Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity.

Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans1-3. Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity4,5. ADCY3 localizes to the primary cilia of neurons 6 , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation 7 . We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons, that obesity-associated MC4R mutations impair ciliary localization and that inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight. These data suggest that impaired signaling from the primary cilia of MC4R neurons is a common pathway underlying genetic causes of obesity in humans

Metabolic biomarkers of appetite control in Parkinson\u27s disease patients with and without cognitive impairment

\ua9 2024 The Author(s)Background: Appetite dysregulation in Parkinson\u27s Disease (PD) appears to be linked to physical and cognitive deterioration. PD patients with and without cognitive impairment (CI) were compared to an age-matched control group to explore predictors of appetite control in fasting and post-prandial conditions. Methods: Fifty-five patients were recruited and divided into three groups: twenty controls (age: 74 y, BMI: 25.8 kg/m2), nineteen PD patients without CI (72.5 y, 25.1 kg/m2) and sixteen PD patients with CI (74.3 y, 24.0 kg/m2). Self-reported appetite perception and circulating blood metabolic biomarkers were measured in fasting and over a 3-h post-prandial period. Biomarkers included glucose, insulin, tumour necrosis factor alpha (TNF-α), leptin, acyl-ghrelin, total ghrelin, peptide YY (PYY), glucagon like peptide 1 (GLP-1), insulin growth factor 1 (IGF-1), growth factor (GF) and triglycerides. Patients were then provided with a mixed meal to eat ad libitum with the aim to evaluate links between metabolic biomarkers and control of energy intake. Results: PD patients with CI had a significant lower protein intake (7.4 \ub1 2.5 g, p = 0.01) compared to controls (21.9 \ub1 3.1 g) and PD patients without CI (14.3 \ub1 3.0 g). Post-prandial plasma GLP-1 concentrations were associated with decreased hunger perception (B\ub1SE, −5.3 \ub1 2.4 mm\ub7h−1, p = 0.04). PYY concentrations were significantly associated with GLP-1 in fasting (r = 0.40, p = 0.005) and post-prandial (r = 0.46, p < 0.001) conditions. In a multivariate model, post-prandial PYY concentrations were a significant predictor of ad libitum energy intake in all subjects (B\ub1SE, −87.5 \ub1 34.9 kcal, p = 0.01) and in patients with PD (B\ub1SE, −106.8 \ub1 44.9 kcal, p = 0.04). Conclusions: PYY and GLP-1 appeared to influence appetite control in PD patients and their roles merit further investigation

Constraint-based interactive assembly planning

The constraints on assembly plans vary depending on the product, assembly facility, assembly volume, and many other factors. This paper describes the principles and implementation of a framework that supports a wide variety of user-specified constraints for interactive assembly planning. Constraints from many sources can be expressed on a sequencing level, specifying orders and conditions on part mating operations in a number of ways. All constraints are implemented as filters that either accept or reject assembly operations proposed by the planner. For efficiency, some constraints are supplemented with special-purpose modifications to the planner`s algorithms. Replanning is fast enough to enable a natural plan-view-constrain-replan cycle that aids in constraint discovery and documentation. We describe an implementation of the framework in a computer-aided assembly planning system and experiments applying the system to several complex assemblies. 12 refs., 2 figs., 3 tabs

A rigorous approach to facilitate and guarantee the correctness of the genetic testing management in human genome information systems

