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This study intends to explore the extraction process, physical and chemical properties, antioxidant and hypoglycemic activities of polysaccharides from wild bitter melon (WBM). Using the peel of fresh WBM fruit as raw material, based on the single factor experimental results, the liquid-to-material ratio, ultrasonic time and ultrasonic power in the ultrasound-assisted extraction (UAE) process were optimized by Box-Behnken response surface. Two polysaccharide components of WBP50 and WBP75 were obtained through UAE of the optimal conditions and gradient alcohol precipitation, and their physical and chemical properties, in vitro antioxidant and hypoglycemic abilities were evaluated. The results showed that: under the conditions of liquid-to-material ratio of 16 mL/g, ultrasonic time of 16 min, and ultrasonic power of 312 W, the actual yield of crude WBM polysaccharide (WBP) was 8.33%±0.13%. The total sugar, protein, total phenols, total flavonoids, and uronic acid contents of WBP50 and WBP75 were 76.73%/73.38%, 4.78%/0.35%, 0.36%/0.25%, 2.06%/0.86% and 72.85%/49.58%, respectively. The average molecular weights were 27.59 kDa and 23.20 kDa, respectively. WBPs were mainly composed of galacturonic acid, galactose, rhamnose, arabinose, and glucose. The DPPH, ABTS+ and hydroxyl radicals scavenging abilities of WBP50 and WBP75 were 11.28/11.40 μg Trolox/mg, 40.87/44.42 μg Trolox/mg, and 52.47/99.89 U/mg, respectively. Regarding hypoglycemic ability, both WBPs had certain α-amylase inhibitory ability and strong α-glucosidase inhibitory ability. The α-glucosidase inhibition rate of WBP50 and WBP75 reached 93.34%±1.11% and 79.04%±0.76% at a concentration of 750 μg/mL. The UAE of WBP has the advantages of time saving, convenience, high efficiency and low energy consumption, and the extracted WBPs have natural antioxidant and hypoglycemic functional activities. This study lays the foundation for future structural analysis and functional mechanism research of WBPs and provides theoretical references for developing hypoglycemic products and high-value utilization of WBPs.

The degradation behavior of biodegradable Mg alloys has become a research hotspot in the fields about biodegradable metallic materials. While the most of the related publications mainly focused on the degradation rate of Mg-based materials, but rare to care about the changes of their mechanical properties during the immersion period, which can significantly affect their service performance. The link between residual strength and Mg degradation is not appreciated enough. In this work, a series media were constructed based on Hanks’ solution, the effects of inorganic ions on the degradation rate and mechanical integrity of Mg-Zn-Y-Nd alloy were investigated. The results indicated that the degradation behavior of Mg alloy was mainly controlled by degradation products and there is no direct correspondence between the degradation rate change and mechanical integrity of Mg alloy. The relevant findings are beneficial for selecting the monitoring index in Mg corrosion tests and evaluating the service reliability of Mg alloys for biomedical applications.

Abstract Synthetic biology applications require finely tuned gene expression, often mediated by synthetic transcription factors (sTFs) compatible with the human genome and transcriptional regulation mechanisms. While various DNA-binding and activation domains have been developed for different applications, advanced artificially controllable sTFs with improved regulatory capabilities are required for increasingly sophisticated applications. Here, in mammalian cells and mice, we validate the transactivator function and homo-/heterodimerization activity of the plant-derived phytochrome chaperone proteins, FHY1 and FHL. Our results demonstrate that FHY1/FHL form a photosensing transcriptional regulation complex (PTRC) through interaction with the phytochrome, ΔPhyA, that can toggle between active and inactive states through exposure to red or far-red light, respectively. Exploiting this capability, we develop a light-switchable platform that allows for orthogonal, modular, and tunable control of gene transcription, and incorporate it into a PTRC-controlled CRISPRa system (PTRCdcas) to modulate endogenous gene expression. We then integrate the PTRC with small molecule- or blue light-inducible regulatory modules to construct a variety of highly tunable systems that allow rapid and reversible control of transcriptional regulation in vitro and in vivo. Validation and deployment of these plant-derived phytochrome chaperone proteins in a PTRC platform have produced a versatile, powerful tool for advanced research and biomedical engineering applications.

The degradation of Mg alloys relates to the service performance of Mg alloy biodegradable implants. In order to investigate the degradation behavior of Mg alloys as vascular stent materials in the near service environment, the hot-extruded fine-grained Mg-Zn-Y-Nd alloy microtubes, which are employed to manufacture vascular stents, were tested under radial compressive stress in the dynamic Hanks’ Balanced Salt Solution (HBSS). The results revealed that the high flow rate accelerates the degradation of Mg alloy microtubes and its degradation is sensitive to radial compressive stress. These results contribute to understanding the service performance of Mg alloys as vascular stent materials.

