Effect of dispersion interactions on the properties of LiF in condensed phases

Classical molecular dynamics simulations are performed on LiF in the framework of the polarizable ion model. The overlap-repulsion and polarization terms of the interaction potential are derived on a purely non empirical, first-principles basis. For the dispersion, three cases are considered: a first one in which the dispersion parameters are set to zero and two others in which they are included, with different parameterizations. Various thermodynamic, structural and dynamic properties are calculated for the solid and liquid phases. The melting temperature is also obtained by direct coexistence simulations of the liquid and solid phases. Dispersion interactions appear to have an important effect on the density of both phases and on the melting point, although the liquid properties are not affected when simulations are performed in the NVT ensemble at the experimental density.Comment: 8 pages, 5 figure

Microscopic mechanism of protein cryopreservation in an aqueous solution with trehalose

In order to investigate the cryoprotective mechanism of trehalose on proteins, we use molecular dynamics computer simulations to study the microscopic dynamics of water upon cooling in an aqueous solution of lysozyme and trehalose. We find that the presence of trehalose causes global retardation of the dynamics of water. Comparing aqueous solutions of lysozyme with/without trehalose, we observe that the dynamics of water in the hydration layers close to the protein is dramatically slower when trehalose is present in the system. We also analyze the structure of water and trehalose around the lysozyme and find that the trehalose molecules form a cage surrounding the protein that contains very slow water molecules. We conclude that the transient cage of trehalose molecules that entraps and slows the water molecules prevents the crystallisation of protein hydration water upon cooling.DC, EGS, and HES thank the NSF chemistry Division for support (Grants CHE-1213217, CHE-0911389, and CHE-0908218). PG gratefully acknowledges the computational support reveived by the INFN RM3-GRID at Roma Tre University. (CHE-1213217 - NSF chemistry Division; CHE-0911389 - NSF chemistry Division; CHE-0908218 - NSF chemistry Division)Published versio

Effect of hydrophobic solutes on the liquid-liquid critical point

Jagla ramp particles, interacting through a ramp potential with two characteristic length scales, are known to show in their bulk phase thermodynamic and dynamic anomalies, similar to what is found in water. Jagla particles also exhibit a line of phase transitions separating a low density liquid phase and a high density liquid phase, terminating in a liquid-liquid critical point in a region of the phase diagram that can be studied by simulations. Employing molecular dynamics computer simulations, we study the thermodynamics and the dynamics of solutions of hard spheres (HS) in a solvent formed by Jagla ramp particles. We consider the cases of HS mole fraction x = 0.10, 0.15 and 0.20, and also the case x = 0.50 (a 1:1 mixture of HS and Jagla particles). We find a liquid-liquid critical point, up to the highest HS mole fraction; its position shifts to higher pressures and lower temperatures upon increasing x. We also find that the diffusion coefficient anomalies appear to be preserved for all the mole fractions studied.Comment: 8 pages, 7 figures, 1 table. In press (Phys. Rev. E

The molecular structure of melts along the carbonatite–kimberlite–basalt compositional joint: CO2and polymerisation

International audienceTransitional melts, intermediate in composition between silicate and carbonate melts, form by low degree partial melting of mantle peridotite and might be the most abundant type of melt in the asthenosphere. Their role in the transport of volatile elements and in metasomatic processes at the planetary scale might be significant yet they have remained largely unstudied. Their molecular structure has remained elusive in part because these melts are difficult to quench to glass. Here we use FTIR, Raman, 13C and 29Si NMR spectroscopy together with First Principle Molecular Dynamic (FPMD) simulations to investigate the molecular structure of transitional melts and in particular to assess the effect of CO2on their structure. We found that carbon in these glasses forms free ionic carbonate groups attracting cations away from their usual ‘depolymerising’ role in breaking up the covalent silicate network. Solution of CO2in these melts strongly modifies their structure resulting in a significant polymerisation of the aluminosilicate network with a decrease in NBO/Si of about 0.2 for every 5 mol% CO2dissolved.This polymerisation effect is expected to influence the physical and transport properties of transitional melts. An increase in viscosity is expected with increasing CO2content, potentially leading to melt ponding at certain levels in the mantle such as at the lithosphere–asthenosphere boundary. Conversely an ascending and degassing transitional melt such as a kimberlite would become increasingly fluid during ascent hence potentially accelerate. Carbon-rich transitional melts are effectively composed of two sub-networks:a carbonate and a silicate one leading to peculiar physical and transport properties

