Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis.

BACKGROUND: Malaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive. METHODS: We first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays. RESULTS: The results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-α were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects. CONCLUSIONS: In conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel. Video Abstract.

A study on siting of emergency shelters for dam failure floods considering population distribution and weather effects.

In recent years, dam failures have occurred frequently because of extreme weather, posing a significant threat to downstream residents. The establishment of emergency shelters is crucial for reducing casualties. The selection of suitable shelters depends on key information such as the number and distribution of affected people, and the effective capacity and accessibility of the shelters. However, previous studies on siting shelters did not fully consider population distribution differences at a finer scale. This limitation hinders the accuracy of estimating the number of affected people. In addition, most studies ignored the impact of extreme rainfall on the effective capacity and accessibility of shelters, leading to a low applicability of the shelter selection results. Therefore, in this study, land-use and land-cover change (LUCC) and nighttime lighting data were used to simulate population distribution and determine the number and distribution of affected people. Qualified candidate shelters were obtained based on screening criteria, and their effective capacity and accessibility information under different weather conditions were quantified. Considering factors such as population transfer efficiency, construction cost and shelter capacity constraints, a multi-objective siting model was established and solved using the non-dominated sorting genetic algorithm II (NSGA- II) to obtain the final siting scheme. The method was applied to the Dafangying Reservoir, and the results showed the following: (1) The overall mean relative error (MRE) of the population in the 35 downstream streets was 11.16 %, with good fitting accuracy. The simulation results truly reflect the population distribution. (2) Normal weather screening generated 352 qualified candidate shelters, whereas extreme rainfall weather screening generated 266 candidate shelters. (3) Based on the population distribution and weather factors, four scenarios were set up, with 63, 106, 73, and 131 shelters selected. These two factors have a significant impact on the selection of shelters and the allocation of evacuees, and should be considered in the event of a dam-failure floods.

Identification of a Novel Mutation of Extracellular Matrix Protein 1 Gene in a Chinese Family with Lipoid Proteinosis.

Lipoid proteinosis (LP) is a rare autosomal recessive disorder caused by mutations in extracellular matrix protein 1 (ECM1), a glycoprotein expressed in skin. Whole-exome sequencing (WES) was used to investigate two Chinese siblings with suggestive clinical features of LP. They shared one known (c.960G>A) and one novel (c.1081G>T) pathogenic variant in ECM1 gene, inherited from their unaffected parents. The novel mutation (c.1081G>T) led to a termination codon at position 361 and caused nonsense-mediated mRNA decay and lost the function. Our finding expands the genetic etiology spectrum of LP.

Multi-omics dissection of stage-specific artemisinin tolerance mechanisms in Kelch13-mutant Plasmodium falciparum.

AIMS: We investigated the stage-specific mechanisms of partial resistance to artemisinin (ART, an antimalarial drug) in Plasmodium falciparum (P. falciparum) carrying the Kelch13 C580Y mutation. METHODS: Using fluorescence labeling and activity-based protein profiling, we systematically profile the ART activation levels in P. falciparum during the entire intra-erythrocytic developmental cycle (IDC), and determined the ART-targets profile of the ART-sensitive and -resistant strains at different stages. We retrieved and integrated datasets of single-cell transcriptomics and label-free proteomics across three IDC stages of wild-type P. falciparum. We also employed lipidomics to validate lipid metabolic reprogramming in the resistant strain. RESULTS: The activation and expression patterns of genes and proteins of ART-targets in both ART-sensitive and resistant strains varied at different stages and periods of P. falciparum development, with the late trophozoite stage harboring the largest number of ART targets. We identified and validated 36 overlapping targets, such as GAPDH, EGF-1a, and SpdSyn, during the IDC stages in both strains. We revealed the ART-insensitivity of fatty acid-associated activities in the partially resistant strain at both the early ring and early trophozoite stages. CONCLUSIONS: Our multi-omics strategies provide novel insights into the mechanisms of ART partial resistance in Kelch13 mutant P. falciparum, demonstrating the stage-specific interaction between ART and malaria parasites.

Association of Interleukin-6 Polymorphisms with Schizophrenia and Depression: A Case-Control Study.

