Size-consistent variational approaches to non-local pseudopotentials: standard and lattice regularized diffusion Monte Carlo methods revisited

We propose improved versions of the standard diffusion Monte Carlo (DMC) and the lattice regularized diffusion Monte Carlo (LRDMC) algorithms. For the DMC method, we refine a scheme recently devised to treat non-local pseudopotential in a variational way. We show that such scheme --when applied to large enough systems-- maintains its effectiveness only at correspondingly small enough time-steps, and we present two simple upgrades of the method which guarantee the variational property in a size-consistent manner. For the LRDMC method, which is size-consistent and variational by construction, we enhance the computational efficiency by introducing (i) an improved definition of the effective lattice Hamiltonian which remains size-consistent and entails a small lattice-space error with a known leading term, and (ii) a new randomization method for the positions of the lattice knots which requires a single lattice-space.Comment: 10 pages, 4 figures, submitted to the Journal of Chemical Physic

Behavioral characterization of co-exposure to cannabinoids and hormonal contraceptives in female rats

Hormonal contraceptives are among the most widely used drugs by young healthy women to block ovulation and avoid pregnancy. They reduce the ovarian secretion of estradiol and progesterone, hormones that also modulate neuronal plasticity, cognitive functions, emotions and mood. Cannabis is the most commonly used illicit drug worldwide and its use is increasing among young women, many of which regularly take the "pill". Despite ev-idence of a bidirectional interaction between the endocannabinoid system and gonadal hormones, only very few studies have examined the consequences of cannabis consumption in young females under hormonal contra-ceptives treatment. To fill this gap, this study evaluated the behavioral effects of co-exposure to chronic 1) hormonal contraceptives, i.e., ethinyl estradiol (EE) plus levonorgestrel (LNG), one of the synthetic estrogen-progestin combinations of hormonal contraceptives, and 2) cannabinoid receptor agonist, i.e., WIN 55,212-2 (WIN), on motor activity, emotional state and cognitive functions in young adult female rats (8-11/experimental group). Hormonal and cannabinoid treatment started at post-natal day (PND) 52 and 56, respectively, while behavioral testing occurred between PND 84-95. The results show that chronic EE-LNG treatment, at doses (0.020 and 0.060 mg/rat, respectively) known to drastically reduce plasma progesterone levels, and the contextual exposure to WIN, at a dose (12.5 mu g/kg/infusion) known to be rewarding in the rat, alters the hor-monal milieu but does not cause further changes in locomotor activity compared to EE-LNG or WIN alone, and does not modify anxiety-like state (as measured by the elevated plus maze and the marble burying tests) and cognitive abilities (as measured by the novel object recognition and the prepulse inhibition tests) in young adult female rats. Although exposure to EE-LNG and WIN tends to increase the duration of immobility and to reduce the time spent swimming in the forced swimming test, there was not a significant additive effect suggestive of a depressive-like state. These findings allow deepening the current knowledge on the interaction between cannabinoid agonists and hormonal contraceptives and suggest that low, rewarding doses of cannabinoids do not significantly alter the motor and cognitive skills and do not induce anxiety or depressive-like states in females that use hormonal contraceptives

High-frequency QRS analysis compared to conventional ST-segment analysis in patients with chest pain and normal ECG referred for exercise tolerance test

Background: The novel analysis of high-frequency QRS components (HFQRS-analysis) has been proposed in patients with chest pain (CP) and normal electrocardiography (ECG) referred for exercise tolerance test (ex-ECG). The aim of the study was to compare the diagnostic value of ex-ECG with ex-HFQRS-analysis. Methods: Patients with CP and normal ECG, troponin, and echocardiography were consid­ered. All patients underwent ex-ECG for conventional ST-segment-analysis and ex-HFQRS-analysis. A decrease ≥ 50% of the HFQRS signal intensity recorded in at least 2 contiguous leads was considered an index of ischemia, as ST-segment depression ≥ 2 mm or ≥ 1 mm and CP on ex-ECG. Exclusion criteria were: QRS duration ≥ 120 ms and inability to exercise. End-point: The composite of coronary stenosis ≥ 70% or acute coronary syndrome, revascu­larization, cardiovascular death at 3-month follow-up. Results: Three-hundred thirty-seven patients were enrolled (age 60 ± 15 years). The percent­age of age-adjusted maximal predicted heart rate was 89 ± 10 beat per minute and the maximal systolic blood pressure was 169 ± 23 mm Hg. Nineteen patients achieved the end-point. In multivariate analysis, both ex-ECG and ex-HFQRS were predictors of the end-point. The ex-HFQRS-analysis showed higher sensitivity (63% vs. 26%; p < 0.05), lower specificity (68% vs. 95%; p < 0.001), and comparable negative predictive value (97% vs. 96%; p = 0.502) when compared to ex-ECG-analysis. Receiver operator characteristics analysis showed the incremental diagnostic value of HFQRS (area: 0.655, 95% CI 0.60–0.71) over conventional ex-ECG (0.608, CI 0.55–0.66) and CP score (0.530, CI 0.48–0.59), however without statistical significance in pairwise comparison by C-statistic. Conclusions: In patients with CP submitted to ex-ECG, the novel ex-HFQRS-analysis shows a valuable incremental diagnostic value over ST-segment-analysis

