost attention in the biomedical sciences. A leading cause of obesity related diseases is due to overeating, especially in industrialized countries. Leptin is the hormone that is secreted by fat cells responsible for communicating body nutritional status to the brain. Leptin interacts with other bodily systems such as the cognitive, digestive, neuronal, and endocrine systems. Leptin acts mainly on the Ob-Rb receptor in the arcuate nucleus of the hypothalamus and largely suppresses food intake and increases energy expenditure by activating Proopiomelanocortin and Cocaine- and amphetamine-regulated transcript (anorexigenic signals) neurons and by suppressing Neuropeptide Y and Agouti-related peptide (orexigenic signals) neurons, among other chemical signaling pathways. In both rodent and human studies, exogenous leptin administration resulted in elevated plasma leptin concentrations. When researchers tried to use leptin for weight reducing medical treatments in humans, the results show difficulty in establishing clinical efficacy. However, for diseases such as congenital leptin deficiency, obesity related leptin resistance, and lipodystrophy, medical treatments involving exogenous leptin have been relatively successful. The goal of this thesis is to give readers an understanding of leptin’s role in regulating appetite and the different leptin associated diseases. Leptin’s role is still continuing to be developed and more research is needed to fully utilize leptin for therapeutic benefit

Overcoming data sparsity

Unilever is currently designing and testing recommendation algorithms that would make recommendations about products to online customers given the customer ID and the current content of their basket. Unilever collected a large amount of purchasing data that demonstrates that most of the items (around 80%) are purchased infrequently and account for 20% of the data while frequently purchased items account for 80% of the data. Therefore, the data is sparse, skewed and demonstrates a long tail. Attempts to incorporate the data from the long tail, so far have proved difficult and current Unilever recommendation systems do not incorporate the information about infrequently purchased items. At the same time, these items are more indicative of customers' preferences and Unilever would like to make recommendations from/about these items, i.e. give a rank ordering of available products in real time. Study Group suggested to use the approach of bipartite networks to construct a similarity matrix that would allow the recommendation scores for different products to be computed. Given a current basket and a customer ID, this approach gives recommendation scores for each available item and recommends the item with the highest score that is not already in the basket. The similarity matrix can be computed offline, while recommendation score calculations can be performed live. This report contains the summary of Study Group findings together with the insights into properties of the similarity matrix and other related issues, such as recommendation for the data collection

Non-enzymatic roles of human RAD51 at stalled replication forks

The central recombination enzyme RAD51 has been implicated in replication fork processing and restart in response to replication stress. Here, we use a separation-of-function allele of RAD51 that retains DNA binding, but not D-loop activity, to reveal mechanistic aspects of RAD51’s roles in the response to replication stress. Here, we find that cells lacking RAD51’s enzymatic activity protect replication forks from MRE11-dependent degradation, as expected from previous studies. Unexpectedly, we find that RAD51’s strand exchange activity is not required to convert stalled forks to a form that can be degraded by DNA2. Such conversion was shown previously to require replication fork regression, supporting a model in which fork regression depends on a non-enzymatic function of RAD51. We also show RAD51 promotes replication restart by both strand exchange-dependent and strand exchange-independent mechanisms

The relationship between psychological distress and adolescent polydrug use

Polydrug use is relatively common among adolescents. Psychological distress is associated with the use of specific drugs, and may be uniquely associated with polydrug use. The purpose of this study was to test the association of psychological distress with polydrug use using a large adolescent sample. The sample consisted of 10,273 students aged 12-17 years from the State of Victoria, Australia. Participants completed frequency measures of tobacco, alcohol, cannabis, inhalant, and other drug use in the past 30 days, and psychological distress. Control variables included age, gender, family socioeconomic status, school suspensions, academic failure, cultural background, and peer drug use. Drug-use classes were derived using latent-class analysis, then the association of psychological distress and controls with drug-use classes was modeled using multinomial ordinal regression. There were 3 distinct classes of drug use: no drug use (47.7%), mainly alcohol use (44.1%), and polydrug use (8.2%). Independent of all controls, psychological distress was higher in polydrug users and alcohol users, relative to nondrug users, and polydrug users reported more psychological distress than alcohol users. Psychological distress was most characteristic of polydrug users, and targeted prevention outcomes may be enhanced by a collateral focus on polydrug use and depression and/or anxiety

