Mesoderm migration in Drosophila is a multi-step process requiring FGF signaling and integrin activity

Migration is a complex, dynamic process that has largely been studied using qualitative or static approaches. As technology has improved, we can now take quantitative approaches towards understanding cell migration using in vivo imaging and tracking analyses. In this manner, we have established a four-step model of mesoderm migration during Drosophila gastrulation: (I) mesodermal tube formation, (II) collapse of the mesoderm, (III) dorsal migration and spreading and (IV) monolayer formation. Our data provide evidence that these steps are temporally distinct and that each might require different chemical inputs. To support this, we analyzed the role of fibroblast growth factor (FGF) signaling, in particular the function of two Drosophila FGF ligands, Pyramus and Thisbe, during mesoderm migration. We determined that FGF signaling through both ligands controls movements in the radial direction. Thisbe is required for the initial collapse of the mesoderm onto the ectoderm, whereas both Pyramus and Thisbe are required for monolayer formation. In addition, we uncovered that the GTPase Rap1 regulates radial movement of cells and localization of the beta-integrin subunit, Myospheroid, which is also required for monolayer formation. Our analyses suggest that distinct signals influence particular movements, as we found that FGF signaling is involved in controlling collapse and monolayer formation but not dorsal movement, whereas integrins are required to support monolayer formation only and not earlier movements. Our work demonstrates that complex cell migration is not necessarily a fluid process, but suggests instead that different types of movements are directed by distinct inputs in a stepwise manner

Nanotubes Make Big Science

Tiny protrusions on the surface of cells might be a more common mechanism for cell communication than previously expecte

Cardiovascular, mortality and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. Methods: We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. Findings: Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82–0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81–0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76–0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84–1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83–0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83–0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78–0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. Interpretation: Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes

Employment status at time of first hospitalization for heart failure is associated with death and rehospitalization for heart failure

Background: Employment status at time of first heart failure (HF) hospitalization may be an indicator of both self-perceived and objective health status. In this study, we examined the association between employment status and the risk of all-cause mortality and recurrent HF hospitalization in a nationwide cohort of patients with HF. Methods and Results: We identified all patients of working age (18-60 years) with a first HF hospitalisation in the period 1997-2015 in Denmark, categorized according to whether or not they were part of the workforce at time of the index admission. The primary outcome was death from any cause and the secondary outcome was readmission for HF. Cumulative incidence curves, binomial regression and Cox regression models were used to assess outcomes. Of 25571 patients with a first hospitalization for HF, 15428 (60%) were part of the workforce at baseline. Patients in the workforce were significantly younger (53 vs. 55 years) more likely to be male (75% vs 64%) and less likely to have diabetes (13% vs 22%) and chronic obstructive pulmonary disease (5% vs 10%), all p-values <0.001. Not being part of the workforce was associated with a significantly higher risk of death (HR: 1.59 [95% CI 1.50–1.68]) and rehospitalisation for HF (HR: 1.09 [95% CI 1.05–1.14]), in analyses adjusted for age, sex, comorbidities, education level, calendar time, duration of first HF hospitalization. Conclusion: Not being part of the workforce at time of first HF hospitalization was independently associated with increased mortality and recurrent HF hospitalization

Guide to Understanding Drosophila Models of Neurodegenerative Diseases

Demystifying how genetic studies inDrosophila inform human disease conditions, this article highlights two studies that identify genetic modifiers of neurodegeneration

Comparison of BNP and NT-proBNP in patients with heart failure and reduced ejection fraction

