Ancient Biomolecules and Evolutionary Inference.

Over the past three decades, studies of ancient biomolecules-particularly ancient DNA, proteins, and lipids-have revolutionized our understanding of evolutionary history. Though initially fraught with many challenges, today the field stands on firm foundations. Researchers now successfully retrieve nucleotide and amino acid sequences, as well as lipid signatures, from progressively older samples, originating from geographic areas and depositional environments that, until recently, were regarded as hostile to long-term preservation of biomolecules. Sampling frequencies and the spatial and temporal scope of studies have also increased markedly, and with them the size and quality of the data sets generated. This progress has been made possible by continuous technical innovations in analytical methods, enhanced criteria for the selection of ancient samples, integrated experimental methods, and advanced computational approaches. Here, we discuss the history and current state of ancient biomolecule research, its applications to evolutionary inference, and future directions for this young and exciting field.

A 2-million-year-old ecosystem in Greenland uncovered by environmental DNA.

Late Pliocene and Early Pleistocene epochs 3.6 to 0.8 million years ago1 had climates resembling those forecasted under future warming2. Palaeoclimatic records show strong polar amplification with mean annual temperatures of 11-19 °C above contemporary values3,4. The biological communities inhabiting the Arctic during this time remain poorly known because fossils are rare5. Here we report an ancient environmental DNA6 (eDNA) record describing the rich plant and animal assemblages of the Kap København Formation in North Greenland, dated to around two million years ago. The record shows an open boreal forest ecosystem with mixed vegetation of poplar, birch and thuja trees, as well as a variety of Arctic and boreal shrubs and herbs, many of which had not previously been detected at the site from macrofossil and pollen records. The DNA record confirms the presence of hare and mitochondrial DNA from animals including mastodons, reindeer, rodents and geese, all ancestral to their present-day and late Pleistocene relatives. The presence of marine species including horseshoe crab and green algae support a warmer climate than today. The reconstructed ecosystem has no modern analogue. The survival of such ancient eDNA probably relates to its binding to mineral surfaces. Our findings open new areas of genetic research, demonstrating that it is possible to track the ecology and evolution of biological communities from two million years ago using ancient eDNA.

Late Quaternary dynamics of Arctic biota from ancient environmental genomics.

During the last glacial-interglacial cycle, Arctic biotas experienced substantial climatic changes, yet the nature, extent and rate of their responses are not fully understood1-8. Here we report a large-scale environmental DNA metagenomic study of ancient plant and mammal communities, analysing 535 permafrost and lake sediment samples from across the Arctic spanning the past 50,000 years. Furthermore, we present 1,541 contemporary plant genome assemblies that were generated as reference sequences. Our study provides several insights into the long-term dynamics of the Arctic biota at the circumpolar and regional scales. Our key findings include: (1) a relatively homogeneous steppe-tundra flora dominated the Arctic during the Last Glacial Maximum, followed by regional divergence of vegetation during the Holocene epoch; (2) certain grazing animals consistently co-occurred in space and time; (3) humans appear to have been a minor factor in driving animal distributions; (4) higher effective precipitation, as well as an increase in the proportion of wetland plants, show negative effects on animal diversity; (5) the persistence of the steppe-tundra vegetation in northern Siberia enabled the late survival of several now-extinct megafauna species, including the woolly mammoth until 3.9 ± 0.2 thousand years ago (ka) and the woolly rhinoceros until 9.8 ± 0.2 ka; and (6) phylogenetic analysis of mammoth environmental DNA reveals a previously unsampled mitochondrial lineage. Our findings highlight the power of ancient environmental metagenomics analyses to advance understanding of population histories and long-term ecological dynamics.

Lactate-lactylation-HSPA6 axis promotes PRRSV replication by impairing IFN-ß production.

