Alchemical approach performance in calculating the ligand-binding free energy.

Alchemical binding free energy calculations are one of the most accurate methods for estimating ligand-binding affinity. Assessing the accuracy of the approach over protein targets is one of the most interesting issues. The free energy difference of binding between a protein and a ligand was calculated via the alchemical approach. The alchemical approach exhibits satisfactory accuracy over four targets, including AmpC beta-lactamase (AmpC); glutamate receptor, ionotropic kainate 1 (GluK1); heat shock protein 90 (Hsp90); and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). In particular, the correlation coefficients between calculated binding free energies and the respective experiments over four targets range from 0.56 to 0.86. The affinity computed via free energy perturbation (FEP) simulations is overestimated over the experimental value. Particularly, the electrostatic interaction free energy rules the binding process of ligands to AmpC and GluK1. However, the van der Waals (vdW) interaction free energy plays an important role in the ligand-binding processes of HSP90 and SARS-CoV-2 Mpro. The obtained results associate with the hydrophilic or hydrophobic properties of the ligands. This observation may enhance computer-aided drug design.

Nanoarchitectonics of Nanocellulose Filament Electrodes by Femtosecond Pulse Laser Deposition of ZnO and In Situ Conjugation of Conductive Polymers.

Electroactive filament electrodes were synthesized by wet-spinning of cellulose nanofibrils (CNF) followed by femtosecond pulse laser deposition of ZnO (CNF@ZnO). A layer of conducting conjugated polymers was further adsorbed by in situ polymerization of either pyrrole or aniline, yielding systems optimized for electron conduction. The resultant hybrid filaments were thoroughly characterized by imaging, spectroscopy, electrochemical impedance, and small- and wide-angle X-ray scattering. For the filaments using polyaniline, the measured conductivity was a result of the synergy between the inorganic and organic layers, while the contribution was additive in the case of the systems containing polypyrrole. This observation is rationalized by the occurrence of charge transfer between ZnO and polyaniline but not that with polypyrrole. The introduced conductive hybrid filaments displayed a performance that competes with that of metallic counterparts, offering great promise for next-generation filament electrodes based on renewable nanocellulose.

Drug-induced liver injury from selective androgen receptor modulators, anabolic-androgenic steroids and bodybuilding supplements in Australia.

BACKGROUND: Reports of DILI due to herbal and dietary supplements have been increasing over time. AIMS: To characterise clinical, laboratory and histopathological phenotypes and outcomes of drug-induced liver injury (DILI) due to anabolic-androgenic steroids (AAS), selective androgen receptor modulators (SARMs), and bodybuilding supplements (BBS) in Australia. METHODS: Retrospective case series. Patients presented to nine Australian tertiary hospitals, 2017-2023. DILI was defined biochemically and patients were included if their treating physician attributed DILI to preceding use of AAS, SARMs or BBS. Primary endpoint was time to normalisation of liver biochemistry. Secondary endpoints were hospitalisation for investigation or management of DILI, death attributable to liver injury, and liver transplantation. RESULTS: Twenty-three cases of DILI were identified, involving 40 drugs: 18 AAS, 14 SARMs and eight BBS. Patients were predominantly male (22/23), with median age 30 years (IQR 26-42). Most were symptomatic (21/23). Median latency of onset was 58 days (IQR 28-112 days) from drug commencement. Most patients (17/23) were admitted to hospital. Based on updated Roussel Uclaf Causality Assessment Method, DILI was possible in 17/23, probable in 2/23 and unlikely in 4/23. Median time to normalisation of liver biochemistry was 175 days (IQR 70-292 days) from presentation. Three (3/23) were treated with corticosteroids, 14/23 were treated for itch, and one (1/23) underwent liver transplantation. There were no deaths. CONCLUSIONS: The prognosis of DILI from AAS, SARMs and BBS is good although liver transplantation may rarely be required. A detailed drug history is important in uncovering DILI due to these supplements.

A study of the impact of an interprofessional education module in Vietnam on students' readiness and competencies.