Polyphosphoester-stabilized cubosomes encapsulating a Ru(II) complex for the photodynamic treatment of lung adenocarcinoma

The clinical translation of photosensitizers based on ruthenium(II) polypyridyl complexes (RPCs) in photodynamic therapy of cancer faces several challenges. To address these limitations, we conducted an investigation to assess the potential of a cubosome formulation stabilized in water against coalescence utilizing a polyphosphoester analog of Pluronic F127 as a stabilizer and loaded with newly synthesized RPC-based photosensitizer [Ru(dppn)2(bpy-morph)](PF6)2 (bpy-morph = 2,2'-bipyridine-4,4'-diylbis(morpholinomethanone)), PS-Ru. The photophysical characterization of PS-Ru revealed its robust capacity to induce the formation of singlet oxygen (1O2). Furthermore, the physicochemical analysis of the PS-Ru-loaded cubosomes dispersion demonstrated that the encapsulation of the photosensitizer within the nanoparticles did not disrupt the three-dimensional arrangement of the lipid bilayer. The biological tests showed that PS-Ru-loaded cubosomes exhibited significant phototoxic activity when exposed to the light source, in stark contrast to empty cubosomes and to the same formulation without irradiation. This promising outcome suggests the potential of the formulation in overcoming the drawbacks associated with the clinical use of RPCs in photodynamic therapy for anticancer treatments

Fluorescent asymmetric bis-ureas for pyrophosphate recognition in pure water

Three fluorescent asymmetric bis-urea receptors (L1–L3) have been synthesised. The binding properties of L1–L3 towards different anions (fluoride, acetate, hydrogencarbonate, dihydrogen phosphate, and hydrogen pyrophosphate HPpi3?) have been studied by means of 1H-NMR, UV-Vis and fluorescence spectroscopy, single crystal X-ray diffraction, and theoretical calculations. In particular, a remarkable affinity for HPpi3? has been observed in the case L1 (DMSO-d6/0.5% H2O) which also acts as a fluorimetric chemosensor for this anion. Interestingly, when L1 is included in cetyltrimethylammonium (CTAB) micelles, hydrogen pyrophosphate recognition can also be achieved in pure water

Halogen-substituted ureas for anion binding: solid state and solution studies

Herein, we report the synthesis and the anion binding properties of a family of N,N′-diphenylureas L1-L15, bearing on the aromatic ring(s) halogens (chlorine and iodine) and/or nitro or trifluoromethyl electron-withdrawing groups. The analysis of the crystal structures obtained from single crystal X-ray diffraction experiments shows that self-assembled chains or tapes connected via N–H···O hydrogen bonds are the most commonly adopted arrangements for this type of molecules in the crystal lattice. In the presence of anion guests or solvent molecules with competing hydrogen bond donors and acceptors, other supramolecular arrangements can be observed. Solution studies conducted in DMSOd 6/0.5% H2O by means of 1H-NMR titrations show the formation of 1:1 adducts with all receptors. The different observed affinities of the receptors for the anion guests were rationalised in terms of steric hindrance of the substituents on the phenyl rings and their electron-withdrawing properties

Halogen-substituted ureas for anion binding: solid state and solution studies

Herein, we report the synthesis and the anion binding properties of a family of N,N′-diphenylureas L1-L15, bearing on the aromatic ring(s) halogens (chlorine and iodine) and/or nitro or trifluoromethyl electron-withdrawing groups. The analysis of the crystal structures obtained from single crystal X-ray diffraction experiments shows that self-assembled chains or tapes connected via N–H···O hydrogen bonds are the most commonly adopted arrangements for this type of molecules in the crystal lattice. In the presence of anion guests or solvent molecules with competing hydrogen bond donors and acceptors, other supramolecular arrangements can be observed. Solution studies conducted in DMSOd 6/0.5% H2O by means of 1H-NMR titrations show the formation of 1:1 adducts with all receptors. The different observed affinities of the receptors for the anion guests were rationalised in terms of steric hindrance of the substituents on the phenyl rings and their electron-withdrawing properties

Cation Distribution and Vacancies in Nickel Cobaltite

Samples of nickel cobaltite, a mixed oxide occurring in the spinel structure which is currently extensively investigated because of its prospective application as ferromagnetic, electrocatalytic, and cost-effective energy storage material were prepared in the form of nanocrystals stabilized in a highly porous silica aerogel and as unsupported nanoparticles. Nickel cobaltite nanocrystals with average size 4 nm are successfully grown for the first time into the silica aerogel provided that a controlled oxidation of the metal precursor phases is carried out, consisting in a reduction under H2 flow followed by mild oxidation in air. The investigation of the average oxidation state of the cations and of their distribution between the sites within the spinel structure, which is commonly described assuming the Ni cations are only located in the octahedral sites, has been carried out by X-ray Absorption Spectroscopy providing evidence for the first time that the unsupported nickel cobaltite sample has a Ni:Co molar ratio higher than the nominal ratio of 1:2 and a larger than expected average overall oxidation state of the cobalt and nickel cations. This is achieved retaining the spinel structure, which accommodates vacancies to counterbalance the variation in oxidation state

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy