Models of Protocells Undergoing Asymmetrical Division.

The conditions that allow for the sustained growth of a protocell population are investigated in the case of asymmetrical division. The results are compared to those of previous studies concerning models of symmetrical division, where synchronization (between duplication of the genetic material and fission of the lipid container) was found under a variety of different assumptions about the kinetic equations and about the place where molecular replication takes place. Such synchronization allows a sustained proliferation of the protocell population. In the asymmetrical case, there can be no true synchronization, since the time to duplication may depend upon the initial size, but we introduce a notion of homogeneous growth that actually allows for the sustained reproduction of a population of protocells. We first analyze Surface Reaction Models, defined in the text, and we show that in many cases they undergo homogeneous growth under the same kinetic laws that lead to synchronization in the symmetrical case. This is the case also for Internal Reaction Models (IRMs), which, however, require a deeper understanding of what homogeneous growth actually means, as discussed below.

Super-Exponential Growth in Models of a Binary String World.

The Theory of the Adjacent Possible (TAP) equation has been proposed as an appropriate description of super-exponential growth phenomena, where a phase of slow growth is followed by a rapid increase, leading to a "hockey stick" curve. This equation, initially conceived to describe the growth in time of the number of new types of artifacts, has also been applied to several natural phenomena. A possible drawback is that it may overestimate the number of new artifact types, since it does not take into account the fact that interactions, among existing types, may produce types which have already been previously discovered. We introduce here a Binary String World (BSW) where new string types can be generated by interactions among (at most two) already existing types. We introduce a continuous limit of the TAP equation for the BSW; we solve it analytically and show that it leads to divergence in finite time. We also introduce a criterion to distinguish this type of behavior from the familiar exponential growth, which diverges only as t → ∝. In the BSW, it is possible to directly model the generation of new types, and to check whether the newborns are actually novel types, thus discarding the rediscoveries of already existing types. We show that the type of growth is still TAP-like, rather than exponential, although of course in simulations one never can observes true divergence. We also show that this property is robust with respect to some changes in the model, as long as it deals with types (and not with individuals).

Association of obstructive sleep apnea with non-alcoholic fatty liver disease in patients with obesity: an observational study.

PURPOSE: Obstructive Sleep Apnea (OSA) is associated with the presence and severity of Non-Alcoholic Fatty Liver Disease (NAFLD). We aimed to investigate the relationship between the severity of OSA and NAFLD and to recognize a polysomnographic parameter correlated with progression of fibrosis, determined by a non-invasive score of liver fibrosis, FIBrosis-4 index (FIB-4), in patients affected by severe obesity and OSA. METHODS: We enrolled 334 patients (Body Mass Index, BMI 44.78 ± 8.99 kg/m2), divided into classes according to severity of OSA evaluated with Apnea Hypopnea Index (AHI): OSAS 0 or absent (17%), mild OSA (26%), moderate OSA (20%), severe OSAS (37%). We studied anthropometric, polysomnographic, biochemical data and FIB-4. A multiple regression model was computed to identify a polysomnographic independent predictor of FIB-4 among those parameters previously simple correlated with FIB-4. RESULTS: The severity of OSA was associated with a decrease in High-Density Lipoprotein-cholesterol (HDL) and an increase in BMI, triglycerides, Homeostasis model assessment insulin-resistance index (HOMA), transaminases and FIB-4. FIB-4 correlated with sex, age, BMI, AHI, mean percentage oxyhaemoglobin (meanSaO2%), number of desaturations, platelets, transaminases, HDL, triglycerides and HOMA. The only variables independently related to FIB-4 were sex, BMI, triglycerides and meanSpO2 (r = 0.47, AdjRsqr = 0.197). CONCLUSION: MeanSpO2% represented an independent determinant for the worsening of FIB-4 in patients with severe obesity and OSA. Hence, it could hypothesize a clinical role of meanSaO2% in recognizing patients with obesity and OSA and higher risk of developing advanced fibrosis and, thus, to undergo further investigation. LEVEL III: Evidence obtained from well-designed cohort analytic studies.

Attractor-Specific and Common Expression Values in Random Boolean Network Models (with a Preliminary Look at Single-Cell Data).