INTRODUCTION: The literature puts forward a range of challenges of interprofessional education (IPE) related to its planning, initiation, implementation, and especially to IPE assessment. The present study aims to map changes in students' readiness and interprofessional collaboration competence (IPCC) in implementing an innovative IPE module. Potential differences in impact related to the health education programs and IPCC scores resulting from self-, peer-, and tutor assessments will also be analysed. METHODS: A pre-post design was adopted. The student's readiness for interprofessional learning was assessed using the Readiness for Interprofessional Learning Scale, and the student's IPCC score was calculated based on self-, peer-, and tutor assessments with the interprofessional collaborator assessment rubric. RESULTS: Students' mean post-test readiness scores and mean post-test IPCC scores were significantly higher than the total and subscales/domain pre-test scores (p<0.01). No significant within-subject differences were observed in students' readiness total or subscale scores when comparing health educational programs. However, significant differences were observed in students' mean total IPCC scores between programs (p<0.01). Significant differences in students' average IPCC scores were found when comparing self-, peer- and tutor assessment scores in six domains (p<0.01). Also, significant correlations between peer and tutor assessment scores were observed (p<0.01). CONCLUSION: The IPE module, designed and implemented to focus on patient-centred practice within a primary care context, positively impacted students' readiness and IPCC development. These results offer insights to expand the implementation of the IPE module to all health educational programs.

A high-quality draft genome sequence of Neonectria faginata, causative agent of beech bark disease of Fagus grandifolia.

The draft genome of Neonectria faginata was sequenced with Oxford Nanopore and Illumina 250 bp paired-end sequencing technologies. The assembled genome was 42.9 Mb distributed over 24 contigs, with N50 of 4.4 Mb and 98.6% BUSCO completeness. This genome sequence will aid in understanding N. faginata population structure and ecology.

The Incidence of Spontaneous Bacterial Peritonitis in Patients With Cirrhosis-Related Ascites Undergoing Elective Outpatient Large-Volume Paracentesis.

Background and aims Large-volume paracentesis (LVP) is a common practice for diuretic-refractory ascites in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is reportedly low in asymptomatic patients presenting for elective outpatient LVP. The benefits and cost-effectiveness of routine testing for SBP in these patients are yet to be established. We aimed to investigate the incidence of SBP in outpatients who underwent elective LVP and the diagnostic yield of routine ascitic fluid testing, specifically fluid culture, and to assess the cost-effectiveness of these tests. Methods This is a retrospective study of adult patients undergoing outpatient LVP at Wollongong Hospital over three years. Symptomatic patients and patients with non-cirrhosis-related ascites were excluded. The ascitic fluid results were reviewed to determine if the polymorphonuclear (PMN) cell count was above 250 x 106/L and whether this was associated with positive fluid culture and clinical outcomes. The primary outcome was the incidence of SBP. The secondary outcome was the incidence of bacterascites. Results There were 26 patients with 122 elective ascitic taps. Two of 122 taps (1.6%) had ascitic PMN count above 250 x 106/L, indicating SBP. Four out of 122 taps (3.2%) had positive ascitic fluid cultures with a normal PMN count. All patients did not have significant clinical outcomes, did not receive antibiotic treatment, and remained asymptomatic over three years of follow-up. Conclusions Routine testing of ascitic fluid cell count and culture in asymptomatic patients with cirrhosis presenting for outpatient LVP yielded a low incidence of SBP and bacterascites, which were not clinically significant. Routine testing is costly and potentially exposes patients to antibiotics unnecessarily.

A Comprehensive Study of the Radical Scavenging Activity of Rosmarinic Acid.

