Density functional formalism in the canonical ensemble

Density functional theory, when applied to systems with $T\neq 0$, is based on the grand canonical extension of the Hohenberg-Kohn-Sham theorem due to Mermin (HKSM theorem). While a straightforward canonical ensemble generalization fails, work in nanopore systems could certainly benefit from such extension. We show that, if the asymptotic behaviour of the canonical distribution functions is taken into account, the HKSM theorem can be extended to the canonical ensemble. We generate $N$-modified correlation and distribution functions hierarchies and prove that, if they are employed, either a modified external field or the density profiles can be indistinctly used as independent variables. We also write down the $N$% -modified free energy functional and prove that its minimum is reached when the equilibrium values of the new hierarchy are used. This completes the extension of the HKSM theorem.Comment: revtex, to be submitted to Phys. Rev. Let

Change in 1-year mortality after hip fracture surgery over the last decade in a European population

Objective: There are scarce data on the mortality after hip fracture surgery for patients treated in the most recent years. The objective of this study was to analyze whether the overall initiatives introduced over the last decade for elderly patients with hip fractures had a positive impact on the 1-year mortality. Methods: Patients treated during 2010–2012 were compared with patients treated during 2018–2020 for all-cause 1-year mortality. Variables influencing mortality were collected based on the literature, including demographic, comorbidity, cognitive status, and preinjury physical function. Crude mortalities were compared between periods, as well as with the expected mortality in the general population adjusted for age, gender, and year of surgery using the standardized mortality ratio (SMR). A multivariate model was used to identify mortality risk factors. Results: 591 patients older than 65 years were treated during 2010–2012 and 642 patients during 2018–2020. The mean age increased significantly between periods (78.9 vs. 82.6 years, respectively, p = 0.001) in both genders, together with an increase in comorbidity (p = 0.014). The in-hospital mortality risk had no significant difference between periods (2.5 vs. 2.0%, p = 0.339), but the 30-day mortality risk (8.3 vs. 5.5%, p = 0.031) and 1-year mortality risk (16.1 vs. 11.9%, p = 0.023) declined significantly. However, 1-year mortality in 2020 had an excess of 1.33 in SMR. Age older than 80 years, male gender, and Charlson comorbidity index > 2 were significant predictors of 1-year mortality. Conclusion: The important evolution achieved in the last decade for the management of patients with hip fracture surgery has led to a significant decline in 1-year mortality, but the 1-year mortality remains significantly higher compared to the general population of similar age and gender.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature

Extraction of pharmacokinetic evidence of drug-drug interactions from the literature

Drug-drug interaction (DDI) is a major cause of morbidity and mortality and a subject of intense scientific interest. Biomedical literature mining can aid DDI research by extracting evidence for large numbers of potential interactions from published literature and clinical databases. Though DDI is investigated in domains ranging in scale from intracellular biochemistry to human populations, literature mining has not been used to extract specific types of experimental evidence, which are reported differently for distinct experimental goals. We focus on pharmacokinetic evidence for DDI, essential for identifying causal mechanisms of putative interactions and as input for further pharmacological and pharmacoepidemiology investigations. We used manually curated corpora of PubMed abstracts and annotated sentences to evaluate the efficacy of literature mining on two tasks: first, identifying PubMed abstracts containing pharmacokinetic evidence of DDIs; second, extracting sentences containing such evidence from abstracts. We implemented a text mining pipeline and evaluated it using several linear classifiers and a variety of feature transforms. The most important textual features in the abstract and sentence classification tasks were analyzed. We also investigated the performance benefits of using features derived from PubMed metadata fields, various publicly available named entity recognizers, and pharmacokinetic dictionaries. Several classifiers performed very well in distinguishing relevant and irrelevant abstracts (reaching F10.93, MCC0.74, iAUC0.99) and sentences (F10.76, MCC0.65, iAUC0.83). We found that word bigram features were important for achieving optimal classifier performance and that features derived from Medical Subject Headings (MeSH) terms significantly improved abstract classification. We also found that some drug-related named entity recognition tools and dictionaries led to slight but significant improvements, especially in classification of evidence sentences. Based on our thorough analysis of classifiers and feature transforms and the high classification performance achieved, we demonstrate that literature mining can aid DDI discovery by supporting automatic extraction of specific types of experimental evidence.National Institutes of Health, National Library of Medicine Program, grant 01LM011945-01 "BLR: Evidence-based Drug-Interaction Discovery: In-Vivo, In-Vitro and Clinical," a grant from the Indiana University Collaborative Research Program 2013, "Drug-Drug Interaction Prediction from Large-scale Mining of Literature and Patient Records," as well as a grant from the joint program between the Fundação Luso-Americana para o Desenvolvimento (Portugal) and National Science Foundation (USA), 2012-2014, "Network Mining For Gene Regulation And Biochemical Signaling.