Lack of efficacy of convalescent plasma in COVID-19 patients with concomitant hematological malignancies: An Italian retrospective study

A multicenter retrospective study was designed to assess clinical outcome of COVID-19 in patients with hematological malignancies (HM) following treatment with anti-SARS-CoV-2 convalescent plasma (CP) or standard of care therapy. To this aim, a propensity score matching was used to assess the role of non-randomized administration of CP in this high-risk cohort of patients from the Italian Hematology Alliance on COVID-19 (ITA-HEMA-COV) project, now including 2049 untreated control patients. We investigated 30- and 90-day mortality, rate of admission to intensive care unit, proportion of patients requiring mechanical ventilatory support, hospitalization time, and SARS-CoV-2 clearance in 79 CP recipients and compared results with 158 propensity score-matched controls. Results indicated a lack of efficacy of CP in the study group compared with the untreated group, thus confirming the negative results obtained from randomized studies in immunocompetent individuals with COVID-19. In conclusion, this retrospective analysis did not meet the primary and secondary end points in any category of immunocompromized patients affected by HM

Safety and Efficacy of Subcutaneous Rituximab in Previously Untreated Patients with CD20+ Diffuse Large B-Cell Lymphoma or Follicular Lymphoma: Results from an Italian Phase IIIb Study

Subcutaneous (SC) rituximab may be beneficial in terms of convenience and tolerability, with potentially fewer and less severe administration-related reactions (ARRs) compared to the intravenous (IV) form. This report presents the results of a phase IIIb study conducted in Italy. The study included adult patients with CD20+ DLBCL or FL having received at least one full dose of IV RTX 375 mg/m2 during induction or maintenance. Patients on induction received ≥4 cycles of RTX SC 1400 mg plus standard chemotherapy and FL patients on maintenance received ≥6 cycles of RTX SC. Overall, 159 patients (73 DLBCL, 86 FL) were enrolled: 103 (54 DLBCL, 49 FL) completed induction and 42 patients with FL completed 12 maintenance cycles. ARRs were reported in 10 patients (6.3%), 3 (4.2%) with DLBCL and 7 (8.1%) with FL, all of mild severity, and resolved without dose delay/discontinuation. Treatment-emergent adverse events (TEAEs) and serious adverse events occurred in 41 (25.9%) and 14 patients (8.9%), respectively. Two patients with DLBCL had fatal events: Klebsiella infection (related to rituximab) and septic shock (related to chemotherapy). Neutropenia (14 patients, 8.9%) was the most common treatment-related TEAE. Two patients with DLBCL (2.8%) and 6 with FL (7.0%) discontinued rituximab due to TEAEs. 65.2% and 69.7% of patients with DLBCL and 67.9% and 73.6% of patients with FL had complete response (CR) and CR unconfirmed, respectively. The median time to events (EFS, PFS, and OS) was not estimable due to the low rate of events. At a median follow-up of 29.5 and 47.8 months in patients with DLBCL and FL, respectively, EFS, PFS, and OS were 70.8%, 70.8%, and 80.6% in patients with DLBCL and 77.9%, 77.9%, and 95.3% in patients with FL, respectively. The switch from IV to SC rituximab in patients with DLBCL and FL was associated with low risk of ARRs and satisfactory response in both groups. This trial was registered with NCT01987505

Integrated clinicopathologic and molecular analysis of endometrial carcinoma: Prognostic impact of the new ESGO-ESTRO-ESP endometrial cancer risk classification and proposal of histopathologic algorithm for its implementation in clinical practice

IntroductionThe European Society of Gynecologic Oncology/European Society of Radiation Therapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) committee recently proposed a new risk stratification system for endometrial carcinoma (EC) patients that incorporates clinicopathologic and molecular features. The aim of the study is to compare the new ESGO/ESTRO/ESP risk classification system with the previous 2016 recommendations, evaluating the impact of molecular classification and defining a new algorithm for selecting cases for molecular analysis to assign the appropriate risk class.MethodsThe cohort included 211 consecutive EC patients. Immunohistochemistry and next-generation sequencing were used to assign molecular subgroups of EC: POLE mutant (POLE), mismatch repair deficient (MMRd), p53 mutant (p53abn), and no specific molecular profile (NSMP).ResultsImmuno-molecular analysis was successful in all cases, identifying the four molecular subgroups: 7.6% POLE, 32.2% MMRd, 20.9% p53abn, and 39.3% NSMP. The recent 2020 guidelines showed a 32.7% risk group change compared with the previous 2016 classification system: the reassignment is due to POLE mutations, abnormal p53 expression, and a better definition of lymphovascular space invasion. The 2020 system assigns more patients to lower-risk groups (42.2%) than the 2016 recommendation (25.6%). Considering the 2020 risk classification system that includes the difference between “unknown molecular classification” and “known,” the integration of molecular subgroups allowed 6.6% of patients to be recategorized into a different risk class. In addition, the use of the proposed algorithm based on histopathologic parameters would have resulted in a 62.6% reduction in molecular analysis, compared to applying molecular classification to all patients.ConclusionApplication of the new 2020 risk classification integrating clinicopathologic and molecular parameters provided more accurate identification of low-and high-risk patients, potentially allowing a more specific selection of patients for post-operative adjuvant therapy. The proposed histopathologic algorithm significantly decreases the number of tests needed and could be a promising tool for cost reduction without compromising prognostic stratification

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

IntroductionImmunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.MethodsHere we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.ResultsWe show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.DiscussionThese data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20

Computer simulations on supercooled aqueous solutions : the effect of solutes on the liquid-liquid critical point