Purpose: Murine models of pancreatic cancer with damp-heat syndrome were established based on two methods to explore the differences in the composition of intestinal flora and to seek characteristic genera with potential for model evaluation. Methods: In our study, thirty-four C57BL/6J male mice were randomly divided into a control group (Con), a model group (Mod), a classic damp-heat syndrome group (CDHS), and a climate-chamber group (CC). CDHS and CC groups were fed with a high-fat diet and glucose water, while the CDHS group was given 2.4 g/kg alcohol by gavage for 10 days, and the CC group was placed in a climatic chamber with a set temperature of (32 ± 1) °C and humidity of (92 ± 2)% for 10 days. The Mod group, CDHS group, and CC group underwent tumor-building experiments on day 11. Tumorigenicity was then assessed twice a week. After 4 weeks, feces, colon tissue, and tumor tissue were taken from the mice and were tested, and the mice were euthanized afterwards. Results: Mice in the CDHS and CC groups showed symptoms similar to the clinical damp-heat syndrome observed in traditional Chinese medicine (TCM), and exhibited a worse general condition and more rapid tumor growth trend than those in the Mod group. The pathological examination indicated that inflammation was prevalent in the CDHS and CC groups. Both groups had a disrupted intestinal barrier and an overgrowth of pathogenic bacteria such as c_Gammaproteobacteria, o_Enterobacteriales, and g_Bacteroides. Their microbiota composition showed greater diversity. Conclusions: Intestinal flora may have a promising future in the discovery of indicators for evaluating a model of damp-heat syndrome in pancreatic cancer.

IntroductionWe performed a single-arm meta-analysis to evaluate the efficacy and safety of JAK inhibitors in the treatment of dermatomyositis (DM)/ polymyositis (PM).MethodsRelevant studies from four databases were systematically searched until April 25, 2023. The primary endpoint was Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and other outcomes were Manual Muscle Testing (MMT) and Creatine Kinase (CK). According to the type of JAK and medication regimen, we conducted subgroup analyses. The registration number in PROSPERO was CRD42023416493.ResultsAccording to the selection criteria, we identified 7 publications with a total of 91 patients. Regarding skin lesions, the CDASI decreased by 17.67 (95% CI: -20.94 ~ -14.41). The CK increased by 8.64 U (95% CI: -28.25 ~ 45.53). About muscle lesions, MMT increased by 10.31 (95% CI: -2.83 ~ 23.46). Subgroup analysis revealed that different types of JAK inhibitors had various degrees of reduction. CDASI in patients treated with RUX had the lowest one [-20.00 (95% CI: -34.9 ~ -5.1)], followed by TOF [-18.29 (95% CI: -21.8 ~ -14.78)] and BAR [-11.2 (95% CI: -21.51 ~ -0.89)]. Additionally, the mean reduction in CDASI in patients treated with TOF alone was 16.16 (95% CI: -21.21 ~ -11.11), in combination with other immunosuppressants was 18.59 (95% CI: -22.74 ~ -14.45). For safety evaluation, one patient developed Orolabial HSV, and two patients developed thromboembolism events.DiscussionIn summary, this meta-analysis demonstrated that JAK inhibitors can potentially treat DM/PM without severe adverse reactions.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42023416493, identifier CRD42023416493.

Summary: Alzheimer’s disease (AD) is the most common neurodegenerative disease often associated with olfactory dysfunction. Aβ is a typical AD hall marker, but Aβ-induced molecular alterations in olfactory memory remain unclear. In this study, we used a 5xFAD mouse model to investigate Aβ-induced olfactory changes. Results showed that 4-month-old 5xFAD have olfactory memory impairment accompanied by piriform cortex neuron activity decline and no sound or working memory impairment. In addition, synapse and glia functional alteration is consistent across different ages at the proteomic level. Microglia and astrocyte specific proteins showed strong interactions in the conserved co-expression network module. Moreover, this interaction declines only in mild cognitive impairment patients in human postmortem brain proteomic data. This suggests that astrocytes-microglia interaction may play a leading role in the early stage of Aβ-induced olfactory memory impairment, and the decreasing of their synergy may accelerate the neurodegeneration.