Random Boolean Networks (RBNs for short) are strongly simplified models of gene regulatory networks (GRNs), which have also been widely studied as abstract models of complex systems and have been used to simulate different phenomena. We define the "common sea" (CS) as the set of nodes that take the same value in all the attractors of a given network realization, and the "specific part" (SP) as the set of all the other nodes, and we study their properties in different ensembles, generated with different parameter values. Both the CS and of the SP can be composed of one or more weakly connected components, which are emergent intermediate-level structures. We show that the study of these sets provides very important information about the behavior of the model. The distribution of distances between attractors is also examined. Moreover, we show how the notion of a "common sea" of genes can be used to analyze data from single-cell experiments.

Easy Access to Energy Fluctuations in Nonequilibrium Quantum Many-Body Systems.

We combine theoretical and experimental efforts to propose a method for studying energy fluctuations, in particular, to obtain the related bistochastic matrix of transition probabilities by means of simple measurements at the end of a protocol that drives a many-body quantum system out of equilibrium. This scheme is integrated with numerical optimizations in order to ensure a proper analysis of the experimental data, leading to physical probabilities. The method is experimentally evaluated employing a two interacting spin-1/2 system in a nuclear magnetic resonance setup. We show how to recover the transition probabilities using only local measures, which enables an experimental verification of the detailed fluctuation theorem in a many-body system driven out of equilibrium.

Experimental Validation of Fully Quantum Fluctuation Theorems Using Dynamic Bayesian Networks.

Fluctuation theorems are fundamental extensions of the second law of thermodynamics for small systems. Their general validity arbitrarily far from equilibrium makes them invaluable in nonequilibrium physics. So far, experimental studies of quantum fluctuation relations do not account for quantum correlations and quantum coherence, two essential quantum properties. We here apply a novel dynamic Bayesian network approach to experimentally test detailed and integral fully quantum fluctuation theorems for heat exchange between two quantum-correlated thermal spins-1/2 in a nuclear magnetic resonance setup. We concretely verify individual integral fluctuation relations for quantum correlations and quantum coherence, as well as for the sum of all quantum contributions. We further investigate the thermodynamic cost of creating correlations and coherence.

Asymptotic Information-Theoretic Detection of Dynamical Organization in Complex Systems.

The identification of emergent structures in complex dynamical systems is a formidable challenge. We propose a computationally efficient methodology to address such a challenge, based on modeling the state of the system as a set of random variables. Specifically, we present a sieving algorithm to navigate the huge space of all subsets of variables and compare them in terms of a simple index that can be computed without resorting to simulations. We obtain such a simple index by studying the asymptotic distribution of an information-theoretic measure of coordination among variables, when there is no coordination at all, which allows us to fairly compare subsets of variables having different cardinalities. We show that increasing the number of observations allows the identification of larger and larger subsets. As an example of relevant application, we make use of a paradigmatic case regarding the identification of groups in autocatalytic sets of reactions, a chemical situation related to the origin of life problem.

Abnormal liver function tests predict transfer to intensive care unit and death in COVID-19.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a relevant threat for humans worldwide. Abnormality in liver function tests (LFTs) has been commonly observed in patients with COVID-19, but there is controversy on its clinical significance. The aim of this study was to assess the prevalence, the characteristics and the clinical impact of abnormal LFTs in hospitalized, non-critically ill patients with COVID-19. METHODS: In this multicentre, retrospective study, we collected data about 565 inpatients with COVID-19. Data on LFTs were collected at admission and every 7 ± 2 days during the hospitalization. The primary outcome was a composite endpoint of death or transfer to intensive care unit (ICU). RESULTS: Upon admission 329 patients (58%) had LFTs abnormality. Patients with abnormal LFTs had more severe inflammation and higher degree of organ dysfunction than those without. During hospitalization, patients with abnormal LFTs had a higher rate of transfer to ICU (20% vs 8%; P < .001), acute kidney injury (22% vs 13%, P = .009), need for mechanical ventilation (14% vs 6%; P = .005) and mortality (21% vs 11%; P = .004) than those without. In multivariate analysis, patients with abnormal LFTs had a higher risk of the composite endpoint of death or transfer to ICU (OR = 3.53; P < .001). During the hospitalization, 86 patients developed de novo LFTs abnormality, which was associated with the use of tocilizumab, lopinavir/ritonavir and acetaminophen and not clearly associated with the composite endpoint. CONCLUSIONS: LFTs abnormality is common at admission in patients with COVID-19, is associated with systemic inflammation, organ dysfunction and is an independent predictor of transfer to ICU or death.

