GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process.

G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.

A Proteomic Screen to Unravel the Molecular Pathways Associated with Warfarin-Induced or TNAP-Inhibited Arterial Calcification in Rats.

Arterial media calcification refers to the pathological deposition of calcium phosphate crystals in the arterial wall. This pathology is a common and life-threatening complication in chronic kidney disease, diabetes and osteoporosis patients. Recently, we reported that the use of a TNAP inhibitor, SBI-425, attenuated arterial media calcification in a warfarin rat model. Employing a high-dimensionality unbiased proteomic approach, we also investigated the molecular signaling events associated with blocking arterial calcification through SBI-425 dosing. The remedial actions of SBI-425 were strongly associated with (i) a significant downregulation of inflammatory (acute phase response signaling) and steroid/glucose nuclear receptor signaling (LXR/RXR signaling) pathways and (ii) an upregulation of mitochondrial metabolic pathways (TCA cycle II and Fatty Acid ß-oxidation I). Interestingly, we previously demonstrated that uremic toxin-induced arterial calcification contributes to the activation of the acute phase response signaling pathway. Therefore, both studies suggest a strong link between acute phase response signaling and arterial calcification across different conditions. The identification of therapeutic targets in these molecular signaling pathways may pave the way to novel therapies against the development of arterial media calcification.

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process.

G protein-coupled receptors (GPCRs) represent one of the most functionally diverse classes of transmembrane proteins. GPCRs and their associated signaling systems have been linked to nearly every physiological process. They also constitute nearly 40% of the current pharmacopeia as direct targets of remedial therapies. Hence, their place as a functional nexus in the interface between physiological and pathophysiological processes suggests that GPCRs may play a central role in the generation of nearly all types of human disease. Perhaps one mechanism through which GPCRs can mediate this pivotal function is through the control of the molecular aging process. It is now appreciated that, indeed, many human disorders/diseases are induced by GPCR signaling processes linked to pathological aging. Here we discuss one such novel member of the GPCR family, GPR19, that may represent an important new target for novel remedial strategies for the aging process. The molecular signaling pathways (metabolic control, circadian rhythm regulation and stress responsiveness) associated with this recently characterized receptor suggest an important role in aging-related disease etiology.

The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease.

During the aging process our body becomes less well equipped to deal with cellular stress, resulting in an increase in unrepaired damage. This causes varying degrees of impaired functionality and an increased risk of mortality. One of the most effective anti-aging strategies involves interventions that combine simultaneous glucometabolic support with augmented DNA damage protection/repair. Thus, it seems prudent to develop therapeutic strategies that target this combinatorial approach. Studies have shown that the ADP-ribosylation factor (ARF) GTPase activating protein GIT2 (GIT2) acts as a keystone protein in the aging process. GIT2 can control both DNA repair and glucose metabolism. Through in vivo co-regulation analyses it was found that GIT2 forms a close coexpression-based relationship with the relaxin-3 receptor (RXFP3). Cellular RXFP3 expression is directly affected by DNA damage and oxidative stress. Overexpression or stimulation of this receptor, by its endogenous ligand relaxin 3 (RLN3), can regulate the DNA damage response and repair processes. Interestingly, RLN3 is an insulin-like peptide and has been shown to control multiple disease processes linked to aging mechanisms, e.g., anxiety, depression, memory dysfunction, appetite, and anti-apoptotic mechanisms. Here we discuss the molecular mechanisms underlying the various roles of RXFP3/RLN3 signaling in aging and age-related disorders.

Making Biomedical Sciences publications more accessible for machines.