The foreseeable global animal production pressure has triggered people to search for sustainable novel feed resources. As the most abundant species in the world, insects are considered to be an alternative feed source. This review is to give comprehensive analysis of the insect as animal feed. In recent years, insect feed has been used in poultry, livestock production, aquaculture and pets. Positive impacts of using insect as feed source include nutritional enrichment, economic benefits and environmental merits. Also, barriers of using insects as feed related to animal products evaluation, insect breeding scale, consumer acceptance and legislation. This paper will be helpful in laying the foundation for the in-depth development and utilization of insect feed resources.

Abstract Background Macrophage polarization has been observed in the process of muscle injuries including rotator cuff (RC) muscle atrophy and fatty infiltration after large tendon tears. In our previous study, we showed that fibrogenesis and white adipogenesis of muscle residential fibro/adipogenic progenitors (FAPs) cause fibrosis and fatty infiltration and that brown/beige adipogenesis of FAPs promotes rotator cuff muscle regeneration. However, how polarized macrophages and their exosomes regulate FAP differentiation remains unknown. Methods We cultured FAPs with M0, M1, and M2 macrophages or 2 × 109 exosomes derived from M0, M1 and M2 with and without GW4869, an exosome inhibitor. In vivo, M0, M1, and M2 macrophages were transplanted or purified macrophage exosomes (M0, M1, M2) were injected into supraspinatus muscle (SS) after massive tendon tears in mice (n = 6). SS were harvested at six weeks after surgery to evaluate the level of muscle atrophy and fatty infiltration. Results Our results showed that M2 rather than M0 or M1 macrophages stimulates brown/beige fat differentiation of FAPs. However, the effect of GW4869, the exosome inhibitor, diminished this effect. M2 exosomes also promoted FAP Beige differentiation in vitro. The transplantation of M2 macrophages reduced supraspinatus muscle atrophy and fatty infiltration. In vivo injections of M2 exosomes significantly reduced muscle atrophy and fatty infiltration in supraspinatus muscle. Conclusion Results from our study demonstrated that polarized macrophages directly regulated FAP differentiation through their exosomes and M2 macrophage-derived exosomes may serve as a novel treatment option for RC muscle atrophy and fatty infiltration.

Surface engineering techniques can be used to develop high-performance gas sensing materials and advance the development of sensors. In this study, we improved the gas sensing performance of two-dimensional (2D) WO3 nanoplates by combining surface Zn modification and the in situ formation of ZnWO4/WO3 heterojunctions. Introducing Zn atoms by surface modification can reconstruct the atomic surface of 2D WO3 nanoplates, creating additional active sites. This allowed for the preparation of various types of ZnWO4/WO3 heterojunctions on the surface of the WO3 nanoplates, which improved the selectivity and sensitivity to the target gas triethylamine. The sensor exhibited good gas sensing performance for triethylamine even at low operating temperatures and strongly resisted humidity changes. The ZnWO4/WO3 material we prepared demonstrated a nearly threefold improvement in the triethylamine (TEA) response, with a gas sensing responsivity of 40.75 for 10 ppm of TEA at 250 °C. The sensor based on ZnWO4/WO3 has a limit of detection (LOD) for TEA of 200 ppb in practical measurements (its theoretical LOD is even as low as 31 ppb). The method of growing ZnWO4 on the surface of WO3 nanoplates using surface modification techniques to form surface heterojunctions differs from ordinary composites. The results suggest that the in situ construction of surface heterojunctions using surface engineering strategies, such as in situ modifying, is a practical approach to enhance the gas sensing properties and resistance to the humidity changes of metal oxide materials.

Abstract Background His-Purkinje system pacing (HPSP), including his-bundle pacing (HBP) and left bundle branch area pacing (LBBaP), imitates the natural conduction of the heart as an alternative to biventricular pacing (BVP) in cardiac resynchronization therapy (CRT). However, the feasibility and efficacy of HPSP were currently only evidenced by studies with a limited sample size, so this study aimed to provide a comprehensive assessment through a systematic review and meta-analysis. Methods In order to compare the clinical outcomes associated with HPSP and BVP in patients for CRT, PubMed, EMBASE, Cochrane Library and Web of Science database were searched from inception to April 10, 2023. Clinical outcomes of interest including QRS duration (QRSd), left ventricular (LV) function and New York Heart Association (NYHA) functional classification, pacing threshold, echocardiographic and clinical response, hospitalization rate of HF and all-cause mortality were also extracted and summarized for meta-analysis. Results A total of 13 studies (ten observational studies and three randomized studies) involving 1,121 patients were finally included. The patients were followed up for 6–27 months. Compared with BVP, CRT patients treated by HPSP presented shorter QRSd [mean difference (MD): -26.23 ms, 95% confidence interval (CI): -34.54 to -17.92, P