Rosmarinic acid (RA) is reported in separate studies to be either an inducer or reliever of oxidative stress, and this contradiction has not been resolved. In this study, we present a comprehensive examination of the radical scavenging activity of RA using density functional theory calculations in comparison with experimental data. In model physiological media, RA exhibited strong HO• radical scavenging activity with overall rate constant values of 2.89 × 1010 and 3.86 × 109 M-1 s-1. RA is anticipated to exhibit excellent scavenging properties for HOO• in an aqueous environment (koverall = 3.18 × 108 M-1 s-1, ≈2446 times of Trolox) following the hydrogen transfer and single electron transfer pathways of the dianion state. The neutral form of the activity is equally noteworthy in a lipid environment (koverall = 3.16 × 104 M-1 s-1) by the formal hydrogen transfer mechanism of the O6(7,15,16)-H bonds. Chelation with RA may prevent Cu(II) from reduction by the ascorbic acid anion (AA-), hence blocking the OIL-1 pathway, suggesting that RA in an aqueous environment also serves as an OIL-1 antioxidant. The computational findings exhibit strong concurrence with the experimental observations, indicating that RA possesses a significant efficacy as a radical scavenger in physiological environments.

Population genomic analyses suggest recent dispersal events of the pathogen Cercospora zeina into East and Southern African maize cropping systems.

A serious factor hampering global maize production is gray leaf spot disease. Cercospora zeina is one of the causative pathogens, but population genomics analysis of C. zeina is lacking. We conducted whole-genome Illumina sequencing of a representative set of 30 C. zeina isolates from Kenya and Uganda (East Africa) and Zambia, Zimbabwe, and South Africa (Southern Africa). Selection of the diverse set was based on microsatellite data from a larger collection of the pathogen. Pangenome analysis of the C. zeina isolates was done by (1) de novo assembly of the reads with SPAdes, (2) annotation with BRAKER, and (3) protein clustering with OrthoFinder. A published long-read assembly of C. zeina (CMW25467) from Zambia was included and annotated using the same pipeline. This analysis revealed 790 non-shared accessory and 10,677 shared core orthogroups (genes) between the 31 isolates. Accessory gene content was largely shared between isolates from all countries, with a few genes unique to populations from Southern Africa (32) or East Africa (6). There was a significantly higher proportion of effector genes in the accessory secretome (44%) compared to the core secretome (24%). PCA, ADMIXTURE, and phylogenetic analysis using a neighbor-net network indicated a population structure with a geographical subdivision between the East African isolates and the Southern African isolates, although gene flow was also evident. The small pangenome and partial population differentiation indicated recent dispersal of C. zeina into Africa, possibly from 2 regional founder populations, followed by recurrent gene flow owing to widespread maize production across sub-Saharan Africa.

ZIF-67 grafted-boehmite-PVA composite membranes with enhanced removal efficiency towards Cr(VI) from aqueous solutions.

In this work, we developed a thin membrane of boehmite-polyvinyl alcohol composite (BOPOM) (diameter âˆ¼ 5 cm) grafted ZIF-67 combing sol-gel and in-situ growth methods. The fabricated materials were characterized using FT-IR, SEM, XRD, TGA, XPS, and N2 sorption techniques. Results indicate that ZIF-67 nanocrystals were well-grafted into the AlOOH-PVA matrix with reduced crystallite size. Furthermore, the decorated ZIF-67 offered additional porous structures and adsorption sites onto the membrane, enhancing their removal efficiency towards Cr6+ compared to the undecorated and pristine ZIF-67. At pH ∼5.5, the harvested ZIF-67/BOPOM exhibited the highest Cr6+ uptake capacity of ∼56.4 mg g-1. Kinetic studies showed that the chromium adsorption on the prepared materials obeyed the pseudo-second-order model, and the kinetic parameters followed the order ZIFF-67/BOPOM (0.020 mg g-1 min-1) > BOPOM (0.011 mg g-1 min-1) > ZIF-67 (0.006 mg g-1 min-1). Notably, the adsorption mechanism study revealed that adsorbed Cr6+ was reduced to Cr3+, and the reduction yield was boosted owing to grafting ZIF-67 into the BOPOM. In addition, the fabricated ZIF-67/BOPOM can simultaneously remove Cr6+ and methyl orange dye (MO) in the solution due to their synergetic effects on each other. Furthermore, the hybrid membrane ZIF-67/BOPOM showed a chromium removal efficiency of ∼78.2% after four successive adsorption-desorption cycles. This study indicates that grafting nanocrystals ZIF-67 onto the super-platform boehmite-PVA is a promising strategy to harvest an adsorbent with a high adsorption ability, cost-effectiveness, and reduced secondary pollution risks.