Water is the most abundant substance on Earth and in the human body. It is the medium in which most biological processes take place. Yet water is an anomalous substance. In fact from a physical point of view, its thermo- dynamic, structural and dynamic properties show peculiar behaviours when compared with those of simple liquids. The anomalies of water are par- ticularly pronounced in the supercooled region, the region in which water can be found in a metastable liquid state, below the freezing point. The experimental investigation of the supercooled region is hampered by the ho- mogeneous nucleation and computer simulations are the prime mean of study of this intriguing region. It has been previously hypothesized by computer simulations that water possesses in the supercooled region a liquid-liquid critical point (LLCP) located at the end of the coexistence line between a high density liquid (HDL) and a low density liquid (LDL) phase of water. These liquid phases would be the counterparts at higher temperature of the experimentally observed two forms of amorphous ice. It is often stated that the ultimate understanding of biology requires rst the comprehension of water. This is even more true for aqueous solutions. In fact aqueous solutions are ubiquitous in nature and their properties at low temperatures can be relevant for many biological phenomena. Furthermore the investigation of aqueous solutions can also help to unravel the mysteries of bulk water. In fact the presence of solutes a ect many thermodynamic properties of water. In particular aqueous solutions of electrolytes are more easily supercooled with respect to bulk water, because of a downward shift in temperature of the homogeneous nucleation in these systems. In this Ph. D. thesis we present the results of three sets of computer simulation studies performed on bulk water and on aqueous solutions, the PR-TIP4P set, the JJ-TIP4P set and the HS-JRP set. The rst two sets of simulations were performed using the standard molecular dynamics (MD) algorithm and they di er by the solute potential employed. The third set was simulated using the discrete molecular dynamics (DMD) algorithm. The PR-TIP4P set includes the simulations performed on bulk TIP4P water and on sodium chloride solutions, NaCl(aq), in TIP4P water with con- centrations c = 0:67; 1:36 and 2:10 mol/kg. In this set the Pettitt-Rossky ionic potential was employed. The analysis of the isotherms and the iso- chores of the systems allowed the determination of important thermody- namic loci such as the temperature of maximum density (TMD) line and the liquid-gas limit of mechanical stability (LG-LMS). These results were also compared with water con ned in a hydrophobic environment of soft spheres as studied in a previous work of our group. The LG-LMS line is not signi cantly altered by the addition of polar solutes, while the TMD line moves to lower temperatures and pressures with respect to bulk water, upon increasing the concentration of salt, with also a progressive narrowing of the amplitude of the curve. In the case of water con ned in the hydrophobic environment, both the LG-LMS line and the TMD line move to higher pres- sures due to excluded volume e ects and the TMD line also moves to lower temperatures, with respect to bulk water. In the NaCl(aq) solutions, indica- tions of the approach of the system to liquid-liquid coexistence are observed, with in ections of the low temperature isotherms and the appearance of min- ima in the behaviour of the potential energy as a function of the density. The structural properties of the c = 1:36 mol/kg NaCl(aq) solution were also studied and compared with those of water con ned in the hydrophobic environment. The hydration structure of ions (hydrophilic solutes) and soft spheres (hydrophobic solutes) are compared at di erent temperatures and densities. The JJ-TIP4P set of simulations consists in the extensive MD simulations performed on bulk TIP4P water and on c = 0:67 mol/kg NaCl(aq) solution aiming to the localization of the LLCP in both systems. For this set of simulations the Jensen-Jorgensen ionic potential was used. The LLCP was found in both systems. In bulk TIP4P water it is located at T = 190 K and P = 150 MPa, in the NaCl(aq) it is located at T = 200 K and P = -50 MPa. Therefore the LLCP is found to shift to higher temperatures and lower pressures in the aqueous solution. The results obtained for TIP4P bulk water are compared with available experimental data and a shift of the simulated phase diagram is proposed to match the experimental results. On the basis of the comparison of the simulated and the experimental TMD point at ambient pressure for NaCl(aq) we hypothesize that the same shift obtained for bulk water can be applied to the solution. With these considerations we propose the liquid-liquid phase diagrams of both bulk water and c = 0:67 mol/kg NaCl(aq) as they should be measurable in experiments. In the shifted phase diagram the LLCP falls at T = 221 K and P = 77 MPa in bulk water, close to the value previously hypothesized by Mishima and Stanley from experimental results on ice. In NaCl(aq) the LLCP falls at T = 231 K and P = -123 MPa, above the homogeneous nucleation line of the solution, making an experimental observation of the LLCP in the NaCl(aq) feasible. In the solution the width of the LDL region is reduced, in accord with experimental results that show an apparent favorable solvation of ions in HDL. We also investigated the structural properties of HDL and LDL both in bulk water and in NaCl(aq). We nd that the LDL phase is more a ected by the presence of ions with respect to the HDL phase. We propose a possible mechanism of disturbance of the LDL phase in terms of the substitution of the oxygen by the chloride ion in the oxygen coordination shells. The systems studied in the HS-JRP set are idealized models for solutions of hydrophobic solutes in water. The solutes were modeled with hard spheres (HS), while the solvent was modeled with the Jagla ramp potential (JRP) particles. The JRP is a spherically symmetric potential with two charac- teristic lengths and it is known to reproduce water anomalies. For this set of simulations the DMD algorithm was employed. We studied the mixtures with HS mole fractions xHS = 0:10; 0:15; 0:20 and 0:50. By the analysis of the isochores and the isotherms planes of the mixtures, the position of the LLCP was determined for all mixtures. The LLCP is found to shift to higher pressures and lower temperatures upon increasing the solute content. On the basis of a rotation of the phase diagram performed to match the sign of the slope of the liquid-liquid coexistence line of the bulk JRP particles to that of real water, we obtain a prediction for the direction of the shift of the LLCP in experiments on solutions of hydrophobic solutes. We expect the LLCP to move to higher pressures and higher temperatures with respect to bulk water. We also studied the di usive behaviour of the mixtures. The di usivity anomaly, indicated by the presence of extrema in the behaviour of the di usion coe cient at constant temperature as a function of the density, is found up to the highest HS mole fraction. For xHS = 0:10; 0:15 and 0:20 a crossover in the behaviour of the di usion coe cient at constant pressure, is also observed above the LLCP upon crossing the Widom line. The results obtained from the three sets of simulations show that the anomalies of bulk water and the LLCP are preserved in solutions of both polar and polar solutes, at least for concentrations from low to moderate. Thus the systematic study of the properties of aqueous solutions can be a novel route for the understanding of the many unsolved mysteries of water. In particular the position of the LLCP moves to higher temperatures with respect to bulk water in the solutions we studied, in the experimentally accessible region. With these results, the experimental measurement of the LLCP in aqueous solutions appears now possible