Abstract Recurrent respiratory papillomatosis (RRP) is a human papilloma virus (HPV)‐driven benign neoplasm, affecting larynx, trachea, and even lung, leading to voice disorders, airway obstruction, and postobstructive pneumonia. Several case reports have documented the promising efficacy of intravenous bevacizumab in reducing the need for surgical intervention among RRP patients. Herein, we present our experience on systemic bevacizumab for pediatric patients with aggressive RRP. Methods We retrospectively analyzed clinical, laboratory, radiological, and bronchoscopy findings of pediatric patients with aggressive RRP treated with systemic bevacizumab from July 26, 2021 to March 1, 2022. Results Eight consecutive patients were included. Median age at treatment initiation was 5.5 (range 2.5–8) years old. Twenty‐five percentage (2/8) of patients experienced tracheotomy. Pulmonary papilloma was present in 62.5% (5/8) patients. Patients received median 10 cycles of bevacizumab (range 5–12). Patients received initial dosing of 4–7.5 mg/kg every 2–10 weeks of bevacizumab and subsequently extended after achieving the maximum response. None of the patients required surgical intervention during a median 10 (range 8.2–15.4) months follow‐up after initiating bevacizumab treatment. Both patients with evaluable lung lesions showed objective response. Only Grade 1 abdominal pain and Grade 1 hyperuricemia were recorded. Conclusion Systemic bevacizumab seems to be a well‐tolerated and effective treatment option for pediatric patients with aggressive RRP.

Straw covering is a protective tillage measure in agricultural production, but there is relatively little research on the allelopathic effects of corn straw on weeds and foxtail millet. This experiment studied the allelopathic effects of corn straw on four weeds (Chenopodium album, Setaria viridis, Echinochloa crus-galli and Amaranthus retroflexus) in foxtail millet fields, and also measured the growth indicators of foxtail millet. The study consisted of Petri dish and field experiments. Five treatments were used in the Petri dish experiment: clear water as control (0 g/L, TCK) and four types of corn straw water extracts. They were, respectively, the stock solution (100 g/L, T1), 10 X dilution (10 g/L, T2), 50 X dilution (2 g/L, T3), and 100 X dilution (1 g/L, T4) of corn straw water extracts. Additionally, seven treatments were set up in the field experiment, consisting of three corn straw covering treatments, with covering amounts of 3000 (Z1), 6000 (Z2) and 12,000 kg/ha (Z3), and four control treatments—one treatment with no corn straw cover (CK) and three treatments involving the use of a black film to create the same shading area as the corn straw covered area, with black film coverage areas of 50% (PZ1), 70% (PZ2), and 100% (PZ3), respectively. The results showed that the corn straw water extract reduced the germination rate of the seeds of the four weeds. The T1 treatment resulted in the allelopathic promotion of C. album growth but the inhibition of S. viridis, E. crus-galli, and A. retroflexus growth. Treatments T2, T3, and T4 all induced the allelopathic promotion of the growth of the four weeds. The order of the effects of the corn straw water extracts on the comprehensive allelopathy index of the four weed seeds was as follows: C. album > S. viridis > A. retroflexus > E. crus-galli. With an increase in the corn straw mulching amount, the density and total coverage of the four weeds showed a gradual downward trend, whereas the plant control effect and fresh weight control effect showed a gradual upward trend. All indices showed the best results under 12,000 kg/ha of mulching and returning to the field. Overall, corn straw coverage significantly impacted the net photosynthetic rate and transpiration rate of foxtail millet and increased the yield of foxtail millet. Under coverages of 6000 and 12,000 kg/ha, the growth of foxtail millet is better. Based on our findings, we recommend a corn straw coverage of 12,000 kg/ha for the allelopathic control of weeds in foxtail millet fields.

The structure and function of phenoyl oligosaccharides in baijiu distillers’ grains (BDGs) have not been identified and investigated yet. This study aimed to elucidate the major phenolic oligosaccharides present in BDGs, optimize their extraction process via a central composite design, and assess their anti-inflammatory properties utilizing the LPS-induced RAW264.7 inflammation model. The main results are as follows: feruloylated oligosaccharides (FOs) were identified as the main phenoyl oligosaccharides in BDGs with a structure of ferulic acid esterified on arabinooligosaccharide xylose. Then, the preparation process of FOs was optimized using the following conditions: pH 5, temperature 55 °C, time 12 h, xylanase addition amount 7 g/L, BDG concentration 120 g/L. Furthermore, the acquired FOs demonstrated notable scavenging activity against DPPH and ABTS free radicals, with Trolox equivalent values of 366.8 ± 10.38 and 0.35 ± 0.01 mM Trolox/mg sample, respectively. However, their efficacy was comparatively lower than that of ferulic acid. Finally, the obtained FOs could effectively inhibit the LPS-induced secretion of TNF-α, IL-6, and IL-1β and promote the secretion of IL-10 in RAW264.7 cells. Based on the above results, FOs from BDGs were determined to have certain antioxidant and anti-inflammatory activities.