OBJECTIVE: Growing evidence suggests a crossover in genetic susceptibility to schizophrenia and depression. We aimed to investigate the association of the rs1800795 and rs1800796 polymorphisms of the IL-6 gene with schizophrenia and depression in the Han Chinese population, combined with IL-6 serum levels. METHODS: Gene sequencing and enzyme-linked immunosorbent assay were performed on 113 subjects with schizophrenia, 114 subjects with depression, and 110 healthy controls. RESULTS: Our findings showed that IL-6 concentrations in schizophrenia and depression groups were significantly higher than in the control group. The rs1800796 CC genotype and C allele were significantly associated with depression (P = .012 and P < .05, respectively). The rs1800796 CC and CG genotype was significantly associated with chronic schizophrenia (P = .020 and P = .009, respectively). Regarding the rs1800795 polymorphism, only one case of CG genotype was detected. The remainder were of the GG genotype. CONCLUSION: The IL-6 rs1800796 might serve as a protective factor for depression and schizophrenia in the Han Chinese population.

Evaluation of the water pollution risk of dam and dike-break floods in the inundated area.

The inundated area of dam and dike-break floods includes various types of land and factories that release considerable amounts of pollutants into floods, causing serious water pollution and further endangering human health. Many pollution sources and factors affect the water pollution risk in inundated areas. Accurate assessment of the water pollution risk for dam and dike-break floods enables people to take measures in advance to reduce public health problems. The existing evaluation methods cannot effectively analyze the water pollution risk for dam and dike-break floods because partial or all pollution sources and influencing factors are ignored. The main factors affecting flood water quality were summarized into point source (PS), non-point source (NPS), flood depth, velocity, duration, and temperature. The water pollution risk caused by NPSs and PSs were quantified, as well as the impact of all main factors on water pollution risk. The evaluation model proposed for water pollution risk in inundated areas of dam and dike-break floods considers all pollution sources and influencing factors. The WPR was proposed to represent the water pollution risk value. The dam-break flood of Luhun Reservoir was simulated to verify the feasibility of the evaluation model. We concluded that (1) WPR varied with space and time in the inundated area and was seriously affected by PS in local areas; (2) the annual average WPR of different land use types from high to low were construction land, cropland, urban, water, rural area, woodland, and grassland. The evaluation model can be used to evaluate the water pollution risk for dam and dike-break floods at macro and micro scales. People can use this method to evaluate the impact, range, and degree of specific pollution sources or pollutants in the inundated area, thus allowing for measures to be taken in advance to reduce associated damages.

Environmental impact assessment of dam-break floods considering multiple influencing factors.

Dam-break floods cause substantial damage to the environment, and evaluating the negative impacts of dam-break floods on the environment (EI) is an important part of flood risk management. EI has been evaluated using various methods with different indices. However, the evaluation results of EI are typically one-sided or inaccurate because of diverse indices and complex influencing factors. A new method was proposed herein to calculate EI with an index system, including geomorphic changes (GC), water pollution (WP), plant biomass loss (PB), and biodiversity loss (BL). Eight factors that influence EI were sorted out, namely, erosion or deposition depth, non-point source (NPS) and point source (PS) pollution, plant biomass, species richness, plant height, and flood depth, velocity, and duration. After combining the proposed damage functions to calculate the influence of flood depth, velocity, and duration, and plant height on the environment, methods to calculate GC, WP, PB, BL, and EI were proposed. A dam-break flood scenario for Luhun Reservoir was used to verify the method. The results showed that (1) the trend in EI was similar to that in geomorphic changes in the inundated area and seriously affected by PS in local areas, (2) the average EI of woodland was the highest, while that of towns was the slowest, and (3) GC and WP contributed 93.7% of EI in the entire inundated area. This study summarized the complex impacts of dam-break floods on the environment from four aspects and proposed a method to quantify the overall impact of dam-break floods on the environment. The evaluation model could evaluate the impact of floods on the environment accurately, presenting the results on a flood inundation map. This provides a scientific basis for evaluating flood consequences and managing flood risk.

A preliminary study of aeolian sand-cement-modified gasification slag-paste backfill: Fluidity, microstructure, and leaching risks.