Diffuse large B-cell lymphoma genotyping on the liquid biopsy.

Accessible and real-time genotyping for diagnostic, prognostic, or treatment purposes is increasingly impelling in diffuse large B-cell lymphoma (DLBCL). Cell-free DNA (cfDNA) is shed into the blood by tumor cells undergoing apoptosis and can be used as source of tumor DNA for the identification of DLBCL mutations, clonal evolution, and genetic mechanisms of resistance. In this study, we aimed at tracking the basal DLBCL genetic profile and its modification upon treatment using plasma cfDNA. Ultra-deep targeted next generation sequencing of pretreatment plasma cfDNA from DLBCL patients correctly discovered DLBCL-associated mutations that were represented in >20% of the alleles of the tumor biopsy with >90% sensitivity and ∼100% specificity. Plasma cfDNA genotyping also allowed for the recovery of mutations that were undetectable in the tissue biopsy, conceivably because, due to spatial tumor heterogeneity, they were restricted to clones that were anatomically distant from the biopsy site. Longitudinal analysis of plasma samples collected under rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) chemotherapy showed a rapid clearance of DLBCL mutations from cfDNA among responding patients. Conversely, among patients who were resistant to R-CHOP, basal DLBCL mutations did not disappear from cfDNA. In addition, among treatment-resistant patients, new mutations were acquired in cfDNA that marked resistant clones selected during the clonal evolution. These results demonstrate that cfDNA genotyping of DLBCL is as accurate as genotyping of the diagnostic biopsy to detect clonally represented somatic tumor mutations and is a real-time and noninvasive approach to tracking clonal evolution and the emergence of treatment-resistant clones.

Experimental Characterization of a Spin Quantum Heat Engine.

Developments in the thermodynamics of small quantum systems envisage nonclassical thermal machines. In this scenario, energy fluctuations play a relevant role in the description of irreversibility. We experimentally implement a quantum heat engine based on a spin-1/2 system and nuclear magnetic resonance techniques. Irreversibility at a microscope scale is fully characterized by the assessment of energy fluctuations associated with the work and heat flows. We also investigate the efficiency lag related to the entropy production at finite time. The implemented heat engine operates in a regime where both thermal and quantum fluctuations (associated with transitions among the instantaneous energy eigenstates) are relevant to its description. Performing a quantum Otto cycle at maximum power, the proof-of-concept quantum heat engine is able to reach an efficiency for work extraction (η≈42%) very close to its thermodynamic limit (η=44%).

The role of thermal balneotherapy in the treatment of obese patient with knee osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis clinically characterized by joint pain, functional limitation, and reduced quality of life. Several studies have shown a clear link between obesity and higher risk of knee OA. According to the multifactorial OA pathogenesis, the management of this condition requires a multidisciplinary approach. The objective of this study is to evaluate hydrokinesitherapy effects in thermal setting in obese patients with knee OA. Fifty-three patients were assessed for eligibility, of which 33 refused the treatment, while 10 patients dropped out after the enrollment for personal reasons or inability to adhere to the program. Ten patients (8 females, 2 males, mean age of 59.4 years) with obesity (range BMI 30-45 kg/m2) and knee OA (II-III grade of Kellgren-Lawrence scale) treated with hydrokinetic therapy in thermal water (two sessions per week for 8 consecutive weeks) completed the study. Primary outcome measure was pain (VAS). Secondary outcomes were clinical knee evaluation (range of motion-ROM, lower-limb muscle strength), WOMAC, and Lequesne Algofunctional Index. Patellar tendon and peri-articular soft tissue ultrasound evaluation and gait analysis at baseline (T0), at the end of treatment (T1), and at 6 months of follow-up (T2) were performed. Significant decrease on VAS pain during walking on a flat surface and going up/down stairs was reached from baseline at T1 (p = 0.0039; p = 0.0098) and was maintained at T2 (p = 0.00954) exclusively for VAS pain during walking on a flat surface. WOMAC score showed a significant reduction between T0 and T1 (p = 0.0137) and between T0 and T2 (p = 0.006438), as ROM evaluations. Kinematic path assessment did not show significant results in individual gait steps, except for the space-time variables of the average speed and the values of ground reaction force (GRF) obtained with force platforms. Hydrokinesitherapy in thermal environment in obese patients with knee OA may determine pain relief, joint function improvement, and walking speed increase until 6 months of follow-up.