Glioblastoma multiforme (GBM) is the most common type of malignant tumor of the central nervous system, characterized by aggressiveness, genetic instability, heterogenesis, and unpredictable clinical behavior. Disappointing results from the current clinical therapeutic methods have fueled a search for new therapeutic targets and treatment modalities. GBM is characterized by various genetic alterations, and RNA-based gene therapy has raised particular attention in GBM therapy. Here, we review the recent advances in engineered non-viral nanocarriers for RNA drug delivery to treat GBM. Therapeutic strategies concerning the brain-targeted delivery of various RNA drugs involving siRNA, microRNA, mRNA, ASO, and short-length RNA and the therapeutical mechanisms of these drugs to tackle the challenges of chemo-/radiotherapy resistance, recurrence, and incurable stem cell-like tumor cells of GBM are herein outlined. We also highlight the progress, prospects, and remaining challenges of non-viral nanocarriers-mediated RNA-based gene therapy.

Recently, despite the increasing availability of treatments for Rheumatoid arthritis (RA), the incidence of RA and associated disability-adjusted life years have been on the rise globally in the late decades. At present, accumulating evidence has been advanced that RA is related to the gut microbiota, therefore, the therapeutic approaches for RA by regulating the gut microbiota are anticipated to become a new means of treatment. Traditional Chinese medicine (TCM) can regulate immunity, reduce inflammation and improve quality of life in various ways. Moreover, it can treat diseases by affecting the gut microbiota, which is a good way to treat RA. In this review, we mainly explore the relationship between TCM and gut microbiota regarding the perspective of treating RA. Moreover, we comprehensively summarize the roles of gut microbiota in the onset, development, progression, and prognosis of RA. Additionally, we elucidate the mechanism of TCM prevention and treatment of RA by the role of microbiota. Finally, we provide an evidence-based rationale for further investigation of microbiota-targeted intervention by TCM.

Abstract Angiogenesis inhibitors (AIs) and immune checkpoint inhibitors (ICIs) are new treatment options for advanced soft tissue sarcoma (STS) patients. This study evaluated the efficacy and safety of AIs plus ICIs in patients with advanced STS. A retrospective cohort study was performed on STS patients treated with AIs and ICIs at Shandong Cancer Hospital and Institute between August 2020 and December 2021. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and adverse events. Thirty-three patients were enrolled; 27 were evaluable for objective response. The ORR and DCR were 48.1% (95% CI 30.7–66.0%) and 85.2% (95% CI 67.5–94.1%). With a median follow-up of 7.6 months (range, 0.8–25.5), the median PFS for all 33 patients was 8.90 months (95% CI 5.98–11.82). The median OS was not reached. The most common treatment-related adverse events (TRAEs) of any grade were hypertension (50.0%), ECG T-wave abnormality (30.0%), hypothyroidism (26.7%), elevated alanine aminotransferase or aspartate aminotransferase (23.3%), elevated thyroid-stimulating hormone (23.3%), and fatigue (16.7%). The most common grade 3–4 TRAE was hypertension (27.3%). Three serious TRAEs (two myocarditis and one rapid atrial fibrillation) were recorded. This study suggests that adding AIs to ICIs is beneficial in STS.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder, and it is unlikely that any single drug or intervention will be very successful. The pathophysiology of Alzheimer's disease involves a range of complicated biological processes, including the accumulation of beta-amyloid protein and tau protein. Given the complexity of AD and amyloid accumulation, a combination of interventions remains to be further explored. Here, we investigated the potential of combining β-asarone and cannabidiol (CBD) as a treatment for AD. The study analyzed the combined effects of these two phytochemicals on beta-amyloid (Aβ) protein aggregation and toxicity in bulk solution, in cells as well as in C.elegans. We detailed the morphological and size changes of Aβ40 aggregates in the presence of β-asarone and cannabidiol. More importantly, the presence of both compounds synergistically inhibited apoptosis and downregulated relative gene expression in cells, and that it may also slow aging, decrease the rate of paralysis, enhance learning capacity, and boost autophagy activity in C.elegans. Our studies suggest that multiple drugs, like β-asarone and CBD, may be potentially developed as a medicinal adjunct in the treatment of AD, although further clinical trials are needed to determine the efficacy and safety of this combination treatment in humans.