To realize low-cost green backfill mining, this paper proposes a novel model of aeolian sand-cement-modified gasification slag-paste backfill (ACGPB). This model realizes the safe disposal and resource utilization of hazardous solid wastes. A comprehensive experiment (including slump test, uniaxial compressive strength tests, microscopic test, and leaching toxicity tests) was conducted to explore how the mechanism of ACGPB depends on activator type and dosage. The results showed that fresh ACGPB slurry can be expressed by the Herschel-Bulkley model (R2 ≥ 0.965 in all recipes). With Na2SO4 as activator type, the yield stress, apparent viscosity, thixotropy, and slump of ACGPB slurry increased with increasing activator dosage. With CaO as activator type, the yield stress, apparent viscosity, thixotropy, and slump of ACGPB slurry fluctuated with increasing activator dosage. The mechanical properties of all recipes (not including Control group and C-C1) met the mechanical requirement (3 d ≥ 0.5 MPa and 28 d ≥ 1.0 MPa). In addition, the concentrations of all heavy metals remained within the range specified by the national standard. Specifically, the activator exerted a positive effect on the stabilization/solidification of heavy metal ions (Cu, Cd, Ba, Ni, Cr, Se, and As). Finally, FTIR, TG-DTG, SEM, and hydration heat were used to analyze the microstructure of ACGPB. The research results provide a creative way for the resource utilization of solid waste.

Developing a reclamation strategy for softening nanofiltration brine: A scaling-free conversion approach via continuous two-stage electrodialysis metathesis.

A significant amount of concentrated, scaling-prone brine can be generated during the conversion of unconventional water resources to freshwater, thus necessitating the zero discharge of concentrated brine to meet environmental and resource requirements. In this study, a two-stage feed-and-bleed electrodialysis metathesis (FB-EDM) process was implemented to reclaim softening nanofiltration (SNF) brine. To determine the optimized process parameters, experiments were conducted with various initial diluate to concentrate volume ratios (VD:VC), applied voltages, replenishment flow rates (Qrp), and initial diluate compartment concentration ratios (CD1:CD2). The results indicated that these parameters (except for the initial volume ratio) significantly influenced the FB-EDM process. The optimized conditions included a VD:VC of 2:1, voltage of 1.5 V per repeating unit, Qrp of 4 L/h, and CD1:CD2 of 1.5:1. The two-stage FB-EDM process operating under the optimized conditions achieved an energy consumption of <0.9 kWh/kg salt, and the total dissolved solids (TDS) in terms of Cl-type and Na-type salts reached 199.1 and 224.4 g/L, respectively; the corresponding overflow rates were 1.17 and 1.14 L/h, respectively. The developed system thus demonstrated approximately 85% TDS removal and ionic conversion of the brine; additionally, the self-crystallization of CaSO4·2H2O was realized by blending the Cl-type and Na-type salts. This process therefore represents a suitable method for converting SNF brine into highly-concentrated liquid salts, and provides a reclamation strategy for miscellaneous salts.

Sustainable disposal of seawater brine by novel hybrid electrodialysis system: Fine utilization of mixed salts.

Sustainable seawater brine treatment demands an essential paradigm shift for effective recovery of resources and high value utilization of mixed-salts. Here, a novel hybrid electrodialysis (ED) system was proposed that integrated an innovative hybrid selective ED (HSED) and a developed selective bipolar membrane ED (SBMED). The HSED process allowed simultaneous recovery of major divalent cations and anions from seawater brine when NaCl was selectively enriched. Then, the impure NaCl-rich stream was fed directly into the SBMED process for acid/base preparation without any purification pretreatment. Detailed analysis of the HSED process showed that increasing unit voltage from 2.33 V to 2.67 V would improve the removal ratio of Ca2+, Mg2+ and SO42- from 54.7%, 41.4% and 13.3% to 78.9%, 76.6% and 32.1%, respectively. In addition, the increment of initial concentration of product streams promoted the transport of various ions from the feed and middle compartments. The fine utilization performance, in terms of ionic removal ratio and fractionation ratio of divalent ions in the HSED process, was more limited by the initial concentration of product streams. Furthermore, the SBMED stack was found to have nearly identical performance over five cycles, indicating that the presence of a trace amount of hardness cations did not induce scaling. The current study thus provided a novel suitable strategy with a perspective of fine utilization for practical applications in sustainable disposal of seawater brine.

Impact evaluation of geomorphic changes caused by extreme floods on inundation area considering geomorphic variations and land use types.

