Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions

Calmodulin, the ubiquitous calcium-activated second messenger in eukaryotes, is an extremely versatile molecule involved in many biological processes: muscular contraction, synaptic plasticity, circadian rhythm, and cell cycle, among others. The protein is structurally organised into two globular lobes, joined by a flexible linker. Calcium modulates calmodulin activity by favoring a conformational transition of each lobe from a closed conformation to an open conformation. Most targets have a strong preference for one conformation over the other, and depending on the free calcium concentration in a cell, particular sets of targets will preferentially interact with calmodulin. In turn, targets can increase or decrease the calcium affinity of the calmodulin molecules to which they bind. Interestingly, experiments with the tryptic fragments showed that most targets have a much lower affinity for the N-lobe than for the C-lobe. Hence, the latter predominates in the formation of most calmodulin-target complexes. We showed that a relatively simple allosteric mechanism, based the classic MWC model, can capture the observed modulation of both the isolated C-lobe, and intact calmodulin, by individual targets. Moreover, our model can be naturally extended to study how the calcium affinity of a single pool of calmodulin is modulated by a mixture of competing targets in vivo

Mitigating aerosol infection risk in school buildings: the role of natural ventilation, volume, occupancy and CO2 monitoring

Issues linked to aerosol physics within school buildings and related infection risk still lack a proper recognition in school safety regulations. Limited spaces and limited available window-surfaces require to precisely investigate the seasonal airing factors and the occupancy/volume ratios in each classroom in order to assess the specific risk levels from viral loads of potentially infective sources. Moreover, most schools are still not provided with mechanical HVAC systems nor with air quality sensors. Fundamental questions are therefore: how the specific classroom volume and the specific airing cycle affects the long-range contagion risk in a given classroom? is linear social distancing the right way to assess a volumetric risk problem? We present here the results of an extended quantitative analysis based on the GN-Riley infection risk model applied to a real classroom scenario. The study discusses seasonality of the airing flow and the effectiveness of single and combined mitigation interventions, such as limiting student groups, equipping teachers with microphones, increasing classroom volumes, and equipping classrooms with CO2 sensors to safely drive airing intervals. Moreover, we show experimental CO2 concentrations as well as occupancy and airing factors monitored in real time in a real classroom scenario. In agreement with recent literature, the results emphasize the need for a dynamic evaluation of the complex risk function over the whole exposure time (and not just the monitoring of the istanteneous CO2 concentration) in order to correctly control the infection risk from aerosolization

Role of perfusion machines in the setting of clinical liver transplantation. A qualitative systematic review

Growing enthusiasm around machine perfusion (MP) in clinical liver transplantation (LT) may be the preamble for standardized practice to expand the donors' pool. The present systematic review investigated all the liver transplantations performed using grafts treated with MP. A systematic review of 309 papers was performed. Eventually, 27 articles were enrolled for the study. A total number of 173 cases was reported. Only 12 cohort studies were identified: the remaining ones were case reports or case series. Hypothermic machine perfusion was performed in 102 (59.0%), normothermic machine perfusion in 65 (37.6%), and controlled oxygenated rewarming in the remaining 6 (3.4%) cases. Donor characteristics, evaluation of graft quality and end-points were not homogeneous among the studies. Overall, post-LT results were excellent, with 1.2 and 4.0% of patients experienced primary non-function and ischemic-type biliary lesions, respectively

Designing peer-to-peer systems for business-to-business environments

Conference held in Firenze, Italy, 30 November -2 December 2005This paper describes the design of a peer-to-peer system integrated in a larger framework for the automatic content production, formatting, distribution and delivery over multiple platforms called AXMEDIS (E.U. IST-2-511299). One of the goals of the project is the reduction of costs and, among the others, the adoption of a collaborative environment based on a virtual database as an abstraction of a multitude of objects shared in a large network of content producers/distributors/aggregators. The peculiar properties of this system are the automation of P2P related operations, the professional query user interface based on Dublin Core and available rights of target objects, and the preemptive exclusion of uncertified participants.219-22

Metabolic syndrome and cardiovascular risk after liver transplantation: a single-center experience.