ABSTRACT: Optimizing the allocation of water resources is critical for promoting the optimization and upgrading of industrial structure and coordinated development in the Beijing–Tianjin–Hebei regions of China. Based on specific regional and water conditions, to strengthen the constraints on water resources, the “three-step” adaptive management approach of “scheme design–scheme diagnosis–scheme optimization” of water resource allocation are adopted to facilitate the coordinated optimal allocation of water resources and industrial structure in the Beijing–Tianjin–Hebei regions. First, from the level of overall industry, a water resource allocation scheme for the regions is designed by applying the master–slave hierarchical mode and a bi-level optimal model to determine the ideal amount of water resource allocation for the regions and respective industries. Second, the diagnostic criteria of spatial balance, structural matching, and coordinated development are constructed to determine the rationality of the water resource allocation scheme. Then a benefit compensation function with water market transactions is developed, to adaptively adjust the water resource allocation scheme. Finally, the optimization and upgrading of industrial structure are promoted to improve water consumption efficiency and the coordinated development of the Beijing–Tianjin–Hebei regions. The study can provide reference for the Beijing–Tianjin–Hebei regions to realize the comprehensive optimal allocation of water resources in the regions and improve the adaptability of water resources and industrial structure optimization.

ABSTRACT: To optimize the overall layout of water resource allocation in the Beijing-Tianjin-Hebei region, the adaptability of the water resource system to the regional social-ecological systems has to be enhanced. Based on the driver-pressure-state-impact-response (DPSIR) framework, this study constructs an evaluation index system to analyze the adaptability mechanisms of Beijing-Tianjin-Hebei’s water resource system according to the three major constituent social-ecological systems (i.e., economic, social, and ecological systems). Moreover, it adopts the technique of order preference similarity to the ideal solution (TOPSIS) to comprehensively evaluate the adaptability of Beijing-Tianjin-Hebei’s water resource system based on three constituent social-ecological systems (i.e., economic, social, and ecological systems) and identifies the spatiotemporal differentiation characteristics of the region. Our results showed that, ① from 2000 to 2020, the adaptability of Beijing-Tianjin-Hebei’s water resource system, as a whole, significantly improved. In terms of stages, from 2000 to 2007, the adaptability of the water resource social system was significantly higher than that of economic and ecological systems in the region. From 2008 to 2015, by accelerating the transformation and upgrading of industrial structures, improving the efficiency of economic water utilization, and strengthening the governance of the water ecosystem, the adaptability of water resource economic and ecological systems rapidly improved; however, that of the water resource ecological system was still the lowest. Additionally, the adaptability of the water resource economic system exceeded that of the social system. From 2016 to 2020, the gap in adaptability of the water resource system to all three major constituent systems gradually narrowed. By 2020, the three systems entered a relatively balanced development stage, with the adaptability of the entire water resource system and the three major constituent systems maintaining a high level. ② The economic system was significantly affected by per capita GDP, per capita water resources, and the efficiency of economic water utilization. Additionally, the social system was significantly affected by water consumption per unit of irrigation area. Meanwhile, the ecological system was significantly influenced by precipitation, water pollution discharge performance indicators, and the structure optimization indicators of water supply. According to the evaluation results, we propose countermeasures and provide recommendations to optimize the overall layout of water resource allocation and promote the coordinated management of water resources in the Beijing-Tianjin-Hebei region.

The M protein, a major virulence factor of Group A Streptococcus (GAS), is regulated by the multigene regulator Mga. An unexplained phenomena frequently occurring with in vitro genetic manipulation or culturing of M1T1 GAS strains is the loss of M protein production. This study was aimed at elucidating the basis for the loss of M protein production. The majority of M protein-negative (M−) variants had one C deletion at a tract of 8 cytidines starting at base 1,571 of the M1 mga gene, which is designated as c.1571C[8]. The C deletion led to a c.1571C[7] mga variant that has an open reading frame shift and encodes a Mga-M protein fusion protein. Transformation with a plasmid containing wild-type mga restored the production of the M protein in the c.1571C[7] mga variant. Isolates producing M protein (M+) were recovered following growth of the c.1571C[7] M protein-negative variant subcutaneously in mice. The majority of the recovered isolates with reestablished M protein production had reverted back from c.1571C[7] to c.1571C[8] tract and some M+ isolates lost another C in the c.1571C[7] tract, leading to a c.1571C[6] variant that encodes a functional Mga with 13 extra amino acid residues at the C-terminus compared with wild-type Mga. The nonfunctional c.1571C[7] and functional c.1571C[6] variants are present in M1, M12, M14, and M23 strains in NCBI genome databases, and a G-to-A nonsense mutation at base 1,657 of M12 c.1574C[7] mga leads to a functional c.1574C[7]/1657A mga variant and is common in clinical M12 isolates. The numbers of the C repeats in this polycytidine tract and the polymorphism at base 1,657 lead to polymorphism in the size of Mga among clinical isolates. These findings demonstrate the slipped-strand mispairing within the c.1574C[8] tract of mga as a reversible switch controlling M protein production phase variation in multiple GAS common M types.