Lactate, traditionally considered a metabolic by-product, has recently been identified as a substrate for the induction of lactylation, a newly identified epigenetic modification that plays an important role in the regulation of host gene expression. Our previous study showed that lactate levels were significantly elevated in cells infected with the porcine reproductive and respiratory syndrome virus (PRRSV), an Arterivirus that has devastated the swine industry worldwide for over 30 years. However, the role of elevated lactate in PRRSV infections remains unknown. In this study, we found that lactate was required for optimal PRRSV proliferation, and PRRSV infection increased cellular lactylation in a dose-dependent manner. Using the Cleavage Under Targets and Tagmentation (CUT&Tag) combined with RNA sequencing (RNA-seq) to screen the downstream genes regulated by lactylation in PRRSV-infected cells, we found that PRRSV-induced lactylation activated the expression of heat shock 70 kDa protein 6 (HSPA6). Follow-up experiments showed that HSPA6 is important for PRRSV proliferation by negatively modulating interferon (IFN)-ß induction. Mechanistically, HSPA6 impeded the interaction between TNF-receptor-associated factor 3 (TRAF3) and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε), thereby hindering the production of IFN-ß. Taken together, these results indicate that the activated lactate-lactylation-HSPA6 axis promotes viral growth by impairing IFN-ß induction, providing new therapeutic targets for the prevention and control of PRRSV infection. The results presented here also link lactylation to the virus life cycle, improving our understanding of epigenetic regulation in viral infection.IMPORTANCEAs a newly identified epigenetic modification, lactate-induced lactylation has received attentions because it plays important roles in gene expression and contributes to tumorigenesis and the innate immune response. Previous studies showed that many viruses upregulate cellular lactate levels; however, whether virus-elevated lactate induces lactylation and the subsequent biological significance of the modification to viral infection have not been reported. In this study, we demonstrated that porcine reproductive and respiratory syndrome virus (PRRSV) infection induced cellular lactylation, which, in turn, upregulated the expression of HSPA6, an IFN-negative regulator. We also dissected the mechanism by which HSPA6 negatively regulates IFN-ß production. To our knowledge, this is the first report to study virus-induced lactylation and establish the relationship between lactylation and virus infection.

Acetylation of transcription factor BpTCP20 by acetyltransferase BpPDCE23 modulates salt tolerance in birch.

Teosinte branched 1/Cycloidea/Proliferating cell factor (TCP) transcription factors function in abiotic stress responses. However, how TCPs confer salt tolerance is unclear. Here, we characterized a TCP transcription factor, BpTCP20, that responds to salt stress in birch (Betula platyphylla Suk). Plants overexpressing BpTCP20 displayed increased salt tolerance, and Bptcp20 knockout mutants displayed reduced salt tolerance relative to the wild-type (WT) birch. BpTCP20 conferred salt tolerance by mediating stomatal closure and reducing reactive oxygen species (ROS) accumulation. Chromatin immunoprecipitation sequencing showed that BpTCP20 binds to NeuroD1, T-box, and two unknown elements (termed TBS1 and TBS2) to regulate target genes. In birch, salt stress led to acetylation of BpTCP20 acetylation at lysine 259. A mutated BpTCP20 variant (abolished for acetylation, termed BpTCP20259) was overexpressed in birch, which led to decreased salt tolerance compared with plants overexpressing BpTCP20. However, BpTCP20259-overexpressing plants still displayed increased salt tolerance relative to untransformed WT plants. BpTCP20259 showed reduced binding to the promoters of target genes and decreased target gene activation, leading to decreased salt tolerance. In addition, we identified dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex (BpPDCE23), an acetyltransferase that interacts with and acetylates BpTCP20 to enhance its binding to DNA motifs. Together, these results suggest that BpTCP20 is a transcriptional regulator of salt tolerance, whose activity is modulated by BpPDCE23-mediated acetylation.

Liquid-liquid and gas-liquid dispersions in electrochemistry: concepts, applications and perspectives.