Preparation and characterization of polymer composite materials based on PLA/TiO2 for antibacterial packaging

Polymer composite materials based on polylactic acid (PLA) filled with titanium dioxide (TiO2) nanoparticles were prepared. The aim of this work was to investigate the antibacterial action of TiO2 against a strain of E. coli (DH5) to obtain information on their potential uses in food and agro-alimentary industry. PLA/TiO2 systems were prepared by a two-step process: Solvent casting followed by a hot-pressing step. Characterization was done as a function of particle size (21 nm and <100 nm) and particle content (0%, 1%, 5%, 10%, and 20%, wt %). Structural characterization carried out by X-ray diffraction (XRD) and Fourier Transformed Infrared spectroscopy (FTIR) did not reveal significant changes in polymer structure due to the presence of TiO2 nanoparticles. Thermal characterization indicated that thermal transitions, measured by differential scanning calorimetry (DSC), did not vary, irrespective of size or content, whereas thermogravimetric analysis (TGA) revealed a slight increase in the temperature of degradation with particle content. Bacterial growth and biofilm formation on the surface of the composites against DH5 Escherichia coli was studied. Results suggested that the presence of TiO2 nanoparticles decreases the amount of extracellular polymeric substance (EPS) and limits bacterial growth

Pranlukast Antagonizes CD49f and Reduces Sternness in Triple-Negative Breast Cancer Cells

Introduction: Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. Materials and Methods: We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clini-cally tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. Results: Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces con-formational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transacti-vation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. Conclusion: Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients

Strategies to design clinical studies to identify predictive biomarkers in cancer research

The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework—the DESIGN guidelines—to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field

Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Subclinical Atherosclerosis in Rheumatoid Arthritis Patients

OBJECTIVES: To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US). RESULTS: RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed. CONCLUSIONS: In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA

New measurement of neutron capture resonances of 209Bi

The neutron capture cross section of Bi209 has been measured at the CERN n TOF facility by employing the pulse-height-weighting technique. Improvements over previous measurements are mainly because of an optimized detection system, which led to a practically negligible neutron sensitivity. Additional experimental sources of systematic error, such as the electronic threshold in the detectors, summing of gamma-rays, internal electron conversion, and the isomeric state in bismuth, have been taken into account. Gamma-ray absorption effects inside the sample have been corrected by employing a nonpolynomial weighting function. Because Bi209 is the last stable isotope in the reaction path of the stellar s-process, the Maxwellian averaged capture cross section is important for the recycling of the reaction flow by alpha-decays. In the relevant stellar range of thermal energies between kT=5 and 8 keV our new capture rate is about 16% higher than the presently accepted value used for nucleosynthesis calculations. At this low temperature an important part of the heavy Pb-Bi isotopes are supposed to be synthesized by the s-process in the He shells of low mass, thermally pulsing asymptotic giant branch stars. With the improved set of cross sections we obtain an s-process fraction of 19(3)% of the solar bismuth abundance, resulting in an r-process residual of 81(3)%. The present (n,gamma) cross-section measurement is also of relevance for the design of accelerator driven systems based on a liquid metal Pb/Bi spallation target.Comment: 10 pages, 5figures, recently published in Phys. Rev.

Measurement of the (90,91,92,93,94,96)Zr(n,gamma) and (139)La(n,gamma) cross sections at n_TOF

Open AccessNeutron capture cross sections of Zr and La isotopes have important implications in the field of nuclear astrophysics as well as in the nuclear technology. In particular the Zr isotopes play a key role for the determination of the neutron density in the He burning zone of the Red Giant star, while the (139)La is important to monitor the s-process abundances from Ba up to Ph. Zr is also largely used as structural materials of traditional and advanced nuclear reactors. The nuclear resonance parameters and the cross section of (90,91,92,93,94,96)Zr and (139)La have been measured at the n_TOF facility at CERN. Based on these data the capture resonance strength and the Maxwellian-averaged cross section were calculated

Measurement of the neutron capture cross section of the s-only isotope 204Pb from 1 eV to 440 keV

The neutron capture cross section of 204Pb has been measured at the CERN n_TOF installation with high resolution in the energy range from 1 eV to 440 keV. An R-matrix analysis of the resolved resonance region, between 1 eV and 100 keV, was carried out using the SAMMY code. In the interval between 100 keV and 440 keV we report the average capture cross section. The background in the entire neutron energy range could be reliably determined from the measurement of a 208Pb sample. Other systematic effects in this measurement could be investigated and precisely corrected by means of detailed Monte Carlo simulations. We obtain a Maxwellian average capture cross section for 204Pb at kT=30 keV of 79(3) mb, in agreement with previous experiments. However our cross section at kT=5 keV is about 35% larger than the values reported so far. The implications of the new cross section for the s-process abundance contributions in the Pb/Bi region are discussed.Comment: 8 pages, 3 figures, article submitted to Phys. Rev.