Both BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro B-type natriuretic peptide) are widely used to aid diagnosis, assess the effect of therapy, and predict outcomes in heart failure and reduced ejection fraction. However, little is known about how these 2 peptides compare in heart failure and reduced ejection fraction, especially with contemporary assays. Both peptides were measured at screening in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). Eligibility criteria in PARADIGM-HF included New York Heart Association functional class II to IV, left ventricular ejection fraction ≤40%, and elevated natriuretic peptides: BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL (for patients with HF hospitalization within 12 months, BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL). BNP and NT-proBNP were measured simultaneously at screening and only patients who fulfilled entry criteria for both natriuretic peptides were included in the present analysis. The BNP/NT-proBNP criteria were not different for patients in atrial fibrillation. Estimated glomerular filtration rate <30 mL/min per 1.73 m was a key exclusion criterion. The median baseline concentration of NT-proBNP was 2067 (Q1, Q3: 1217-4003) and BNP 318 (Q1, Q3: 207-559), and the ratio, calculated from the raw data, was ≈6.25:1. This ratio varied considerably according to rhythm (atrial fibrillation 8.03:1; no atrial fibrillation 5.75:1) and with age, renal function, and body mass index but not with left ventricular ejection fraction. Each peptide was similarly predictive of death (all-cause, cardiovascular, sudden and pump failure) and heart failure hospitalization, for example, cardiovascular death: BNP hazard ratio, 1.41 (95% CI, 1.33-1.49) per 1 SD increase, <0.0001; NT-proBNP, 1.45 (1.36-1.54); <0.0001. The ratio of NT-proBNP to BNP in heart failure and reduced ejection fraction appears to be greater than generally appreciated, differs between patients with and without atrial fibrillation, and increases substantially with increasing age and decreasing renal function. These findings are important for comparison of natriuretic peptide concentrations in heart failure and reduced ejection fraction

FLYSNPdb: a high-density SNP database of Drosophila melanogaster

FLYSNPdb provides high-resolution single nucleotide polymorphism (SNP) data of Drosophila melanogaster. The database currently contains 27 367 polymorphisms, including >3700 indels (insertions/deletions), covering all major chromsomes. These SNPs are clustered into 2238 markers, which are evenly distributed with an average density of one marker every 50.3 kb or 6.6 genes. SNPs were identified automatically, filtered for high quality and partly manually curated. The database provides detailed information on the SNP data including molecular and cytological locations (genome Releases 3–5), alleles of up to five commonly used laboratory stocks, flanking sequences, SNP marker amplification primers, quality scores and genotyping assays. Data specific for a certain region, particular stocks or a certain genome assembly version are easily retrievable through the interface of a publicly accessible website (http://flysnp.imp.ac.at/flysnpdb.php)

Polyglutamine Genes Interact to Modulate the Severity and Progression of Neurodegeneration in Drosophila

The expansion of polyglutamine tracts in a variety of proteins causes devastating, dominantly inherited neurodegenerative diseases, including six forms of spinal cerebellar ataxia (SCA). Although a polyglutamine expansion encoded in a single allele of each of the responsible genes is sufficient for the onset of each disease, clinical observations suggest that interactions between these genes may affect disease progression. In a screen for modifiers of neurodegeneration due to SCA3 in Drosophila, we isolated atx2, the fly ortholog of the human gene that causes a related ataxia, SCA2. We show that the normal activity of Ataxin-2 (Atx2) is critical for SCA3 degeneration and that Atx2 activity hastens the onset of nuclear inclusions associated with SCA3. These activities depend on a conserved protein interaction domain of Atx2, the PAM2 motif, which mediates binding of cytoplasmic poly(A)-binding protein (PABP). We show here that PABP also influences SCA3-associated neurodegeneration. These studies indicate that the toxicity of one polyglutamine disease protein can be dramatically modulated by the normal activity of another. We propose that functional links between these genes are critical to disease severity and progression, such that therapeutics for one disease may be applicable to others

Fz2 and Cdc42 Mediate Melanization and Actin Polymerization but Are Dispensable for Plasmodium Killing in the Mosquito Midgut

The midgut epithelium of the mosquito malaria vector Anopheles is a hostile environment for Plasmodium, with most parasites succumbing to host defenses. This study addresses morphological and ultrastructural features associated with Plasmodium berghei ookinete invasion in Anopheles gambiae midguts to define the sites and possible mechanisms of parasite killing. We show by transmission electron microscopy and immunofluorescence that the majority of ookinetes are killed in the extracellular space. Dead or dying ookinetes are surrounded by a polymerized actin zone formed within the basal cytoplasm of adjacent host epithelial cells. In refractory strain mosquitoes, we found that formation of this zone is strongly linked to prophenoloxidase activation leading to melanization. Furthermore, we identify two factors controlling both phenomena: the transmembrane receptor frizzled-2 and the guanosine triphosphate–binding protein cell division cycle 42. However, the disruption of actin polymerization and melanization by double-stranded RNA inhibition did not affect ookinete survival. Our results separate the mechanisms of parasite killing from subsequent reactions manifested by actin polymerization and prophenoloxidase activation in the A. gambiae–P. berghei model. These latter processes are reminiscent of wound healing in other organisms, and we propose that they represent a form of wound-healing response directed towards a moribund ookinete, which is perceived as damaged tissue