Electrochemistry plays a pivotal role in a vast number of domains spanning from sensing and manufacturing to energy storage, environmental conservation, and healthcare. Electrochemical applications encompassing gaseous or organic substrates encounter shortcomings ascribed to high mass transfer/internal resistances and low solubility in aqueous electrolytes, resulting in high overpotentials. In practice, strong acids and expensive organic electrolytes are required to promote charge transfer in electrochemical cells, resulting in a high carbon footprint. Liquid-liquid (L-L) and gas-liquid (G-L) dispersions involve the dispersion of a nano/micro gas or liquid into a continuous liquid phase such as micelles, (macro)emulsions, microemulsions, and microfoams stabilised by surface-active agents such as surfactants and colloidal particles. These dispersions hold promise in addressing the drawbacks of electrochemical reactions by fostering the interfacial surface area between immiscible reagents and mass transfer of electroactive organic and gas reactants and products from/to the bulk to/from the electrode surface. This tutorial review provides a taxonomy of liquid-liquid and gas-liquid dispersions for applications in electrochemistry, with emphasis on their assets and challenges in industrially relevant reactions for fine chemistry and depollution.

Heterostructured Pt-PbS Nanobelt Achieves Remarkable Direct Formic Acid Oxidation Catalysis.

Developing efficient and CO-tolerant platinum (Pt)-based anodic catalysts is challenging for a direct formic acid fuel cell (DFAFC). Herein, we report heterostructured Pt-lead-sulfur (PtPbS)-based nanomaterials with gradual phase regulation as efficient formic acid oxidation reaction (FAOR) catalysts. The optimized Pt-PbS nanobelts (Pt-PbS NBs/C) display the mass and specific activities of 5.90 A mgPt-1 and 21.4 mA cm-2, 2.2/1.2, 1.5/1.1, and 36.9/79.3 times greater than those of PtPb-PbS NBs/C, Pt-PbSO4 NBs/C, and commercial Pt/C, respectively. Simultaneously, it exhibits a higher membrane electrode assembly (MEA) power density (183.5 mW cm-2) than commercial Pt/C (40.3 mW cm-2). This MEA stably operates at 0.4 V for 25 h, demonstrating a competitive potential of device application. The distinctive heterostructure endows the Pt-PbS NBs/C with optimized dehydrogenation steps and resisting the CO poisoning, thus presenting the remarkable FAOR performance. This work paves an effective avenue for creating high-performance anodic catalysts for fuel cells and beyond.

Unlocking Superior Hydrogen Oxidation and CO Poisoning Resistance on Pt Enabled by Tungsten Nitride-Mediated Electronic Modulation.

Enhancing the activity and CO poisoning resistance of Pt-based catalysts for the anodic hydrogen oxidation reaction (HOR) poses a significant challenge in the development of proton exchange membrane fuel cells. Herein, we leverage theoretical calculations to demonstrate that tungsten nitride (WN) can intricately modulate the electronic structure of Pt. This modulation optimizes the hydrogen adsorption, significantly boosting HOR activity, and simultaneously weakens the CO adsorption, markedly improving resistance to CO poisoning. Through prescreening with rational design, we synthesized an efficient catalyst comprising a minimal Pt content (only 1.4 wt %) supported on the small-sized WN/reduced graphite oxide (Pt@WN/rGO). As anticipated, this catalyst showcases a remarkable acidic HOR mass activity of 3060 A gPt-1, which is approximately 11.8 times greater than that of the commercial 20 wt % Pt/C catalyst. Impressively, it maintains high activity with 98.2% retention even in the presence of 1000 ppm of CO, indicating exceptional poison resistance. Operando synchrotron radiation analyses reveal that WN harmonizes the electron state of Pt during electrochemical reactions, optimizing hydrogen adsorption/desorption dynamics. This leads to a lower peak potential of CO stripping on Pt@WN/rGO compared to that on Pt/rGO, suggesting that WN mitigates competitive CO adsorption and enhances the availability of hydrogen adsorption sites on Pt. The synergistic effect significantly accelerates HOR activity and increases antipoisoning efficacy. The assembled PEMFC demonstrates substantial tolerance to CO concentration from 10 to 1000 ppm in the H2/CO mixture.

An Ultrasmall Ordered High-Entropy Intermetallic with Multiple Active Sites for the Oxygen Reduction Reaction.

