Divergent genetic control of protein solubility and conformational quality in Escherichia coli.

In bacteria, protein overproduction results in the formation of inclusion bodies, sized protein aggregates showing amyloid-like properties such as seeding-driven formation, amyloid-tropic dye binding, intermolecular beta-sheet architecture and cytotoxicity on mammalian cells. During protein deposition, exposed hydrophobic patches force intermolecular clustering and aggregation but these aggregation determinants coexist with properly folded stretches, exhibiting native-like secondary structure. Several reports indicate that inclusion bodies formed by different enzymes or fluorescent proteins show detectable biological activity. By using an engineered green fluorescent protein as reporter we have examined how the cell quality control distributes such active but misfolded protein species between the soluble and insoluble cell fractions and how aggregation determinants act in cells deficient in quality control functions. Most of the tested genetic deficiencies in different cytosolic chaperones and proteases (affecting DnaK, GroEL, GroES, ClpB, ClpP and Lon at different extents) resulted in much less soluble but unexpectedly more fluorescent polypeptides. The enrichment of aggregates with fluorescent species results from a dramatic inhibition of ClpP and Lon-mediated, DnaK-surveyed green fluorescent protein degradation, and it does not perturb the amyloid-like architecture of inclusion bodies. Therefore, the Escherichia coli quality control system promotes protein solubility instead of conformational quality through an overcommitted proteolysis of aggregation-prone polypeptides, irrespective of their global conformational status and biological properties

Treatment and long-term clinical outcomes of incidental pulmonary embolism in patients with cancer: An international prospective cohort study

PURPOSE Pulmonary embolism is incidentally diagnosed in up to 5% of patients with cancer on routine imaging scans. The clinical relevance and optimal therapy for incidental pulmonary embolism, particularly distal clots, is unclear. The aim of the current study was to assess current treatment strategies and the long-term clinical outcomes of incidentally detected pulmonary embolism in patients with cancer. PATIENTS AND METHODS We conducted an international, prospective, observational cohort study between October 22, 2012, and December 31, 2017. Unselected adults with active cancer and a recent diagnosis of incidental pulmonary embolism were eligible. Outcomes were recurrent venous thromboembolism, major bleeding, and all-cause mortality during 12 months of follow-up. Outcome events were centrally adjudicated. RESULTS A total of 695 patients were included. Mean age was 66 years and 58% of patients were male. Most frequent cancer types were colorectal (21%) and lung cancer (15%). Anticoagulant therapy was initiated in 675 patients (97%), of whom 600 (89%) were treated with low-molecular-weight heparin. Recurrent venous thromboembolism occurred in 41 patients (12-month cumulative incidence, 6.0%; 95% CI, 4.4% to 8.1%), major bleeding in 39 patients (12-month cumulative incidence, 5.7%; 95% CI, 4.1% to 7.7%), and 283 patients died (12-month cumulative incidence, 43%; 95% CI, 39% to 46%). The 12-month incidence of recurrent venous thromboembolism was 6.4% in those with subsegmental pulmonary embolism compared with 6.0% in those with more proximal pulmonary embolism (subdistribution hazard ratio, 1.1; 95% CI, 0.37 to 2.9; P = .93). CONCLUSION In patients with cancer with incidental pulmonary embolism, risk of recurrent venous thromboembolism is significant despite anticoagulant treatment. Patients with subsegmental pulmonary embolism seemed to have a risk of recurrent venous thromboembolism comparable to that of patients with more proximal clots

An international SUrvey on non-iNvaSive tecHniques to assess the mIcrocirculation in patients with RayNaud'\u80\u99s phEnomenon (SUNSHINE survey)

To canvas opinion concerning the role of non-invasive techniques in the assessment of patients with Raynaud's phenomenon (Rp) in clinical and research settings: four nailfold capillaroscopy methods [videocapillaroscopy (NVC), dermoscopy, stereomicroscopy, digital USB microscopy], four laser Doppler methods (laser Doppler flowmetry, imaging, anemometry/velocimetry, laser speckle contrast analysis), thermographic imaging, and upper limb arterial Doppler ultrasound. Emails with a link to the survey were sent to physicians from the European Scleroderma Trials and Research group (EUSTAR), the EULAR Study Group on Microcirculation in Rheumatic Diseases (SG_MC/RD) and members of the pediatric rheumatology Email board. The main descriptive analysis related to physicians looking after adult patients, with some analysis also of opinions from paediatric rheumatologists. 106 'adult physicians' responded (a response rate of 25.8%), of whom 68.9% were European, and 81.1% practising for more than 10 years. Nineteen paediatricians responded. The most widely available technique was NVC (72.7%). Nailfold capillaroscopy was most frequently performed by the physician him/herself, using different types of equipment relating to availability. Most rheumatologists reported high levels of appropriateness for NVC in both clinical and research settings for global assessment and differential diagnosis of Rp. Other techniques were less used. Of all the different techniques, nailfold capillaroscopy was the one most used in both clinical and research settings by adult physicians, the majority of whom use NVC in their everyday practice. The low proportion of clinicians using other techniques suggests that these are currently mainly research tools, available only in specialist centres

Evolutionary success of prokaryotes

How can the evolutionary success of prokaryotes be explained ? How did they manage to survive conditions that have fluctuated, with drastic events over 3.5 billion years ? Which significant metabolisms and mechanisms have appeared over the course of evolution that have permitted them to survive the most inhospitable conditions from the physicochemical point of view ? In a 'Red Queen Race', prokaryotes have always run sufficiently fast to adapt to constraints imposed by the environment and the other living species with which they have established interactions. If the criterion retained to define the level of evolution of an organism is its capacity to survive and to yield the largest number of offsprings, prokaryotes must be considered highly evolved organisms