Experimental Rectification of Entropy Production by Maxwell's Demon in a Quantum System.

Maxwell's demon explores the role of information in physical processes. Employing information about microscopic degrees of freedom, this "intelligent observer" is capable of compensating entropy production (or extracting work), apparently challenging the second law of thermodynamics. In a modern standpoint, it is regarded as a feedback control mechanism and the limits of thermodynamics are recast incorporating information-to-energy conversion. We derive a trade-off relation between information-theoretic quantities empowering the design of an efficient Maxwell's demon in a quantum system. The demon is experimentally implemented as a spin-1/2 quantum memory that acquires information, and employs it to control the dynamics of another spin-1/2 system, through a natural interaction. Noise and imperfections in this protocol are investigated by the assessment of its effectiveness. This realization provides experimental evidence that the irreversibility in a nonequilibrium dynamics can be mitigated by assessing microscopic information and applying a feed-forward strategy at the quantum scale.

Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia.

The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a training-validation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring +12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions.

Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia.

Genetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). However, scant data are available on preferential associations between specific genetic alterations and stereotyped BCR subsets. By analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched in specific molecular alterations influencing disease course. SF3B1 mutations are the genetic hallmark of IGHV3-21-CLL belonging to subset 2 (52%) but are evenly represented in nonstereotyped IGHV3-21-CLL. Trisomy 12 (87%) and NOTCH1 mutations (62%) characterize IGHV4-39-CLL belonging to subset 8 but occur with the expected frequency in IGHV4-39-CLL with heterogeneous BCR. Clinically, co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, +12, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome.

Molecular characterization of toxigenic Clostridium difficile in a northern Italian hospital.

Clostridium difficile is responsible for more than 90 % of cases of antibiotic-associated diarrhea and pseudomembranous colitis. The most important virulence factors are two toxins called enterotoxin A and cytotoxin B; some C. difficile strains contain the C. difficile binary toxin (CDT). The aim of our study was to prospectively analyze C. difficile clinical isolates in a single center to determine the molecular features of collected strains. Among the 252 isolates, 217 were A + B + (86.1 %), 33 were A + B + cdt + (13.1 %) and 2 were A - B + (0.8 %). There were 15 different ribotypes with a predominance of 018.

Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism.

Endurance exercise training increases cardiac energy metabolism through poorly understood mechanisms. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) in cardiomyocytes contributes to cardiac adaptation. Here we demonstrate that the NO donor diethylenetriamine-NO (DETA-NO) activated mitochondrial biogenesis and function, as assessed by upregulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (Tfam) expression, and by increased mitochondrial DNA content and citrate synthase activity in primary mouse cardiomyocytes. DETA-NO also induced mitochondrial biogenesis and function and enhanced both basal and insulin-stimulated glucose uptake in HL-1 cardiomyocytes. The DETA-NO-mediated effects were suppressed by either PGC-1α or Tfam small-interference RNA in HL-1 cardiomyocytes. Wild-type and eNOS(-/-) mice were subjected to 6 wk graduated swim training. We found that eNOS expression, mitochondrial biogenesis, mitochondrial volume density and number, and both basal and insulin-stimulated glucose uptake were increased in left ventricles of swim-trained wild-type mice. On the contrary, the genetic deletion of eNOS prevented all these adaptive phenomena. Our findings demonstrate that exercise training promotes eNOS-dependent mitochondrial biogenesis in heart, which behaves as an essential step in cardiac glucose transport.

Experimental reconstruction of work distribution and study of fluctuation relations in a closed quantum system.