<p>Abstract</p> <p>Background</p> <p>Recent medical and biological technology advances have stimulated the development of new testing systems that have been providing huge, varied amounts of molecular and clinical data. Growing data volumes pose significant challenges for information processing systems in research centers. Additionally, the routines of genomics laboratory are typically characterized by high parallelism in testing and constant procedure changes.</p> <p>Results</p> <p>This paper describes a formal approach to address this challenge through the implementation of a genetic testing management system applied to human genome laboratory. We introduced the Human Genome Research Center Information System (CEGH) in Brazil, a system that is able to support constant changes in human genome testing and can provide patients updated results based on the most recent and validated genetic knowledge. Our approach uses a common repository for process planning to ensure reusability, specification, instantiation, monitoring, and execution of processes, which are defined using a relational database and rigorous control flow specifications based on process algebra (ACP). The main difference between our approach and related works is that we were able to join two important aspects: 1) process scalability achieved through relational database implementation, and 2) correctness of processes using process algebra. Furthermore, the software allows end users to define genetic testing without requiring any knowledge about business process notation or process algebra.</p> <p>Conclusions</p> <p>This paper presents the CEGH information system that is a Laboratory Information Management System (LIMS) based on a formal framework to support genetic testing management for Mendelian disorder studies. We have proved the feasibility and showed usability benefits of a rigorous approach that is able to specify, validate, and perform genetic testing using easy end user interfaces.</p

Opinion piece: the case for establishing a minimal medication alternative for psychosis and schizophrenia

The development of severe mental health conditions is strongly linked to our environments, particularly experiences of trauma and adversity. However treatments for severe mental health conditions are often primarily biomedical, centred around medication. In the case of schizophrenia and psychosis, this is antipsychotic medication. Although antipsychotics have been found to reduce symptoms and risk of relapse, some patients derive little benefit from these drugs, and they can lead to severe adverse effects. Subsequently a high proportion of people do not want to take antipsychotics and request an alternative. Yet in the UK and in many countries there are currently no guidelines for stopping antipsychotics or formal treatment alternatives, despite such alternatives being available in some countries. For example, in Norway and Vermont (USA), in response to pressure from service user organisations, governments have mandated the establishment of ‘minimal medication’ services. We examine whether everyone with a psychotic condition needs long-term antipsychotic treatment and evidence for alternative models of care. We recommend that healthcare providers should be encouraged to develop a psychosocial treatment package for people with psychosis or schizophrenia that provides a realistic possibility of minimising antipsychotic exposure

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome

The Archimedes 2 mechanical assembly planning system

We describe the implementation and performance of Archimedes 2, an integrated mechanical assembly planning system. Archimedes 2 includes two planners, two assembly sequence animation facilities, and an associated robotic workcell. Both planners use full 3 dimensional data. A rudimentary translator from high level assembly plans to control code for the robotic workcell has also been implemented. We can translate data from a commercial CAD system into input data for the system, which has allowed us to plan assembly sequences for many industrial assemblies. Archimedes 2 has been used to plan sequences for assemblies consisting of 5 to 109 parts. We have also successfully taken a CAD model of an assembly, produced an optimized assembly sequence for it, and translated the plan into robot code, which successfully assembles the device specified in the model

LDRD final report: Automated planning and programming of assembly of fully 3D mechanisms

This report describes the results of assembly planning research under the LDRD. The assembly planning problem is that of finding a sequence of assembly operations, starting from individual parts, that will result in complete assembly of a device specified as a CAD model. The automated assembly programming problem is that of automatically producing a robot program that will carry out a given assembly sequence. Given solutions to both of these problems, it is possible to automatically program a robot to assemble a mechanical device given as a CAD data file. This report describes the current state of our solutions to both of these problems, and a software system called Archimedes 2 we have constructed to automate these solutions. Because Archimedes 2 can input CAD data in several standard formats, we have been able to test it on a number of industrial assembly models more complex than any before attempted by automated assembly planning systems, some having over 100 parts. A complete path from a CAD model to an automatically generated robot program for assembling the device represented by the CAD model has also been demonstrated

Combination Therapies Targeting Alk-Aberrant Neuroblastoma in Preclinical Models.

BACKGROUND: ALK activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1-2% of cases. Lorlatinib, a third generation ALK inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data has suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. AIMS: To study the preclinical activity of ALK inhibitors alone and combined with chemotherapy or idasanutlin. METHODS: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient derived xenografts (PDX). RESULTS: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSION: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma