Leaf morphometric analysis and potential distribution modelling contribute to taxonomic differentiation in the Quercus microphylla complex.

Mexico is a major center of evolutionary radiation for the genus Quercus, with oak species occurring across different habitat types and showing a wide variation in morphology and growth form. Despite representing about 20% of Mexican species, scrub oaks have received little attention and even basic aspects of their taxonomy and geographic distribution remain unresolved. In this study, we analyzed the morphological and climatic niche differentiation of scrub oak populations forming a complex constituted by six named species, Quercus cordifolia, Quercus frutex, Quercus intricata, Quercus microphylla, Quercus repanda, Quercus striatula and a distinct morphotype of Q. striatula identified during field and herbarium work (hereafter named Q. striatula II). Samples were obtained from 35 sites covering the geographic distribution of the complex in northern and central Mexico. Morphological differentiation was analyzed through geometric morphometrics of leaf shape and quantification of trichome traits. Our results indicated the presence of two main morphological groups with geographic concordance. The first was formed by Q. frutex, Q. microphylla, Q. repanda and Q. striatula, distributed in the Trans-Mexican Volcanic Belt, the Sierra Madre Occidental and a little portion of the south of the Mexican Altiplano (MA). The second group consists of Q. cordifola, Q. intricata and Q. striatula II, found in the Sierra Madre Oriental and the MA. Therefore, our evidence supports the distinctness of the Q. striatula II morphotype, indicating the need for a taxonomic revision. Within the two groups, morphological differentiation among taxa varied from very clear to low or inexistent (i.e. Q. microphylla-Q. striatula and Q. cordifolia-Q. striatula II) but niche comparisons revealed significant niche differentiation in all pairwise comparisons, highlighting the relevance of integrative approaches for the taxonomic resolution of complicated groups such as the one studied here.

Nuclear and chloroplast DNA phylogeography reveals high genetic diversity and postglacial range expansion in Quercus mexicana.

PREMISE: Phylogeographical studies are fundamental for understanding factors that influence the spatial distribution of genetic lineages within species. Population expansions and contractions, distribution shifts, and climate changes are among the most important factors shaping the genetic compositions of populations. METHODS: We investigated the phylogeography of an endemic oak, Quercus mexicana (Fagaceae), which has a restricted distribution in northeastern Mexico along the Sierra Madre Oriental and adjacent areas. Nuclear and chloroplast DNA microsatellite markers were used to describe the genetic diversity and structure of 39 populations of Q. mexicana along its entire distribution area. We tested whether population expansion or contraction events influenced the genetic diversity and structure of the species. We also modeled the historical distributional range of Q. mexicana (for the Mid Holocene, the Last Glacial Maximum, and the Last Interglacial) to estimate the extent to which climate fluctuations have impacted the distribution of this oak species. RESULTS: Our results revealed high genetic diversity and low genetic structure in Q. mexicana populations. Ecological niche models suggested historical fluctuations in the distributional range of Q. mexicana. Historical range changes, gene flow, and physical barriers seem to have played an important role in shaping the phylogeographic structure of Q. mexicana. CONCLUSIONS: Our study indicates that the genetic structure of Q. mexicana may have been the result of responses of oak trees not only to heterogeneous environments present in the Sierra Madre Oriental and adjacent areas, but also to elevational and latitudinal shifts in response to climate changes in the past.

Chromatin network markers of leukemia.

MOTIVATION: The structure of chromatin impacts gene expression. Its alteration has been shown to coincide with the occurrence of cancer. A key challenge is in understanding the role of chromatin structure (CS) in cellular processes and its implications in diseases. RESULTS: We propose a comparative pipeline to analyze CSs and apply it to study chronic lymphocytic leukemia (CLL). We model the chromatin of the affected and control cells as networks and analyze the network topology by state-of-the-art methods. Our results show that CSs are a rich source of new biological and functional information about DNA elements and cells that can complement protein-protein and co-expression data. Importantly, we show the existence of structural markers of cancer-related DNA elements in the chromatin. Surprisingly, CLL driver genes are characterized by specific local wiring patterns not only in the CS network of CLL cells, but also of healthy cells. This allows us to successfully predict new CLL-related DNA elements. Importantly, this shows that we can identify cancer-related DNA elements in other cancer types by investigating the CS network of the healthy cell of origin, a key new insight paving the road to new therapeutic strategies. This gives us an opportunity to exploit chromosome conformation data in healthy cells to predict new drivers. AVAILABILITY AND IMPLEMENTATION: Our predicted CLL genes and RNAs are provided as a free resource to the community at https://life.bsc.es/iconbi/chromatin/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A systematic review and trial sequential analysis of intravenous vs. oral peri-operative paracetamol.

Postoperative pain might be different after intravenous vs. oral paracetamol. We systematically reviewed randomised controlled trials in patients >15 years that compared intravenous with oral paracetamol for postoperative pain. We identified 14 trials with 1695 participants. There was inconclusive evidence for an effect of route of paracetamol administration on postoperative pain at 0-2 h (734 participants), 2-6 h (766 participants), 6-24 h (1115 participants) and >24 h (248 participants), with differences in standardised mean (95%CI) pain scores for intravenous vs. oral of -0.17 (-0.45 to 0.10), -0.09 (-0.24 to 0.06), 0.06 (-0.12 to 0.23) and 0.03 (-0.22 to 0.28), respectively. Trial sequential analyses suggested that a total of 3948 participants would be needed to demonstrate a meaningful difference in pain or its absence at 0-2 h. There were no differences in secondary outcomes. Intravenous paracetamol is more expensive than oral paracetamol. Substitution of oral paracetamol in half the patients given intravenous paracetamol in our hospital would save around £ 38,711 (€ 43,960 or US$ 47,498) per annum.

Ampicillin and Ceftriaxone Solution Stability at Different Temperatures in Outpatient Parenteral Antimicrobial Therapy.

The inclusion of ampicillin-containing regimens in outpatient parenteral antimicrobial therapy programs (OPAT) depends upon solution stability under conditions similar to those experienced in these programs. Lack of this information could hinder the inclusion in OPAT of patients suffering from Enterococcus faecalis infective endocarditis treated with ampicillin plus ceftriaxone. The purpose of this study is to determine the stability of ampicillin and ampicillin plus ceftriaxone solutions in a simulated outpatient setting conditions. Solutions of ampicillin 24 g/liter and ampicillin 24 g/liter combined with ceftriaxone 8 g/liter were stored at 25°C ± 2°C, 30°C ± 2°C and 37°C ± 2°C for 48 h. Chemical and physical stability were evaluated at 20, 24, 30, and 48 h after manufacturing. The solutions were considered stable if the percentage of intact drug was ≥90% and color and clearness remained unchanged. After 24 h of storage at a controlled temperature, ampicillin solution in 0.9% sodium chloride was found to be stable for 30 h at 25 and 30°C and for 24 h at 37°C. In the ampicillin plus ceftriaxone combined solution, both antibiotics were found to be stable after 30 h of storage at 25 and 30°C, but at 37°C, the stability criterion was not met at any time point. Our study offers solid evidence demonstrating that the concentrations of both drugs at two of the tested temperatures (25°C and 30°C) were stable for up to 30 h. Therefore, both ampicillin alone and ampicillin plus ceftriaxone solutions would be appropriate candidates for inclusion in OPAT programs.

Neoantigen prediction and computational perspectives towards clinical benefit: recommendations from the ESMO Precision Medicine Working Group.

BACKGROUND: The use of next-generation sequencing technologies has enabled the rapid identification of non-synonymous somatic mutations in cancer cells. Neoantigens are mutated peptides derived from somatic mutations not present in normal tissues that may result in the presentation of tumour-specific peptides capable of eliciting antitumour T-cell responses. Personalised neoantigen-based cancer vaccines and adoptive T-cell therapies have been shown to prime host immunity against tumour cells and are under clinical trial development. However, the optimisation and standardisation of neoantigen identification, as well as its delivery as immunotherapy are needed to increase tumour-specific T-cell responses and, thus, the clinical efficacy of current cancer immunotherapies. METHODS: In this recommendation article, launched by the European Society for Medical Oncology (ESMO), we outline and discuss the available framework for neoantigen prediction and present a systematic review of the current scientific evidence. RESULTS: A number of computational pipelines for neoantigen prediction are available. Most of them provide peptide major histocompatibility complex (MHC) binding affinity predictions, but more recent approaches incorporate additional features like variant allele fraction, gene expression, and clonality of mutations. Neoantigens can be predicted in all cancer types with high and low tumour mutation burden, in part by exploiting tumour-specific aberrations derived from mutational frameshifts, splice variants, gene fusions, endogenous retroelements and other tumour-specific processes that could yield more potently immunogenic tumour neoantigens. Ongoing clinical trials will highlight those cancer types and combinations of immune therapies that would derive the most benefit from neoantigen-based immunotherapies. CONCLUSIONS: Improved identification, selection and prioritisation of tumour-specific neoantigens are needed to increase the scope of benefit from cancer vaccines and adoptive T-cell therapies. Novel pipelines are being developed to resolve the challenges posed by high-throughput sequencing and to predict immunogenic neoantigens.

Managing microbial communities in membrane biofilm reactors.

Membrane biofilm reactors (MBfRs) deliver gaseous substrates to biofilms that develop on the outside of gas-transfer membranes. When an MBfR delivers electron donors hydrogen (H2) or methane (CH4), a wide range of oxidized contaminants can be reduced as electron acceptors, e.g., nitrate, perchlorate, selenate, and trichloroethene. When O2 is delivered as an electron acceptor, reduced contaminants can be oxidized, e.g., benzene, toluene, and surfactants. The MBfR's biofilm often harbors a complex microbial community; failure to control the growth of undesirable microorganisms can result in poor performance. Fortunately, the community's structure and function can be managed using a set of design and operation features as follows: gas pressure, membrane type, and surface loadings. Proper selection of these features ensures that the best microbial community is selected and sustained. Successful design and operation of an MBfR depends on a holistic understanding of the microbial community's structure and function. This involves integrating performance data with omics results, such as with stoichiometric and kinetic modeling.

Universal, In Situ Transformation of Bulky Compounds into Nanoscale Catalysts by High-Temperature Pulse.

The synthesis of nanoscale metal compound catalysts has attracted much research attention in the past decade. The challenges of preparation of the metal compound include the complexity of the synthesis process and difficulty of precise control of the reaction conditions. Herein, we report an in situ synthesis of nanoparticles via a high-temperature pulse method where the bulk material acts as the precursor. During the process of rapid heating and cooling, swift melting, anchoring, and recrystallization occur, resulting in the generation of high-purity nanoparticles. In our work, the cobalt boride (Co2B) nanoparticles with a diameter of 10-20 nm uniformly anchored on the reduced graphene oxide (rGO) nanosheets were successfully prepared using the high temperature pulse method. The as-prepared Co2B/rGO composite displayed remarkable electrocatalytic performance for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). We also prepared molybdenum disulfide (MoS2) and cobalt oxide (Co3O4) nanoparticles, thereby demonstrating that the high-temperature pulse is a universal method to synthesize ultrafine metal compound nanoparticles.

Allosteric modulation model of the mu opioid receptor by herkinorin, a potent not alkaloidal agonist.