We report the experimental reconstruction of the nonequilibrium work probability distribution in a closed quantum system, and the study of the corresponding quantum fluctuation relations. The experiment uses a liquid-state nuclear magnetic resonance platform that offers full control on the preparation and dynamics of the system. Our endeavors enable the characterization of the out-of-equilibrium dynamics of a quantum spin from a finite-time thermodynamics viewpoint.

Surveillance of healthcare-associated infections in Piemonte, Italy: results from a second regional prevalence study.

BACKGROUND: A prevalence survey of healthcare-associated infections (HAIs) was previously performed in the Piemonte region in 2000. In the decade following the survey, many studies were performed at both the regional and hospital levels, and training courses were developed to address issues highlighted by the survey. In 2010, a second regional prevalence study was performed. The aim of this paper is to present the results of the second prevalence study and discuss them within the context of the HAI prevention and control programmes that have been implemented in the decade since the original survey was conducted. METHODS: The study involved all public hospitals in the Piemonte region. Uni- and multivariate analyses were performed to assess the main risk factors associated with HAIs, including both overall and site-specific infections. RESULTS: A total of 7841 patients were enrolled: 6.8% were affected by at least one HAI. The highest prevalence of HAIs was found in intensive care units (18.0%, 95% CI 14.0-22.6), while UTIs presented the highest relative frequency (26.7%), followed by respiratory tract infections (21.9%). The age of the patient, hospital size and urinary and central venous catheter status were significantly associated with HAIs. CONCLUSIONS: The study results showed an increase in HAI prevalence, despite prevention and control efforts, as well as training implemented after the first regional survey. Nevertheless, these data are consistent with the current literature. Furthermore, despite its limits, the prevalence approach remains an important means for involving healthcare workers, emphasising HAIs and revealing critical problems that need be addressed.

Mortality in patients with early- or late-onset candidaemia.

OBJECTIVES: Although candidaemia is a well-known complication of hospital stay and has a crude mortality of ∼40%, few data are available for episodes diagnosed within 10 days after hospital admission. In this paper, we compared the risk factors for mortality according to the onset of candidaemia. METHODS: This was a retrospective study of hospitalized patients with early-onset candidaemia (EOC; ≤ 10 days) or late-onset candidaemia (LOC; >10 days) to identify any distinct clinical characteristics and risk factors for 30 day mortality in two Italian academic centres. RESULTS: A total of 779 patients were included in the study: 183 EOC and 596 LOC. Mortality was significantly lower in EOC (71/183, 38.8% versus 283/596, 47.5%, P=0.03). In EOC, multivariate analysis showed that inadequate initial antifungal therapy (IIAT) (P=0.005, OR 3.02, 95% CI 1.40-6.51), Candida albicans aetiology (P=0.02, OR 2.17, 95% CI 1.11-4.26) and older age (P<0.001, OR 1.05, 95% CI 1.02-1.07) were independent risk factors for mortality. In LOC, liver disease (P=0.003, OR 2.46, 95% CI 1.36-4.43), IIAT (P=0.002, OR 2.01, 95% CI 1.28-3.15) and older age (P<0.001, OR 1.03, 95% CI 1.02-1.04) were independently associated with a fatal outcome, while treatment with caspofungin was associated with survival (P<0.001, OR 0.42, 95% CI 0.26-0.67). CONCLUSIONS: EOC has different clinical characteristics and risk factors for mortality compared with LOC. Although EOC mortality is significantly lower, the rate of inappropriate antifungal treatment is higher. Treatment with caspofungin is significantly associated with survival in patients with LOC. Efforts are needed to improve the diagnosis and treatment of EOC.

Nontoxigenic Vibrio parahaemolyticus strains causing acute gastroenteritis.

We investigated the virulence properties of four Vibrio parahaemolyticus strains causing acute gastroenteritis following consumption of indigenous mussels in Italy. The isolated strains were cytotoxic and adhesive but, surprisingly, lacked tdh, trh, and type three secretion system 2 (T3SS2) genes. We emphasize that nontoxigenic V. parahaemolyticus can induce acute gastroenteritis, highlighting the need for more investigation of the pathogenicity of this microorganism.