Background: A large gap exists between the latest Global Air Quality Guidelines (AQG 2021) and Chinese air quality standards for NO2. Assessing whether and to what extent air quality standards for NO2 should be tightened in China requires a comprehensive understanding of the spatiotemporal characteristics of population exposure to ambient NO2 and related health risks, which have not been studied to date. Objective: We predicted ground NO2 concentrations with high resolution in mainland China, explored exposure characteristics to NO2 pollution, and assessed the mortality burden attributable to NO2 exposure. Methods: Daily NO2 concentrations in 2019 were predicted at 1-km spatial resolution in mainland China using random forest models incorporating multiple predictors. From these high-resolution predictions, we explored the spatiotemporal distribution of NO2, population and area percentages with NO2 exposure exceeding criterion levels, and premature deaths attributable to long- and short-term NO2 exposure in China. Results: The cross-validation R2 and root mean squared error of the NO2 predicting model were 0.80 and 7.78 μg/m3, respectively, at the daily level in 2019. The percentage of people (population number) with annual NO2 exposure over 40 μg/m3 in mainland China in 2019 was 10.40 % (145,605,200), and it reached 99.68 % (1,395,569,840) with the AQG guideline value of 10 μg/m3. NO2 levels and population exposure risk were elevated in urban areas than in rural. Long- and short-term exposures to NO2 were associated with 285,036 and 121,263 non-accidental deaths, respectively, in China in 2019. Tightening standards in steps gradually would increase the potential health benefit. Conclusion: In China, NO2 pollution is associated with significant mortality burden. Spatial disparities exist in NO2 pollution and exposure risks. China’s current air quality standards may no longer objectively reflect the severity of NO2 pollution and exposure risk. Tightening the national standards for NO2 is needed and will lead to significant health benefits.

This paper presents a monocular biological microscope with colorful 3D reconstruction and an extended depth of field using an electrically tunable lens. It is based on a 4f optical system with an electrically tunable lens at the confocal plane. Rapid and extensive depth scanning while maintaining consistent magnification without mechanical movement is achieved. We propose an improved Laplacian operator that considers pixels in diagonal directions to provide enhanced fusion effects and obtain more details of the object. Accurate 3D reconstruction is achieved using the shape-from-focus method by tuning the focal power of the electrically tunable lens. We validate the proposed method by performing experiments on biological samples. The 3D reconstructed images obtained from the biological samples match the actual shrimp larvae and bee antenna samples. Two standard gauge blocks are used to evaluate the 3D reconstruction performance of the proposed method. The experimental results show that the extended depth of fields are 120 µm, 240 µm, and 1440 µm for shrimp larvae, bee tentacle samples, and gauge blocks, respectively. The maximum absolute errors are −39.9 μm and −30.6 μm for the first and second gauge blocks, which indicates 3D reconstruction deviations are 0.78% and 1.52%, respectively. Since the procedure does not require any custom hardware, it can be used to transform a biological microscope into one that effectively extends the depth of field and achieves highly accurate 3D reconstruction results, as long as the requirements are met. Such a microscope presents a broad range of applications, such as biological detection and microbiological diagnosis, where colorful 3D reconstruction and an extended depth of field are critical.