Modulation of opioid receptors is the primary choice for pain management and structural information studies have gained new horizons with the recently available X-ray crystal structures. Herkinorin is one of the most remarkable salvinorin A derivative with high affinity for the mu opioid receptor, moderate selectivity and lack of nitrogen atoms on its structure. Surprisingly, binding models for herkinorin are lacking. In this work, we explore binding models of herkinorin using automated docking, molecular dynamics simulations, free energy calculations and available experimental information. Our herkinorin D-ICM-1 binding model predicted a binding free energy of -11.52 ± 1.14 kcal mol-1 by alchemical free energy estimations, which is close to the experimental values -10.91 ± 0.2 and -10.80 ± 0.05 kcal mol-1 and is in agreement with experimental structural information. Specifically, D-ICM-1 molecular dynamics simulations showed a water-mediated interaction between D-ICM-1 and the amino acid H2976.52, this interaction coincides with the co-crystallized ligands. Another relevant interaction, with N1272.63, allowed to rationalize herkinorin's selectivity to mu over delta opioid receptors. Our suggested binding model for herkinorin is in agreement with this and additional experimental data. The most remarkable observation derived from our D-ICM-1 model is that herkinorin reaches an allosteric sodium ion binding site near N1503.35. Key interactions in that region appear relevant for the lack of ß-arrestin recruitment by herkinorin. This interaction is key for downstream signaling pathways involved in the development of side effects, such as tolerance. Future SAR studies and medicinal chemistry efforts will benefit from the structural information presented in this work.

Women's interest in a personal breast cancer risk assessment and lifestyle advice at NHS mammography screening.

Background: Although mortality from breast cancer is declining, incidence continues to increase and is often detected at routine NHS screening. Most middle aged and older women in England attend for screening every 3 years. Assessing their personal breast cancer risk and providing preventative lifestyle advice could help to further reduce breast cancer incidence. Methods: A cross-sectional, self-complete postal survey measured attendees' interest in having a personal risk assessment, expected impact on screening attendance, knowledge of associations between lifestyle and breast cancer and preferred ways of accessing preventative lifestyle advice. Results: A total of 1803/4948 (36.4%) completed questionnaires were returned. Most participants (93.7%) expressed interest in a personal risk assessment and 95% (1713/1803) believed it would make no difference or encourage re-attendance. Two-thirds (1208/1803) associated lifestyle with breast cancer, but many were unaware of specific risks such as weight gain, obesity, alcohol consumption and physical inactivity. NHS sourced advice was expected to be more credible than other sources, and booklets, brief counselling or an interactive website were most preferred for accessing this. Conclusions: Attendees appear to welcome an intervention that would facilitate more proactive clinical and lifestyle prevention and address critical research gaps in breast cancer prevention and early detection.

Reduced Graphene Oxide Films with Ultrahigh Conductivity as Li-Ion Battery Current Collectors.

Solution processed, highly conductive films are extremely attractive for a range of electronic devices, especially for printed macroelectronics. For example, replacing heavy, metal-based current collectors with thin, light, flexible, and highly conductive films will further improve the energy density of such devices. Films with two-dimensional building blocks, such as graphene or reduced graphene oxide (RGO) nanosheets, are particularly promising due to their low percolation threshold with a high aspect ratio, excellent flexibility, and low cost. However, the electrical conductivity of these films is low, typically less than 1000 S/cm. In this work, we for the first time report a RGO film with an electrical conductivity of up to 3112 S/cm. We achieve high conductivity in RGO films through an electrical current-induced annealing process at high temperature of up to 2750 K in less than 1 min of anneal time. We studied in detail the unique Joule heating process at ultrahigh temperature. Through a combination of experimental and computational studies, we investigated the fundamental mechanism behind the formation of a highly conductive three-dimensional structure composed of well-connected RGO layers. The highly conductive RGO film with high direct current conductivity, low thickness (∼4 µm) and low sheet resistance (0.8 Ω/sq.) was used as a lightweight current collector in Li-ion batteries.

Rapid, in Situ Synthesis of High Capacity Battery Anodes through High Temperature Radiation-Based Thermal Shock.

