A comparative transcriptomic analysis of glucagon-like peptide-1 receptor- and glucose-dependent insulinotropic polypeptide-expressing cells in the hypothalamus

ObjectiveThe hypothalamus is a key region of the brain implicated in homeostatic regulation, and is an integral centre for the control of feeding behaviour. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones with potent glucoregulatory function through engagement of their respective cognate receptors, GLP-1R and GIPR. Recent evidence indicates that there is a synergistic effect of combining GIP- and GLP-1-based pharmacology on appetite and body weight. The mechanisms underlying the enhanced weight loss exhibited by GIPR/GLP-1R co-agonism are unknown. Gipr and Glp1r are expressed in the hypothalamus in both rodents and humans. To better understand incretin receptor-expressing cell populations, we compared the cell types and expression profiles of Gipr- and Glp1r-expressing hypothalamic cells using single-cell RNA sequencing.MethodsUsing Glp1r-Cre or Gipr-Cre transgenic mouse lines, fluorescent reporters were introduced into either Glp1r- or Gipr-expressing cells, respectively, upon crossing with a ROSA26-EYFP reporter strain. From the hypothalami of these mice, fluorescent Glp1rEYFP+ or GiprEYFP+ cells were FACS-purified and sequenced using single-cell RNA sequencing. Transcriptomic analysis provided a survey of both non-neuronal and neuronal cells, and comparisons between Glp1rEYFP+ and GiprEYFP + populations were made.ResultsA total of 14,091 Glp1rEYFP+ and GiprEYFP+ cells were isolated, sequenced and taken forward for bioinformatic analysis. Both Glp1rEYFP+ and GiprEYFP+ hypothalamic populations were transcriptomically highly heterogeneous, representing vascular cell types, oligodendrocytes, astrocytes, microglia, and neurons. The majority of GiprEYFP+ cells were non-neuronal, whereas the Glp1rEYFP+ population was evenly split between neuronal and non-neuronal cell types. Both Glp1rEYFP+ and GiprEYFP+ oligodendrocytes express markers for mature, myelin-forming oligodendrocytes. While mural cells are represented in both Glp1rEYFP+ and GiprEYFP+ populations, Glp1rEYFP+ mural cells are largely smooth muscle cells, while the majority of GiprEYFP+ mural cells are pericytes. The co-expression of regional markers indicate that clusters of Glp1rEYFP+ and GiprEYFP+ neurons have been isolated from the arcuate, ventromedial, lateral, tuberal, suprachiasmatic, and premammillary nuclei of the hypothalamus.ConclusionsWe have provided a detailed comparison of Glp1r and Gipr cells of the hypothalamus with single-cell resolution. This resource will provide mechanistic insight into how engaging Gipr- and Glp1r-expressing cells of the hypothalamus may result in changes in feeding behaviour and energy balance

COVID-19 epidemic strongly affected cancer research in Italy: a survey of the Italian Cancer Society (SIC)

Background: Italy was among the first countries hit by the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The application of strict lockdown measures disproportionately affected both cancer patient care as well as basic and translational cancer research. Materials and methods: The Italian Cancer Society (SIC) conducted a survey on the effect of lockdown on laboratories involved in cancer research in Italy. The survey was completed by 570 researchers at different stages of their career, working in cancer centers, research institutes and universities from 19 Italian regions. Results: During the lockdown period, the impact of the COVID-19 pandemic emergency on face-to-face research activities was high, with a complete (47.7%) or partial (36.1%) shutdown of the laboratories. In the post-lockdown period, research activities were resumed in most of the respondents’ institutions (80.4%), though with some restrictions (77.2%). COVID-19 testing was offered to research personnel only in ~50% of research institutions. Overall, the response to the pandemic was fragmented as in many cases institutions adopted different strategies often aimed at limiting possible infections without a clearly defined contingency plan. Nevertheless, research was able to provide the first answers and possible ways out of the pandemic, also with the contribution of many cancer researchers that sacrificed their research programs to help overcome the pandemic by offering their knowledge and technologies. Conclusions: Given the current persistence of an emergency situation in many European countries, a more adequate organization of research centers will be urgent and necessary to ensure the continuity of laboratory activities in a safe environment

Prevention of incisional hernia post emergency laparotomy: A time to change? A case series.