Upgrading nirmatrelvir to inhibit SARS-CoV-2 Mpro via DeepFrag and free energy calculations.

The first oral drug for the treatment of COVID-19, Paxlovid, has been authorized; however, nirmatrelvir, a major component of the drug, is reported to be associated with some side effects. Moreover, the appearance of many novel variants raises concerns about drug resistance, and designing new potent inhibitors to prevent viral replication is thus urgent. In this context, using a hybrid approach combining machine learning (ML) and free energy simulations, 6 compounds obtained by modifying nirmatrelvir were proposed to bind strongly to SARS-CoV-2 Mpro. The structural modification of nirmatrelvir significantly enhances the electrostatic interaction free energy between the protein and ligand and slightly decreases the vdW term. However, the vdW term is the most important factor in controlling the ligand-binding affinity. In addition, the modified nirmatrelvir might be less toxic to the human body than the original inhibitor.

In silico secretome analyses of the polyphagous root-knot nematode Meloidogyne javanica: a resource for studying M. javanica secreted proteins.

BACKGROUND: Plant-parasitic nematodes (PPNs) that cause most damage include root-knot nematodes (RKNs) which are a major impediment to crop production. Root-knot nematodes, like other parasites, secrete proteins which are required for parasite proliferation and survival within the host during the infection process. RESULTS: Here, we used various computational tools to predict and identify classically and non-classically secreted proteins encoded in the Meloidogyne javanica genome. Furthermore, functional annotation analysis was performed using various integrated bioinformatic tools to determine the biological significance of the predicted secretome. In total, 7,458 proteins were identified as secreted ones. A large percentage of this secretome is comprised of small proteins of ≤ 300 aa sequence length. Functional analyses showed that M. javanica secretome comprises cell wall degrading enzymes for facilitating nematode invasion, and migration by disintegrating the complex plant cell wall components. In addition, peptidases and peptidase inhibitors are an important category of M. javanica secretome involved in compatible host-nematode interactions. CONCLUSION: This study identifies the putative secretome encoded in the M. javanica genome. Future experimental validation analyses can greatly benefit from this global analysis of M. javanica secretome. Equally, our analyses will advance knowledge of the interaction between plants and nematodes.

Ultrasonic spray pyrolysis synthesis of TiO2/Al2O3 microspheres with enhanced removal efficiency towards toxic industrial dyes.

Developing low-cost and highly effective adsorbent materials to decolorate wastewater is still challenging in the industry. In this study, TiO2-modified Al2O3 microspheres with different TiO2 contents were produced by spray pyrolysis, which is rapid and easy to scale up. Results reveal that the modification of γ-Al2O3 with TiO2 reduced the crystallite size of Al2O3 and generated more active sites in the composite sample. The as-synthesized Al2O3-TiO2 microspheres were applied to remove anionic methyl orange (MO) and cationic rhodamine B (RB) dyes in an aqueous solution using batch and continuous flow column sorption processes. Results show that the Al2O3 microspheres modified with 15 wt% of TiO2 exhibited the maximum adsorbing capacity of ∼41.15 mg g-1 and ∼32.28 mg g-1 for MO and RB, respectively, exceeding the bare γ-Al2O3 and TiO2. The impact of environmental complexities on the material's reactivity for the organic pollutants was further delineated by adjusting the pH and adding coexisting ions. At pH ∼5.5, the TiO2/Al2O3 microspheres showed higher sorption selectivity towards MO. In the continuous flow column removal, the TiO2/Al2O3 microspheres achieved sorption capacities of ∼31 mg g-1 and ∼19 mg g-1 until the breakthrough point for MO and RB, respectively. The findings reveal that TiO2-modified Al2O3 microspheres were rapidly prepared by spray pyrolysis, and they effectively treated organic dyes in water in batch and continuous flow removal processes.