High capacity battery electrodes require nanosized components to avoid pulverization associated with volume changes during the charge-discharge process. Additionally, these nanosized electrodes need an electronically conductive matrix to facilitate electron transport. Here, for the first time, we report a rapid thermal shock process using high-temperature radiative heating to fabricate a conductive reduced graphene oxide (RGO) composite with silicon nanoparticles. Silicon (Si) particles on the order of a few micrometers are initially embedded in the RGO host and in situ transformed into 10-15 nm nanoparticles in less than a minute through radiative heating. The as-prepared composites of ultrafine Si nanoparticles embedded in a RGO matrix show great performance as a Li-ion battery (LIB) anode. The in situ nanoparticle synthesis method can also be adopted for other high capacity battery anode materials including tin (Sn) and aluminum (Al). This method for synthesizing high capacity anodes in a RGO matrix can be envisioned for roll-to-roll nanomanufacturing due to the ease and scalability of this high-temperature radiative heating process.

Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models.

Immune response stimulation to prevent infection progression may be an adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC) is an immunomodulator involved in immune cell recruitment and activation. In this study, we aimed to evaluate the efficacy of LPC in combination with colistin, tigecycline, or imipenem in experimental murine models of peritoneal sepsis and pneumonia. We used Acinetobacter baumannii strain Ab9, which is susceptible to colistin, tigecycline, and imipenem, and multidrug-resistant strain Ab186, which is susceptible to colistin and resistant to tigecycline and imipenem. Pharmacokinetic and pharmacodynamic parameters for colistin, tigecycline, and imipenem and the 100% minimal lethal dose (MLD100) were determined for both strains. The therapeutic efficacies of LPC, colistin (60 mg/kg of body weight/day), tigecycline (10 mg/kg/day), and imipenem (180 mg/kg/day), alone or in combination, were assessed against Ab9 and Ab186 at the MLD100 in murine peritoneal sepsis and pneumonia models. The levels of pro- and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA) for the same experimental models after inoculating mice with the MLD of both strains. LPC in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance of Ab9 and Ab186 from the spleen and lungs and reduced bacteremia and mouse mortality rates (P < 0.05) compared with those for colistin, tigecycline, and imipenem monotherapies. Moreover, at 4 h post-bacterial infection, Ab9 induced higher TNF-α and lower IL-10 levels than those with Ab186 (4 µg/ml versus 3 µg/ml [P < 0.05] and 2 µg/ml versus 3.4 µg/ml [P < 0.05], respectively). LPC treatment combined with colistin, tigecycline, or imipenem modestly reduced the severity of infection by A. baumannii strains with different resistance phenotypes compared to LPC monotherapy in both experimental models.

Low concordance and resistance mutation emergence in the HIV protease gene among circulating and cell-associated viruses at viral replication episodes during darunavir/ritonavir monotherapy.

OBJECTIVE: To assess the changes on the HIV protease gene in plasma and peripheral blood mononuclear cell (PBMC) compartments during viral replication episodes in patients on boosted-darunavir monotherapy (mtDRV/rtv). METHODS: A prospective study was carried out in which adult HIV-1-infected patients who started mtDRV/rtv after viral suppression for ≥ 6 months with no major darunavir-related resistance mutations were enrolled. Patients with two consecutive plasma HIV RNA measurements >200 HIV-1 RNA copies/mL were considered as having virological failure (VF), while patients with two consecutive plasma HIV RNA measurements >50 copies/mL without meeting the VF criteria were considered to have virological rebound (VR). HIV protease genotypic profiles from plasma and PBMCs were performed at baseline and at VF and VR episodes. RESULTS: One hundred and fifty patients were included in the study, with overall VF and VR rates of 14% (n=21) and 14.7% (n=22), respectively. No major darunavir resistance mutations were observed in the plasma or PBMC samples. Circulating and cell-associated viruses showed a wild-type protease gene sequence in 54% and 23% of patients, respectively while the remainder patients only harboured minor protease inhibitor-associated mutations. Full concordance between plasma RNA and PBMC DNA protease genotypes was found in 23% of the sequences. CONCLUSIONS: No darunavir-related mutations were found in patients with VF or VR, either in plasma or in PBMCs; thus, simplification to mtDRV/rtv does not comprise future antiretroviral treatment options.