Controlling multimetallic ensembles at the atomic level is significantly challenging, particularly for high-entropy alloys with more than five elements. Herein, we report an innovative ultrasmall (∼2 nm) PtFeCoNiCuZn high-entropy intermetallic (PFCNCZ-HEI) with a well-ordered structure synthesized by using the space-confined strategy. By exploiting these combined metals, the PFCNCZ-HEI nanoparticles achieve an ultrahigh mass activity of 2.403 A mgPt-1 at 0.90 V vs reversible hydrogen electrode for the oxygen reduction reaction, which is up to 19-fold higher than that of state-of-the-art commercial Pt/C. A proton exchange membrane fuel cell assembled with PFCNCZ-HEI as the cathode (0.03 mgPt cm-2) exhibits a power density of 1.4 W cm-2 and a high mass-normalized rated power of 45 W mgPt-1. Furthermore, theoretical calculations reveal that the outer electrons of the non-noble-metal atoms on the surface of the PFCNCZ-HEI nanoparticle are modulated to show characteristics of multiple active centers. This work offers a promising catalyst design direction for developing highly ordered HEI nanoparticles for electrocatalysis.

hnRNPA0 promotes MYB expression by interacting with enhancer lncRNA MY34UE-AS in human leukemia cells.

MYB is a key regulator of hematopoiesis and erythropoiesis, and dysregulation of MYB is closely involved in the development of leukemia, however the mechanism of MYB regulation remains still unclear so far. Our previous study identified a long noncoding RNA (lncRNA) derived from the -34 kb enhancer of the MYB locus, which can promote MYB expression, the proliferation and migration of human leukemia cells, and is therefore termed MY34UE-AS. Then the interacting partner proteins of MY34UE-AS were identified and studied in the present study. hnRNPA0 was identified as a binding partner of MY34UE-AS through RNA pulldown assay, which was further validated through RNA immunoprecipitation (RIP). hnRNPA0 interacted with MY34UE-AS mainly through its RRM2 domain. hnRNPA0 overexpression upregulated MYB and increased the proliferation and migration of K562 cells, whereas hnRNPA0 knockdown showed opposite effects. Rescue experiments showed MY34UE-AS was required for above mentioned functions of hnRNPA0. These results reveal that hnRNPA0 is involved in leukemia through upregulating MYB expression by interacting with MY34UE-AS, suggesting that the hnRNPA0/MY34UE-AS axis could serve as a potential target for leukemia treatment.

Crystallography, Charge Transfer, and Two-Photon Absorption Relations in Molecular Cocrystals for Two-Photon Excited Fluorescence Imaging.

Two-photon excited fluorescence imaging requires high-performance two-photon absorption (TPA) active materials, which are commonly intramolecular charge transfer systems prepared by traditional chemical synthesis. However, this typically needs harsh conditions and new methods are becoming crucial. In this work, based on a collaborative intermolecular charge transfer (inter-CT) strategy, three centimeter-sized organic TPA cocrystals are successfully obtained. All three cocrystals exhibit a mixed stacking arrangement, which can effectively generate inter-CT between the donor and acceptor. The ground and excited state characterizations compare their inter-CT ability: 1,2-BTC > 2D-BTC > 1D-BTC. Transient absorption spectroscopy detects TCNB•-, indicating that the TPA mechanism arises from molecular polarization caused by inter-CT. Meanwhile, 1,2-BTC exhibits the highest excited-state absorption and the longest excited-state lifetime, suggesting a stronger TPA response. First-principles calculations also confirm the presence of inter-CT interactions, and the significant parameter Δµ which can assess the TPA capability indicates that inter-CT enhances the TPA response. Besides, cocrystals also demonstrate excellent water solubility and two-photon excited fluorescence imaging capabilities. This research not only provides an effective method for synthesizing TPA crystal materials and elucidates the connection between inter-CT ability and TPA property but also successfully applies them in the fields of multi-photon fluorescence bioimaging.