With the rapidly expanding catalogue of scientific publications, especially within the Biomedical Sciences field, it is becoming increasingly difficult for researchers to search for, read or even interpret emerging scientific findings. PubMed, just one of the current biomedical data repositories, comprises over 33 million citations for biomedical research, and over 2500 publications are added each day. To further strengthen the impact biomedical research, we suggest that there should be more synergy between publications and machines. By bringing machines into the realm of research and publication, we can greatly augment the assessment, investigation and cataloging of the biomedical literary corpus. The effective application of machine-based manuscript assessment and interpretation is now crucial, and potentially stands as the most effective way for researchers to comprehend and process the tsunami of biomedical data and literature. Many biomedical manuscripts are currently published online in poorly searchable document types, with figures and data presented in formats that are partially inaccessible to machine-based approaches. The structure and format of biomedical manuscripts should be adapted to facilitate machine-assisted interrogation of this important literary corpus. In this context, it is important to embrace the concept that biomedical scientists should also write manuscripts that can be read by machines. It is likely that an enhanced human-machine synergy in reading biomedical publications will greatly enhance biomedical data retrieval and reveal novel insights into complex datasets.

GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease.

GPCRs arguably represent the most effective current therapeutic targets for a plethora of diseases. GPCRs also possess a pivotal role in the regulation of the physiological balance between healthy and pathological conditions; thus, their importance in systems biology cannot be underestimated. The molecular diversity of GPCR signaling systems is likely to be closely associated with disease-associated changes in organismal tissue complexity and compartmentalization, thus enabling a nuanced GPCR-based capacity to interdict multiple disease pathomechanisms at a systemic level. GPCRs have been long considered as controllers of communication between tissues and cells. This communication involves the ligand-mediated control of cell surface receptors that then direct their stimuli to impact cell physiology. Given the tremendous success of GPCRs as therapeutic targets, considerable focus has been placed on the ability of these therapeutics to modulate diseases by acting at cell surface receptors. In the past decade, however, attention has focused upon how stable multiprotein GPCR superstructures, termed receptorsomes, both at the cell surface membrane and in the intracellular domain dictate and condition long-term GPCR activities associated with the regulation of protein expression patterns, cellular stress responses and DNA integrity management. The ability of these receptorsomes (often in the absence of typical cell surface ligands) to control complex cellular activities implicates them as key controllers of the functional balance between health and disease. A greater understanding of this function of GPCRs is likely to significantly augment our ability to further employ these proteins in a multitude of diseases.

Cost sharing and branded antidepressant initiation among patients treated with generics.

OBJECTIVES: To determine the relationship between consumer cost sharing for branded antidepressants and the initiation of branded therapy among patients with major depressive disorder (MDD) filling a prescription for generic MDD medication. STUDY DESIGN: Retrospective cross-sectional analyses. METHODS: Patients aged 18 to 64 years with MDD who filled a generic antidepressant were identified in commercial claims data for 2012 to 2014. For each year-specific analysis, an average cost-sharing index for branded antidepressants at the level of the plan was computed. Multivariable models were used to estimate the relationship between plan-level cost sharing for branded antidepressant medications and the filling of branded prescriptions, with demographic and clinical variables as covariates. RESULTS: For patients with MDD filling a generic prescription, increases in branded cost sharing were associated with significant decreases in the likelihood of filling a branded antidepressant in each year (P <.001). Results in 2012 imply that a shift from the 0th to 90th percentile in the branded cost-sharing index corresponded with a 9.5% decrease in the relative likelihood of a branded fill among patients receiving a generic antidepressant. The corresponding figures for 2013 and 2014 were 9.3% and 3.5%, respectively. CONCLUSIONS: In MDD, patients and clinicians who dutifully adhere to guidelines requiring a trial of first-line medication may ultimately require therapy with alternate agents to achieve adequate disease control. A "reward the good soldier" benefit design would lower cost sharing for higher-tier evidence-based therapies when clinically indicated. Results suggest that narrowing the gap in cost sharing between branded and generic medications following a trial of a generic agent might improve access to second-line treatment in MDD.

Patient Outcomes and Cost Effects of Medicaid Formulary Restrictions on Antidepressants.

Many state Medicaid programs have implemented policies designed to reduce spending on prescription drugs by restricting access to branded products. For patients with major depressive disorder, formulary restrictions could severely limit access to antidepressant therapies and disrupt care. We linked data on patient outcomes and spending from 24 state Medicaid programs to information on formulary restrictions from 2001 to 2008. Outcomes included frequency of MDD-related hospitalizations and ER visits per patient and total healthcare spending. We estimated the effect of the policies on patient outcomes and spending using a difference-and-difference approach. We found that restricting access to antidepressants increased the probability of an MDD-related hospitalization by 1.7 percentage points (16.6%). Furthermore, we found no evidence that these restrictions resulted in any net savings for Medicaid.