Excessive weight gain, hypertension, hyperlipidemia, and diabetes are frequently observed among orthotopic liver transplantation (OLT) patients. These alterations, which are probably multifactorial in origin, contribute to posttransplantation metabolic syndrome (PTMS), which increases the risk of cardiovascular events. We assessed the prevalence of PTMS (diagnosed according to modified NCEP Adult Treatment Panel III criteria) in 156 OLT patients undergoing regular follow-up after transplantation (median 68 months; range, 6 to 234 months). Several pre- and post-OLT data were collected to identify the factors associated with the presence of PTMS which was found in 28% of cases. The only independent predictive factors for PTMS were diabetes mellitus and patients who were overweight or obese before-OLT. The prevalence of PTSM was lower among patients on tacrolimus immunosuppression. In our population, 21% of patients showed a high cardiovascular risk score with a 4% incidence of cardiovascular events, which was higher among subjects with PTMS. Close follow-up is mandatory to prevent the development of PTMS mainly among overweight and diabetic patients before transplantation

Donor-to-recipient gender match in liver transplantation. A systematic review and meta-analysis

AIM To perform a systematic review and meta-analysis on donor-to-recipient gender mismatch as a risk factor for post-transplant graft loss. METHODS A systematic literature search was performed using PubMed, Cochrane Library database and EMBASE. The primary outcome was graft loss after liver transplantation. Odds ratios and 95% confidence intervals were calculated to compare the pooled data between groups with different donor-to-recipient gender matches. Three analyses were done considering (1) gender mismatches (F-M and M-F) vs matches (M-M and F-F); (2) Female-to-Male mismatch vs other matches; and (3) Male-to-Female mismatch vs other matches. RESULTS A total of 7 articles were analysed. Gender mismatch (M-F and F-M) was associated with a significant increase of graft loss respect to match (M-M and F-F) (OR: 1.30; 95%CI: 1.13-1.50; P < 0.001). When F-M mismatch was specifically investigated, it confirmed its detrimental role in terms of graft survival (OR: 1.83; 95%CI: 1.20-2.80; P = 0.005). M-F mismatch failed to present a significant role (OR: 1.09; 95%CI: 0.73-1.62; P = 0.68). CONCLUSION Gender mismatch is a risk factor for poor graft survival after liver transplantation. Female-to-male mismatch represents the worst combination. More studies are needed with the intent to better clarify the reasons for these results

Platelet-to-lymphocyte ratio in the setting of liver transplantation for hepatocellular cancer. A systematic review and meta-analysis

AIM: To perform a systematic review and meta-analysis on platelet-to-lymphocyte ratio (PLR) as a risk factor for post-transplant hepatocellular cancer (HCC) recurrence. METHODS: A systematic literature search was performed using PubMed. Participants of any age and sex, who underwent liver transplantation for HCC were considered following these criteria: (1) studies comparing pre-transplant low vs high PLR values; (2) studies reporting post-transplant recurrence rates; and (3) if more than one study was reported by the same institute, only the most recent was included. The primary outcome measure was set for HCC recurrence after transplantation. RESULTS: A total of 5 articles, published between 2014 and 2017, fulfilled the selection criteria. As for the quality of the reported studies, all the investigated articles presented an overall high quality. A total of 899 cases were investigated: 718 cases (80.0%) were males. Three studies coming from European countries and one from Japan presented HCV as the main cause of cirrhosis. On the opposite, one Chinese study presented a greater incidence of HBV-related cirrhotic cases. In all the studies apart one, the PLR cut-off value of 150 was reported. At meta-analysis, high PLR value was associated with a significant increase in recurrence after transplantation (OR = 3.33; 95%CI: 1.78-6.25; p &lt; 0.001). A moderate heterogeneity was observed among the identified studies according to the Higgins I 2 statistic value. CONCLUSION: Pre-transplant high PLR values are connected with an increased risk of post-operative recurrence of hepatocellular cancer. More studies are needed for better clarify the biological mechanisms of this results

Neurological, psychological, and cognitive disorders in patients with chronic kidney disease on conservative and replacement therapy