The Nonvolatile Memory and Neuromorphic Simulation of ReS2/h-BN/Graphene Floating Gate Devices Under Photoelectrical Hybrid Modulations.

The floating gate devices, as a kind of nonvolatile memory, obtain great application potential in logic-in-memory chips. The 2D materials have been greatly studied due to atomically flat surfaces, higher carrier mobility, and excellent photoelectrical response. The 2D ReS2 flake is an excellent candidate for channel materials due to thickness-independent direct bandgap and outstanding optoelectronic response. In this paper, the floating gate devices are prepared with the ReS2/h-BN/Gr heterojunction. It obtains superior nonvolatile electrical memory characteristics, including a higher memory window ratio (81.82%), tiny writing/erasing voltage (±8 V/2 ms), long retention (>1000 s), and stable endurance (>1000 times) as well as multiple memory states. Meanwhile, electrical writing and optical erasing are achieved by applying electrical and optical pulses, and multilevel storage can easily be achieved by regulating light pulse parameters. Finally, due to the ideal long-time potentiation/depression synaptic weights regulated by light pulses and electrical pulses, the convolutional neural network (CNN) constructed by ReS2/h-BN/Gr floating gate devices can achieve image recognition with an accuracy of up to 98.15% for MNIST dataset and 91.24% for Fashion-MNIST dataset. The research work adds a powerful option for 2D materials floating gate devices to apply to logic-in-memory chips and neuromorphic computing.

Decrypting biocontrol functions and application modes by genomes data of three Trichoderma Strains/Species.

Trichoderma is an excellent biocontrol agent, but most Trichoderma genomes remained at the scaffold level, which greatly limits the research of biocontrol mechanism. Here, we reported the chromosome-level genome of Trichoderma harzianum CGMCC20739 (Tha739), T. asperellum CGMCC11653 (Tas653) and T. atroviride CGMCC40488 (Tat488), they were assembled into 7 chromosomes, genome size were 40 Mb (10,611 genes), 37.3 Mb (10,102 genes) and 36.3 Mb (9,896 genes), respectively. The positive selected genes of three strains were associated to response to stimulus, signaling transduction, immune system and localization. Furthermore, the number of transcription factors in Tha739, Tas653 and Tat488 strains had significant difference, which may contribute to the differential biocontrol function and stress tolerance. The genes related to signal transduction and gene clusters related to antimicrobial compounds in Tha739 were more than those in Tas653 and Tat488, which showed Tha739 may keenly sense other fungi and quickly secret antimicrobial compounds to inhibit other fungi. Tha739 also contained more genes associated to detoxification, antioxidant and nutrition utilization, indicating it had higher stress-tolerance to hostile environments. And the substrate for synthesizing IAA in Tha739 was mainly 3-indole acetonitrile and indole acetaldehyde, but in Tat488, it was indole-3-acetamide, moreover, Tha739 secreted more phosphatase and phytase and was more related to soil phosphorus metabolism, Tat488 secreted more urease and was more related to soil nitrogen metabolism. These candidate genes related to biocontrol function and stress-tolerance laid foundations for construction of functional strains. All above proved the difference in biocontrol function of Tha739, Tas653 and Tat488 strains, however, the defects in individual strains could be compensated for through Trichoderma-biome during the commercial application process of biocontrol Trichoderma strains.

Long noncoding RNA from Betula platyphylla, BplncSIR1, confers salt tolerance by regulating BpNAC2 to mediate reactive oxygen species scavenging and stomatal movement.