Extreme floods caused by dam breaches, dike breaches, and rainstorms cause significant erosion and deposition in the flooded area. Furthermore, geomorphic changes have various impacts on different land use types, which is an important aspect extreme flood outcomes. The impact type and degree depend on geomorphic variations and land characteristics. However, neither the amount of geomorphic variations nor its impact on the inundation area have been fully understood. Firstly, we propose the use of a numerical simulation method to calculate erosion and deposition depths of the whole inundation area caused by extreme floods. Secondly, combined with the characteristics of erosion, deposition, and land use types, the impact type of geomorphic changes on different land use types were divided into positive, negative, and negligible impacts, and the impact degree was expressed by two indices of impact grade and impact score. In addition, the calculation methods of the two indices were put forward. Then, we propose a method for evaluating the impacts of geomorphic changes on the whole inundation area from five aspects of mesh, land use type, overall erosion region, overall deposition region, and overall inundation area. Combined with the simulation of the flood process caused by dam breach of Luhun Reservoir in China, this method was verified, and the results showed that: (a) geomorphic changes had a negative impact on 94.7% of the inundation area, and only part of the water bodies were positively affected and the towns were not affected, accounting for 2.1% and 3.2% respectively; (b) the negative impact degree of each land use type in descending order was grassland, town, cropland, forest, shrubland and water body; and (c) the area of deposition was larger than that of erosion, whereas the severity of negative impact was opposite.

Electrodialysis with porous membrane for bioproduct separation: Technology, features, and progress.

Electrodialysis with porous membrane (EDPM) is a recently developed membrane separation process, in which one or more porous filtration membranes stacked in an electrodialysis cell. It is a promising technology for separation, purification or concentration of bioactive components for it associates the excellent properties of electrodialysis (ED), porous filtration membrane, and electrophoresis. There are a number of studies having attempted to optimize the performance of EDPM processing, however, it still has some limitations involving low productivity with one pair of separation unit, membrane fouling and few applications on the fractionation of components with high molecular weight. This paper offers a comprehensive overview of recent studies devoted to EDPM, including principles, configurations, mathematical model regarding mass transfer, process performance optimization, membrane fouling and applications in as much detail as possible. In addition, a collection of other separation technologies based on electrophoresis at a preparative scale are presented to illustrate their limitations on the large-scale application. Some drawbacks of EDPM have been put forward. To achieve full scale applications of EDPM, there are still many issues to overcome. Finally, an outlook for prospective development of EDPM technology is given.

Research on the Mechanical Properties of Recycled Aggregate Concrete under Uniaxial Compression Based on the Statistical Damage Model.

In this paper, uniaxial compression tests were carried out for recycled aggregate concrete with water cement ratios of 0.38, 0.49, and 0.66 and replacement ratios of 0%, 25%, 50%, 75%, and 100%, respectively. The influence of the replacement ratio of recycled aggregate and water cement ratio on the strength, elastic modulus, and deformation characteristics of concrete was discussed. The results show that the replacement rate of recycled aggregate has a significant effect on the macro stress-strain behavior of concrete. In the case of a constant water cement ratio, the peak nominal stress first decreases and then increases with the increase of the replacement rate; while the water cement ratios equal 0.38, 0.49, and 0.66, the corresponding transition states are 25%, 50%, and 50% of the replacement rate, respectively. The deformation and failure is characterized by two stages: distributed damage and local failure. Combined with the statistical damage mechanics, the influence of the aggregate replacement rate on the damage evolution mechanism of recycled concrete on a mesoscopic scale was explored. Two mesoscopic damage modes, fracture and yield, are considered. Their cumulative evolutions are assumed to follow triangular probability distributions, which could be characterized by four parameters. The peak nominal stress state and the critical state are distinguished, and the latter is defined as a precursor to local failure. With the increase of the replacement rate of recycled aggregate, the inhomogeneous evolution of mesoscopic damage shows obvious regular change, which is consistent with the internal chemical and physical mechanism and macro nonlinear stress-strain behavior.

Novel energy-efficient electrodialysis system for continuous brackish water desalination: Innovative stack configurations and optimal inflow modes.