Introduction: Complicated acute diverticulitis (CAD) is a surgical challenge in which a mini-invasive approach may be offered. Laparoscopic peritoneal lavage (LPL) was introduced as an alternative to sigmoid resection. However, the role of LPL is still under debate. Aim of this study was to evaluate which surgical strategy between LPL and Laparoscopic Sigmoidectomy (LS) could give better outcomes in CAD. Materials and methods: This prospective, observational, multicenter study lasted from 2015 until to 2018. Inclusion criteria: left colonic or sigmoid CAD (modified Hinchey’’s classification: grade II not responder to conservative treatment and grade III). Exclusion criteria: septic shock, immunodepression, previous multiple surgical operations, modified Hinchey’’s grade I and IV,\15 and[85 years. Comparisons were made between LPL and LS groups. Results: 66 patients were enrolled: 28 (42%) had LPL and 38 (58%) LS. Following sigmoidectomy, 24 pts (63%) had a primary anastomosis and 14 pts (37%) an end-colostomy (Hartmann’’s procedure). There were no significant differences regarding age, male gender rate and mean BMI (p = 0.314, p = 0.07, p = 0.129, respectively). ASA score [2 was significantly higher in LPL (p = 0.05). The number of previous episodes of diverticulitis and the mean C-Reactive Protein dosage were similar (p = 0.756 and 0.846). Mannheim Peritonitis Index was significantly higher in LPL (0.004). No differences were found regarding to the distribution of Hinchey’’s grades II and III (p = 0.727). 1 (4%) patient in LPL and 5 pts (13%) in LS needed a conversion to open surgery (p = 0.181). Overall, the morbidity rates were 33% in LPL and 18% in LS (p = 0.169). Organ space infection (30% vs 3%, p = 0.002) and the re-operation rates (18.5% vs 0; p = 0.006) resulted significantly higher in the LPL group. Mortality was nihil. Mean post-op length of stay was 11.4 days in LPL and 8.23 days in LS (p = 0.088). Diverticular recurrence was significantly increased in LPL (p = 0.003). Conclusions: Compared to LS, LPL is associated with increased ongoing sepsis, emergency re-intervention and recurrence of acute diverticulitis. The role of LPL for patients with CAD remains questionabl

A Taxonomy of Causality-Based Biological Properties

We formally characterize a set of causality-based properties of metabolic networks. This set of properties aims at making precise several notions on the production of metabolites, which are familiar in the biologists' terminology. From a theoretical point of view, biochemical reactions are abstractly represented as causal implications and the produced metabolites as causal consequences of the implication representing the corresponding reaction. The fact that a reactant is produced is represented by means of the chain of reactions that have made it exist. Such representation abstracts away from quantities, stoichiometric and thermodynamic parameters and constitutes the basis for the characterization of our properties. Moreover, we propose an effective method for verifying our properties based on an abstract model of system dynamics. This consists of a new abstract semantics for the system seen as a concurrent network and expressed using the Chemical Ground Form calculus. We illustrate an application of this framework to a portion of a real metabolic pathway

Lipid Remodeling in Hepatocyte Proliferation and Hepatocellular Carcinoma

Background and Aims: Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state-of-the-art systems biology approaches to models of liver regeneration, pharmacologically and genetically activated cell proliferation, and HCC. Approach and Results: Integrating metabolomics, lipidomics, and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated PC with hallmarks of cell proliferation and hepatic carcinogenesis. Conclusions: Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of therapeutic strategies and prognostic biomarkers of HCC