Long noncoding RNAs (lncRNAs) play an important role in abiotic stress tolerance. However, their function in conferring abiotic stress tolerance is still unclear. Herein, we characterized the function of a salt-responsive nuclear lncRNA (BplncSIR1) from Betula platyphylla (birch). Birch plants overexpressing and knocking out for BplncSIR1 were generated. BplncSIR1 was found to improve salt tolerance by inducing antioxidant activity and stomatal closure, and also accelerate plant growth. Chromatin isolation by RNA purification (ChIRP) combined with RNA sequencing indicated that BplncSIR1 binds to the promoter of BpNAC2 (encoding NAC domain-containing protein 2) to activate its expression. Plants overexpressing and knocking out for BpNAC2 were generated. Consistent with that of BplncSIR1, overexpression of BpNAC2 also accelerated plant growth and conferred salt tolerance. In addition, BpNAC2 binds to different cis-acting elements, such as G-box and 'CCAAT' sequences, to regulate the genes involved in salt tolerance, resulting in reduced ROS accumulation and decreased water loss rate by stomatal closure. Taken together, BplncSIR1 serves as the regulator of BpNAC2 to induce its expression in response to salt stress, and activated BpNAC2 accelerates plant growth and improves salt tolerance. Therefore, BplncSIR1 might be a candidate gene for molecular breeding to cultivate plants with both a high growth rate and improved salt tolerance.

The BpPP2C-BpMADS11-BpERF61 signaling confers drought tolerance in Betula platyphylla.

Plant MADS-box proteins are vital for abiotic stress tolerance, yet their mechanisms for responding to drought remain poorly understood. Here, we investigated the drought tolerance mechanism of a MADS-box protein (BpMADS11) from birch (Betula platyphylla) using immunoprecipitation, Western blotting, yeast two-hybrid, yeast one-hybrid, ChIP, RNA-seq, and dual-luciferase assays to explore post-translational modifications, protein interactions, and gene regulation. Birch plants overexpressing BpMADS11 exhibited enhanced drought tolerance, while knockout lines displayed reduced tolerance. Under drought conditions, BpMADS11 interacts with protein phosphatase 2C22 (BpPP2C22), which dephosphorylates BpMADS11. Birch plants that overexpress BpMADS11 and lack BpPP2C22 show significantly reduced drought tolerance compared with those that only overexpress BpMADS11. BpMADS11 regulates the expression of BpERF61 by binding to CArG-box in its promoter. The dephosphorylated BpMADS11 exhibits increased DNA binding ability and increased expression of BpERF61. Like BpMADS11, birch plants overexpressing BpERF61 show improved drought tolerance, while those with BpERF61 knockout exhibit decreased tolerance. BpERF61 binds to specific DNA motifs including 'CACGTG' (G-box), 'GGGCCCC', and 'TTGGAT' to regulate the genes related to drought stress. Collectively, BpMADS11 undergoes dephosphorylation through its interaction with BpPP2C22, prompting the expression of BpERF61. Subsequently, BpERF61 regulates downstream genes by binding to specific DNA motifs, thereby enhancing drought tolerance.

A reverse chromatin immunoprecipitation technique based on the CRISPR-dCas9 system.

DNA-protein interaction is one of the most crucial interactions in biological processes. However, the technologies available to study DNA-protein interactions are all based on DNA hybridization; however, DNA hybridization is not highly specific and is relatively low in efficiency. RNA-guided DNA recognition is highly specific and efficient. To overcome the limitations of technologies based on DNA hybridization, we built a DNA-binding protein capture technology based on the clustered regularly interspaced palindromic repeats (CRISPR)-dead Cas9 (dCas9) system and transient genetic transformation, termed reverse chromatin immunoprecipitation based on CRISPR-dCas9 system (R-ChIP-dCas9). In this system, dCas9 was fused with Strep-Tag II to form a fusion protein for StrepTactin affinity purification. Transient transformation was performed for the expression of dCas9 and guide RNA (gRNA) to form the dCas9-gRNA complex in birch (Betula platyphylla) plants, which binds to the target genomic DNA region. The dCas9-gRNA-DNA complex was crosslinked, then the chromatin was sonicated into fragments, and purified using StrepTactin beads. The proteins binding to the target genomic DNA region were identified using mass spectrometry. Using this method, we determined the upstream regulators of a NAM, ATAF, and CUC (NAC) transcription factor (TF), BpNAC090, and 32 TFs potentially regulating BpNAC090 were identified. The reliability of R-ChIP-dCas9 was further confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assays, and yeast one-hybrid. This technology can be adapted to various plant species and does not depend on the availability of a stable transformation system; therefore, it has wide application in identifying proteins bound to genomic DNA.