Electrodialysis (ED) is a well-established brackish water (BW) desalination technology that has been commercially applied for decades. However, the energy efficiency of BWED cannot approach optimization because of the low salt concentration of BW. In this study, a novel two hydraulic-stage ED desalination system was presented to enhance mass transfer and reduce energy consumption. In terms of energy-efficient strategies, it involved not only innovative membrane stack configurations (resin-filled electrode cells and asymmetric cell pairs design) but also optimizing inflow modes (electrolytes parallel flow and dilute/concentrate counter flow). Results showed that thin resin-filled (1 mm) electrode cells, asymmetric cell pair design (cell pairs ratio of 1st and 2nd-hydraulic stages, 1.2), and optimizations of general inflow mode were beneficial for savings 10-30% of energy consumption at the same salt removal ratio (SR). The synergistic effects of these strategies indicated that this novel ED system could save ∼40% of the energy consumption at the same SR, compared with conventional two hydraulic-stage ED system (CED). Three stage continuous BWED performance tests, compared with a CED, showed that a 36.9% total energy saving could be achieved using the novel ED system when the BW concentration decreased from 3500 mg/L to the quality requirement of drinking water (∼450 mg/L). It was therefore possible to open the way for saving energy in BWED systems.

Identification of a Novel SBP1-Containing SCFSFB Complex in Wild Dwarf Almond (Prunus tenella).

S-RNase-based gametophytic self-incompatibility (SI), in which specificities of pistil and pollen are determined by S-RNase and the S locus F-box protein, respectively, has been discovered in the Solanaceae, Plantaginaceae, and Rosaceae families, but some underlying molecular mechanisms remain elusive and controversial. Previous studies discovered SI in wild dwarf almond (Prunus tenella), and pistil S (S-RNase) and pollen S (SFB) determinant genes have been investigated. However, the SCF (SKP1-Cullin1-F-box-Rbx1) complex, which serves as an E3 ubiquitin ligase on non-self S-RNase, has not been investigated. In the current study, PetSSK1 (SLF-interacting-SKP1-like1), SBP1 (S-RNase binding protein 1), CUL1, and SFB genes (S-haplotype-specific F-box) were identified in an accession (ZB1) of P. tenella. Yeast two-hybrid assays revealed interactions between PetSBP1 and PetCUL1 and between PetSBP1 and PetSFBs (SFB16 and SFB17), and subsequent pull-down assays confirmed these interactions, suggesting a novel SBP1-containing SCFSFB complex in wild dwarf almond. Moreover, despite a putative interaction between PetSSK1 and PetCUL1, we revealed that PetSSK1 does not interact with PetSFB16 or PetSFB17, and thus the canonical SSK1-containing SCFSFB complex could not be identified. This suggests a novel molecular mechanism of gametophytic SI in Prunus species.

A missense variant of the ABCC11 gene is associated with Axillary Osmidrosis susceptibility and clinical phenotypes in the Chinese Han Population.

Axillary osmidrosis (AO) is a common condition characterized by an offensive odor arising from apocrine gland secretions in the axillae that socially and psychologically impairs affected individuals. The exact aetiology of AO is still not fully understood, but genetic factors have been suggested to play an important role. Recently, a single nucleotide polymorphism (SNP) rs17822931 in the ABCC11 gene located on human chromosome 16q12.1 has been shown to be associated with AO. In this study, we genotyped rs17822931 in two independent samples of Chinese Hans including 93 AO individuals vs 95 controls and 81 AO individuals vs 106 controls by using SNaPshot Multiplex Kit. We confirmed the association for ABCC11 gene, showing that rs17822931-G was significantly associated with increased risk for AO (Pcombined = 1.42E-21, OR = 83.94, 95% CI = 83.03-84.85). We also found rs17822931 was associated with subphenotypes of AO. AO individuals carrying the risk allele G are more likely to show wet earwax (P = 2.40E-05), higher frequency of family history (P = 1.04E-02) and early age of onset (P = 3.81E-02). Our study concluded that the association of rs17822931 in the ABCC11 gene with AO was replicated in Chinese Han population.

Multiple facial basal cell carcinomas in xeroderma pigmentosum treated with topical imiquimod 5% cream.

Xeroderma pigmentosum (XP) is an autosomal recessive disease characterized by solar sensitivity, photophobia, early onset of freckling, and solar-induced cutaneous neoplastic changes. Management of patients with XP is a therapeutic challenge as they usually develop multiple cutaneous malignancies, making surgical therapy difficult, and continue to form skin malignancies at a high rate. We describe a 30-year-old Chinese man with XP who had been previously treated with excision and dermatoplasty. Upon recurrence of multiple superficial, ulcerative, and pigmented lesions, imiquimod 5% cream was recommended for 4 months. His multiple facial lesions demonstrated an excellent response to topical imiquimod 5% cream with minor side effects. This favorable response indicates that topical application of imiquimod 5% cream is an effective means of treating multiple basal cell carcinomas in XP.