Haplotype mining panel for genetic dissection and breeding in Eucalyptus.

To improve our understanding of genetic mechanisms underlying complex traits in plants, a comprehensive analysis of gene variants is required. Eucalyptus is an important forest plantation genus that is highly outbred. Trait dissection and molecular breeding in eucalypts currently relies on biallelic single-nucleotide polymorphism (SNP) markers. These markers fail to capture the large amount of haplotype diversity in these species, and thus multi-allelic markers are required. We aimed to develop a gene-based haplotype mining panel for Eucalyptus species. We generated 17 999 oligonucleotide probe sets for targeted sequencing of selected regions of 6293 genes implicated in growth and wood properties, pest and disease resistance, and abiotic stress responses. We identified and phased 195 834 SNPs using a read-based phasing approach to reveal SNP-based haplotypes. A total of 8915 target regions (at 4637 gene loci) passed tests for Mendelian inheritance. We evaluated the haplotype panel in four Eucalyptus species (E. grandis, E. urophylla, E. dunnii and E. nitens) to determine its ability to capture diversity across eucalypt species. This revealed an average of 3.13-4.52 haplotypes per target region in each species, and 33.36% of the identified haplotypes were shared by at least two species. This haplotype mining panel will enable the analysis of haplotype diversity within and between species, and provide multi-allelic markers that can be used for genome-wide association studies and gene-based breeding approaches.

Calonectria queenslandica: Causal Agent of Eucalyptus Leaf Blight in Southern China.

Calonectria leaf blight caused by Calonectria spp. is among the most serious diseases affecting the health and sustainability of Eucalyptus plantations in southern China. Recent outbreaks of this disease in GuangDong Province prompted a need to identify the species involved. Typical symptoms of Calonectria leaf blight were observed on 2-year-old Eucalyptus urophylla × E. grandis trees in a plantation in the ZhaoQing region. In total, 38 Calonectria isolates were collected from 32 diseased trees. All isolates were identified using DNA sequence analyses of the translation elongation factor 1-α (tef1), ß-tubulin (tub2), calmodulin (cmdA), and histone H3 (his3) gene regions. Phylogenetic analyses revealed that Calonectria queenslandica was the dominant species, accounting for 81.6% of the isolates collected. Other species isolated included C. pseudoreteaudii (10.5%), C. reteaudii (5.3%), and C. aconidialis (2.6%). This is the first report of C. queenslandica in China and all isolates had identical sequences in all four gene regions. PCR amplification using primers targeting the MAT1-1-1 and MAT1-2-1 genes in all C. queenslandica isolates revealed that only the MAT1-2 idiomorph was present. The results suggest that C. queenslandica was introduced into the sampled area with very limited genetic diversity. Pathogenicity tests were conducted on two Eucalyptus genotypes widely planted in the GuangDong Province using isolates representing all species collected. The results showed that these species could all cause disease but the predominance of C. queenslandica on infected trees suggests that it is the major driver of the disease problem studied. Different Eucalyptus genotypes used in the pathogenicity tests differed in susceptibility to infection by the Calonectria spp. tested, providing opportunities to avoid leaf blight by deploying disease-tolerant planting stock.

The genome of the king protea, Protea cynaroides.

The king protea (Protea cynaroides), an early-diverging eudicot, is the most iconic species from the Megadiverse Cape Floristic Region, and the national flower of South Africa. Perhaps best known for its iconic flower head, Protea is a key genus for the South African horticulture industry and cut-flower market. Ecologically, the genus and the family Proteaceae are important models for radiation and adaptation, particularly to soils with limited phosphorus bio-availability. Here, we present a high-quality chromosome-scale assembly of the P. cynaroides genome as the first representative of the fynbos biome. We reveal an ancestral whole-genome duplication event that occurred in the Proteaceae around the late Cretaceous that preceded the divergence of all crown groups within the family and its extant diversity in all Southern continents. The relatively stable genome structure of P. cynaroides is invaluable for comparative studies and for unveiling paleopolyploidy in other groups, such as the distantly related sister group Ranunculales. Comparative genomics in sequenced genomes of the Proteales shows loss of key arbuscular mycorrhizal symbiosis genes likely ancestral to the family, and possibly the order. The P. cynaroides genome empowers new research in plant diversification, horticulture and adaptation, particularly to nutrient-poor soils.