Dissipation-Induced Extended-Localized Transition.

A mobility edge (ME), representing the critical energy that distinguishes between extended and localized states, is a key concept in understanding the transition between extended (metallic) and localized (insulating) states in disordered and quasiperiodic systems. Here we explore the impact of dissipation on a quasiperiodic system featuring MEs by calculating steady-state density matrix and analyzing quench dynamics with sudden introduction of dissipation. We demonstrate that dissipation can lead the system into specific states predominantly characterized by either extended or localized states, irrespective of the initial state. Our results establish the use of dissipation as a new avenue for inducing transitions between extended and localized states and for manipulating dynamic behaviors of particles.

Urinary C4d and progression of kidney disease in IgA vasculitis.

BACKGROUND: Immunoglobulin A (IgA) vasculitis nephritis (IgAVN) is the most common secondary IgA nephropathy (IgAN). Urinary C4d have been identified associated with the development and progression in primary IgAN; however, its role in kidney disease progression of IgAVN is still unclear. METHODS: This study enrolled 139 patients with IgAVN, 18 healthy subjects, 23 focal segmental glomerulosclerosis patients and 38 IgAN patients. Urinary C4d levels at kidney biopsy were measured using enzyme-linked immunosorbent assay. The association between urinary C4d/creatinine and kidney disease progression event, defined as 40% estimated glomerular filtration rate decline or end-stage kidney disease, was assessed using Cox proportional hazards models and restricted cubic splines. RESULTS: The levels of urinary C4d/creatinine (Cr) in IgAVN and IgAN patients were higher than in healthy controls. Higher levels of urinary C4d/Cr were associated with higher proteinuria and severe Oxford C lesions, and glomerular C4d deposition. After a median follow-up of 52.79 months, 18 (12.95%) participants reached composite kidney disease progression event. The risk of kidney disease progression event was higher with higher levels of Ln(urinary C4d/Cr). After adjustment for clinical data, higher levels of urinary C4d/Cr were associated with kidney disease progression in IgAVN [per Ln-transformed urinary C4d/Cr, hazard ratio 1.573, 95% confidence interval (CI) 1.101-2.245; P = .013]. Compared with the lower C4d/Cr group, the hazard ratio was 5.539 (95% CI 1.135-27.035; P = .034) for the higher levels group. CONCLUSIONS: Higher levels of urinary C4d/Cr were associated with kidney disease progression event in patients with IgAVN.

Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants.

A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.

Selection of antioxidants for capacitor grade polypropylene film: Insights into electrical performance of the oil-film system.

High voltage power capacitors employ the oil-impregnated polypropylene film as the insulation. The swelling phenomenon might drive the antioxidants and small molecules within the film to migrate into the oil. It is necessary to comprehensively investigate the physical migration mechanism of antioxidants and their impact on the electrical performance of the oil-film combination insulation system and, consequently, formulate the proper selective prescription of antioxidants. Theoretical elucidation of the competitive interaction mechanism between the film and the oil in attracting antioxidant molecules was achieved through the calculation of inter-molecular binding energy, and the migration coefficient ηm was introduced to quantify the migration characteristics of antioxidants. Experimentally, the effects of antioxidants on the space charge distribution of the film, the dielectric properties of the oil, and the breakdown characteristics of both the film and oil were investigated. The experimental conclusions are consistent with theoretical analysis. The lamellar structure antioxidant molecules with ηm > 1 tend to migrate from the film to the oil, which results in increased dielectric loss and decreased breakdown strength of the insulating oil. In addition, the presence of phosphorus atoms in phosphite antioxidants contributes to a reduction in the breakdown strength of the film. For capacitor grade polypropylene film, in addition to the synergistic effect between different types of antioxidants on the thermo-oxidative stability, the structure of the antioxidant molecules and its influence on the electrical performance of the oil-film systems should also be taken into account.