Designed beta-hairpins inhibit LDH5 oligomerization and enzymatic activity

Lactate dehydrogenase 5 (LDH5) is overexpressed in metastatic tumors and is an attractive target for anticancer therapy. Small-molecule drugs have been developed to target the substrate/cofactor sites of LDH5, but none has reached the clinic to date, and alternative strategies remain almost unexplored. Combining rational and computer-based approaches, we identified peptidic sequences with high affinity toward a β-sheet region that is involved in protein-protein interactions (PPIs) required for the activity of LDH5. To improve stability and potency, these sequences were grafted into a cyclic cell-penetrating β-hairpin peptide scaffold. The lead grafted peptide, cGmC9, inhibited LDH5 activity in vitro in low micromolar range and more efficiently than the small-molecule inhibitor GNE-140. cGmC9 inhibits LDH5 by targeting an interface unlikely to be inhibited by small-molecule drugs. This lead will guide the development of new LDH5 inhibitors and challenges the landscape of drug discovery programs exclusively dedicated to small molecules. </p

Colorectal cancer with synchronous liver-limited metastases : the protocol of an Inception Cohort study (CoSMIC)

Introduction Colorectal cancer is the fourth most common cancer in the UK and an important cause of cancer-related death. In 20% of patients, there is metastasis to the liver or beyond at the time of diagnosis. The management of synchronous disease is complex. Conventional surgery removes the colorectal primary first, followed by chemotherapy, with resection of liver metastases as a final step. Advances in the availability and safety of liver surgery, anaesthesia and critical care have made two alternative options feasible. The first is synchronous resection of the primary and liver metastases. The second is resection of the metastatic disease as the first step, termed the reverse or liver-first approach. Currently, evidence is inadequate to inform the selection of care pathway for patients with colorectal cancer and synchronous liver-limited metastases. Specifically, optimal pathways are not defined and there is a dearth of prospectively recorded cohort-defining factors influencing treatment selection or outcome. Methods and analysis Colorectal cancer with Synchronous liver-limited Metastases: an Inception Cohort (CoSMIC) is an inception cohort study of patients with a new diagnosis of colorectal cancer with synchronous liver-limited metastases. The sequence of treatment received, and factors influencing treatment decisions, will be evaluated against European Society of Medical Oncology guidelines. Clinical data will be collected, and quality of life, morbidity, mortality and long-term outcome compared for different treatment sequences adjusted for prognostic factors. Disease-free survival or progression will be measured at 1, 2 and 5 years. A nested qualitative study will ascertain patient experiences and clinician perspectives on delivery of care. Ethics and dissemination The full study protocol was independently peer reviewed by Professor Kees de Jong (University of Maastricht, Holland). CoSMIC has ethical approval from the National Health Service Research Ethics Committee (14/NW/1397). Results will be disseminated to healthcare professionals and patient groups, and may be used to design a definitive trial addressing areas of equipoise in treatment pathways, as well as optimising current pathways to improve outcomes and experiences

Design of dry powder formulations of pH responsive peptide/plasmid DNA complexes for pulmonary delivery

Poster Presentation: no. 13PS50Respiratory diseases are substantial public health problems around the world. Recently, nucleic acid was developed as a potential therapeutic strategy to tackle a series of lung diseases. Delivery still poses one of the major challenges for their clinical application. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar fluid (BALF), which make them promising vectors for delivering therapeutic nucleic acid to the airways .....published_or_final_versio

Natural Progression of Biochemical Markers of Biliary Tract Obstruction in Patients with Gallstone Pancreatitis

The presenting pattern and natural progression of biochemical markers of biliary tract obstruction in patients with gallstone pancreatitis have not been elucidated. We analyzed serial values of bilirubin levels following admission to discharge in 143 patients. Ninety-four of patients demonstrated a Decrescendo (falling) pattern of bilirubin levels from admission until normalization at 21 hours (median). Forty-nine patients demonstrated a Crescendo-Decrescendo (initially rising) pattern with peak levels of bilirubin occurring at 39 hours after admission followed by a subsequent normalization after a median of 119 hours. Patients in the Decrescendo group were significantly younger (33 versus 41 years, P = .02) and more patients had experienced symptoms for greater than 48 hours (65% versus 47%, P = .05). Ten percent of patients in the Decrescendo group and 29% of patients in the Crescendo-Decrescendo group underwent ERCP (P = .02). Normalization of biochemical markers after ERCP was significantly delayed in both groups compared to no ERCP. Older patients present earlier, with higher bilirubin levels and normalize slower than younger patients, perhaps due to fibrosis of the ampulla and decreased compliance of the common bile duct. Patients who disobstruct spontaneously (90%) normalize quicker than patients undergoing ERCP