Bioinspired Triboelectric Nanosensors for Self-Powered Wearable Applications.

The sustainable operation of wearable sensors plays an important role in continuous and longtime health monitoring. Conventional batteries, which are bulky and rigid, do not satisfy these requirements and, rather, cause additional economic burdens and environmental problems by regular replacement of power sources. This article provides a review on an alternative solution in the form of self-powered devices that can harvest energy from the surrounding environment to support the operation of the wearable sensor. The Review starts with an introduction of the self-powered triboelectric nanosensors (TENSs) and its two independent modules: the energy harvester and the sensing module. The Review continues with the TENS-related bioinspired designs for wearable applications, while providing a bird's-eye view of their characteristics and applications. The ongoing challenges and prospects for providing personal healthcare with self-powered TENS are presented and discussed.

Searching for potential inhibitors of SARS-COV-2 main protease using supervised learning and perturbation calculations.

Inhibiting the biological activity of SARS-CoV-2 Mpro can prevent viral replication. In this context, a hybrid approach using knowledge- and physics-based methods was proposed to characterize potential inhibitors for SARS-CoV-2 Mpro. Initially, supervised machine learning (ML) models were trained to predict a ligand-binding affinity of ca. 2 million compounds with the correlation on a test set of R = 0.748 ± 0.044 . Atomistic simulations were then used to refine the outcome of the ML model. Using LIE/FEP calculations, nine compounds from the top 100 ML inhibitors were suggested to bind well to the protease with the domination of van der Waals interactions. Furthermore, the binding affinity of these compounds is also higher than that of nirmatrelvir, which was recently approved by the US FDA to treat COVID-19. In addition, the ligands altered the catalytic triad Cys145 - His41 - Asp187, possibly disturbing the biological activity of SARS-CoV-2.

Chemical Fractionations of Lead and Zinc in the Contaminated Soil Amended with the Blended Biochar/Apatite.

Heavy metal contamination in agricultural land is an alarming issue in Vietnam. It is necessary to develop suitable remediation methods for environmental and farming purposes. The present study investigated the effectiveness of using peanut shell-derived biochar to remediate the two heavy metals Zn and Pb in laboratory soil assays following Tessier's sequential extraction procedure. The concentration of heavy metals was analyzed using Inductively coupled plasma mass spectrometry (ICP-MS). This study also compared the effectiveness of the blend of biochar and apatite applied and the mere biochar amendment on the chemical fractions of Pb and Zn in the contaminated agricultural soil. Results have shown that the investigated soil was extremely polluted by Pb (3047.8 mg kg−1) and Zn (2034.3 mg kg−1). In addition, the pH, organic carbon, and electrical conductivity values of amended soil samples increased with the increase in the amendment's ratios. The distribution of heavy metals in soil samples was in the descending order of carbonate fraction (F2) > residue fraction (F5) > exchangeable fraction (F1) > Fe/Mn oxide fraction (F3) > organic fraction (F4) for Pb and F5 ≈ F2 > F1 > F3 > F4 for Zn. The peanut shell-derived biochar produced at 400 °C and 600 °C amended at a 10% ratio (PB4:10 and PB6:10) could significantly reduce the exchangeable fraction Zn from 424.82 mg kg−1 to 277.69 mg kg−1 and 302.89 mg kg−1, respectively, and Pb from 495.77 mg kg−1 to 234.55 mg kg−1 and 275.15 mg kg−1, respectively, and immobilize them in soil. Amending the biochar and apatite combination increased the soil pH, then produced a highly negative charge on the soil surface and facilitated Pb and Zn adsorption. This study shows that the amendment of biochar and biochar blended with apatite could stabilize Pb and Zn fractions, indicating the potential of these amendments to remediate Pb and Zn in contaminated soil.