Successful surgical closure of an arterial duct in 18 children in a third world country.

OBJECTIVES: To perform surgical closure of a clinically significant arterial duct on children in a third world country. BACKGROUND: An arterial duct is one of the most common congenital cardiac defects. Large arterial ducts can cause significant pulmonary overcirculation, causing symptoms of congestive cardiac failure, ultimately resulting in premature death. Closure of an arterial duct is usually curative, allowing for a normal quality of life and expectancy. In western countries, arterial duct closure in children is usually performed by deployment of a device through a catheter-based approach, replacing previous surgical approaches. In third world countries, there is limited access to the necessary resources for performing catheter-based closure of an arterial duct. Consequently, children with an arterial duct in a third world country may only receive palliative care, can be markedly symptomatic, and often do not survive to adulthood. METHODS: We assembled a team of 11 healthcare workers with extensive experience in the medical and surgical management of children with congenital cardiac disease. In all, 21 patients with a history of an arterial duct were screened by performing a comprehensive history, physical, and echocardiogram at the Angkor Hospital for Children in Siem Reap, Cambodia. RESULTS: A total of 18 children (eight male and ten female), ranging in age from 10 months to 14 years, were deemed suitable to undergo surgery. All patients were symptomatic, and the arterial ducts ranged in size from 4 to 15 millimetres. Surgical closure was performed using two clips, and in four cases with the largest arterial duct, sutures were also placed. All patients had successful closure without any significant complications, and were able to be discharged home within 2 days of surgery. Of note, four children with arterial ducts died in the 5 months before our arrival. CONCLUSION: Surgical closure of an arterial duct can be performed safely and effectively by an experienced paediatric cardiothoracic surgical team on children in a third world country. We hope that our experience will inspire others to perform similar missions throughout the world.

Future generation CT imaging.

X-ray CT technology has been available for more than 30 years, yet continued technological advances have kept CT imaging at the forefront of medical imaging innovation. Consequently, the number of clinical CT applications has increased steadily. Other imaging modalities might be superior to CT imaging for some specific applications, but no other single modality is more often used in chest imaging today. Future technological developments in the area of high-resolution detectors, high-capacity x-ray tubes, advanced reconstruction algorithms, and improved visualization techniques will continue to expand the imaging capability. Future CT imaging technology will combine improved imaging capability with advanced and specific computer-assisted tools, which will expand the usefulness of CT imaging in many areas.

Model-based detection of lung nodules in computed tomography exams. Thoracic computer-aided diagnosis.

RATIONALE AND OBJECTIVES: In this study, we developed a prototype model-based computer aided detection (CAD) system designed to automatically detect both solid and subsolid pulmonary nodules in computed tomography (CT) images. By using this CAD algorithm, along with the radiologist's initial interpretation, we aim to improve the sensitivity of radiologic readings of CT lung exams. MATERIALS AND METHODS: We have developed a model-based CAD algorithm through the use of precise mathematic models that capture scanner physics and anatomic information. Our model-based CAD algorithm uses multiple segmentation algorithms to extract noteworthy structures in the lungs and a Bayesian statistical model selection framework to determine the probability of various anatomical events throughout the lung. We tested this algorithm on 50 low-dose CT lung cancer screening cases in which ground truth was produced through readings by three expert chest radiologists. RESULTS: Using this model-based CAD algorithm on 50 low-dose CT cases, we measured potential sensitivity improvements of 7% and 5% in two radiologists with respect to all noncalcified nodules, solid and subsolid, greater than 5 mm in diameter. The third radiologist did not miss any nodules in the ground truth set. The CAD algorithm produced 8.3 false positives per case. CONCLUSION: Our prototype CAD system demonstrates promising results as a tool to improve the quality of radiologic readings by increasing radiologist sensitivity. A significant advantage of this model-based approach is that it can be easily extended to support additional anatomic models as clinical understanding and scanning practices improve.