Chronic kidney disease (CKD) is a highly prevalent condition in the world. Neurological, psychological, and cognitive disorders, related to CKD, could contribute to the morbidity, mortality, and poor quality of life of these patients. The aim of this study was to assess the neurological, psychological, and cognitive imbalance in patients with CKD on conservative and replacement therapy. Seventy-four clinically stable patients affected by CKD on conservative therapy, replacement therapy (hemodialysis (HD), peritoneal dialysis (PD)), or with kidney transplantation (KT) and 25 healthy controls (HC), matched for age and sex were enrolled. Clinical, laboratory, and instrumental examinations, as renal function, inflammation and mineral metabolism indexes, electroencephalogram (EEG), psychological (MMPI-2, Sat P), and cognitive tests (neuropsychological tests, NPZ5) were carried out. The results showed a significant differences in the absolute and relative power of delta band and relative power of theta band of EEG (P=0.008, P<0.001, P=0.051), a positive correlation between relative power of delta band and C-reactive protein (CRP) (P< 0.001) and a negative correlation between estimated glomerular filtration rate (eGFR) (P<0.001) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) (P<0.001), in all the samples. Qualitative analysis of EEG showed alterations of Grade 2 (according to Parsons-Smith classification) in patients on conservative therapy, and Grade 2-3 in KT patients. The scales of MMPI-2 hysteria and paranoia, are significantly correlated with creatinine, eGFR, serum nitrogen, CRP, 1,25-(OH)2D3, intact parathyroid hormone (iPTH), phosphorus, and cynical and hysterical personality, are correlated with higher relative power of delta (P=0.016) and theta band (P= 0.016). Moreover, all NPZ5 scores showed a significant difference between the means of nephropathic patients and the means of the HC, and a positive correlation with eGFR, serum nitrogen, CRP, iPTH, and vitamin D. In CKD patients, simple and noninvasive instruments, as EEG, and cognitive-psychological tests, should be performed and careful and constant monitoring of renal risk factors, probably involved in neuropsychological complications (inflammation, disorders of mineral metabolism, electrolyte disorders, etc.), should be carried out. Early identification and adequate therapy of neuropsychological, and cognitive disorders, might enable a better quality of life and a major compliance with a probable reduction in the healthcare costs

Mechanochemical Treatment of Soils Contaminated by Heavy Metals in Attritor and Impact Mills: Experiments and Modeling

An integrative approach was developed to support the scale-up from lab-into pilot-scale mechano-chemical reactors for immobilize heavy metals in contaminated mining soil

Peritoneal dialysis in older adults: evaluation of clinical, nutritional, metabolic outcomes, and quality of life

The number of older adults requiring dialysis is increasing worldwide, whereas the use of peritoneal dialysis (PD) in this population is lower respect to younger patients, despite the theoretical advantages of PD respect to hemodialysis. This is most likely due to the concern that older patients may not be able to correctly and safely manage PD. We aimed to prospectively compare clinical, nutritional and metabolic outcomes and measures of quality of life between younger (&lt;65years old) and older (≥65years old) patients on PD. PD patients were enrolled and divided into 2 groups according to age (Group A &lt; 65 years, Group B ≥ 65 years). Clinical and instrumental parameters, and quality of life were evaluated at baseline (start of PD) (T0) and at 24 months (T1). Technique survival, mortality, total number of hospitalizations, and the index of peritonitis (episodes of peritonitis/month) were also evaluated. Fifty-one patients starting PD were enrolled. Group A included 22 patients (48.7±8.3 years), and Group B consisted of 29 patients (74.1 ± 6.4 years). At baseline, the 2 groups showed no differences in cognitive status, whereas Group A showed higher total cholesterol (p=0.03), LDL (p=0.03), and triglycerides (p=0.03) levels and lower body mass index (p=0.02) and carotid intima media thickness (p&lt;0.0001) with respect to Group B. At T1 Group B showed, compared to baseline, a significant reduction in albumin (p&lt;0.0001) and phosphorus (p=0.045) levels, while no significant differences on body composition, technique survival, total number of hospitalizations, index of peritonitis and quality of life indices were observed. Our data do not show clinically relevant barriers to use PD in older adult patients, supporting its use in this population. Nutritional and metabolic parameters should be carefully monitored in older PD patients