Summary: N6-methyladenosine (m6A) modification controls cell fate determination. Here, we show that liquid-liquid phase separation (LLPS) of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a pivotal m6A “reader” protein, promotes the transdifferentiation of spermatogonial stem cells (SSCs) into neural stem cell-like cells by activating the IκB-nuclear factor κB (NF-κB)-CCND1 axis. The inhibition of IκBα/β mRNA translation mediated by YTHDF1 LLPS is the key to the activation of the IκB-NF-κB-CCND1 axis. Disrupting either YTHDF1 LLPS or NF-κB activation inhibits transdifferentiation efficiency. Moreover, overexpression of the YTH domain of YTHDF1 inhibits the activation of the IκB-NF-κB-CCND1 axis by promoting IκBα/β mRNA translation. Overexpression of the tau-YTH fusion protein reactivates IκB-NF-κB-CCND1 axis by inhibiting the translation of IκBα/β mRNAs, and tau LLPS is observed, which can restore transdifferentiation efficiency. Our findings demonstrate that the protein-RNA LLPS plays essential roles in cell fate transition and provide insights into translational medicine and the therapy of neurological diseases.

Abstract Background Effective and accurate screening of oncological biomarkers in peripheral blood circulation plays an increasingly vital role in diagnosis and prognosis. High-sensitivity assays can effectively aid clinical decision-making and intervene in cancer in a localized status before they metastasize and become unmanageable. Meanwhile, it is equally pivotal to prevent overdiagnosis of non-life-threatening cancer by eliminating unnecessary treatment and repeated blood draws. Unfortunately, current clinical screening methodologies can hardly simultaneously attain sufficient sensitivity and specificity, especially under resource-restrained circumstances. To circumvent such limitations, particularly for cancer biomarkers from early-onset and recurrence, we aim to develop a universal plasmonic platform for clinical applications, which macroscopically amplifies multiplexed fluorescence signals in a broad spectral window and readily adapts to current assay setups without sophisticated accessories or expertise at low cost. Methods The plasmonic substrate was chemically synthesized in situ at the solid–liquid interface by rationally screening a panel of reducing monosaccharides and tuning the redox reactions at various catalyst densities and precursor concentrations. The redox properties were studied by Benedict’s assay and electrochemistry. We systemically characterized the morphologies and optical properties of the engineered plasmonic Ag structures by scanning electron microscopy (SEM) and spectroscopy. The structure-fluorescence enhancement correlation was explicitly explained by the finite-difference time-domain (FDTD) simulation and a computational model for gap distribution. Next, we established an enhanced fluoroimmunoassay (eFIA) using a model biomarker for prostate cancer (PCa) and validated it in healthy and PCa cohorts. Prognosis was explored in patients subject to surgical and hormonal interventions following recommended PCa guidelines. Results The monosaccharide-mediated redox reaction yielded a broad category of Ag structures, including sparsely dispersed nanoparticles (NPs) of various sizes, semi-continuous nanoislands, and crackless continuous films. Optimal broad-spectral fluorescence enhancement from green to far-red was observed for the inhomogeneous, irregularly-shaped semi-continuous Ag nanoisland substrate (AgNIS), synthesized from a well-balanced redox reaction at a stable rate mediated by mannose. In addition, different local electric field intensity distributions in response to various incident excitations were observed at the nanoscale, elucidating the need for irregular and inhomogeneous structures. AgNIS enabled a maximized 54.7-fold macroscopically amplified fluorescence and long-lasting photostability. Point-of-care availability was fulfilled using a customized smartphone prototype with well-paired optics. The eFIA effectively detected the PCa marker in cell lines, xenograft tumors, and patient sera. The plasmonic platform rendered a diagnostic sensitivity of 86.0% and a specificity of 94.7% and capably staged high-grade PCa that the clinical gold standard test failed to stratify. Patient prognosis of robotic-assisted surgeries and hormone therapies was non-invasively monitored following efficient medical interventions. The assay time was significantly curtailed on the plasmonic platform upon microwave irradiation. Conclusions By investigating the effects of reducing monosaccharides on the seed-mediated chemical synthesis of plasmonic Ag structures, we deduced that potent multiplexed fluorescence enhancement originated from both an adequate reducing power and a steady reduction rate. Furthermore, the inhomogeneous structure with adequate medium gap distances afforded optimal multiwavelength fluorescence enhancement, thus empowering an effective eFIA for PCa. The clinically validated diagnostic and prognostic features, along with the low sample volume, point-of-care feasibility with a smartphone, and microwave-shortened assay time, warrant its potential clinical translation for widespread cancer biomarker analysis. Graphical Abstract

Eleutheroside E (EE) is a monomer compound isolated from Acanthopanax senticosus, which has functions of antifatigue, antioxidation, and immune regulation. However, the function of EE in inhibiting cancer has rarely been reported. In this study, we used bioinformatics to determine the role and mechanisms of EE in inhibiting breast cancer (BRCA), prostate cancer (PRAD), lung cancer (LUAD), and bladder cancer (BLCA). Finally, the MTT method was used to evaluate the inhibitory effect of EE on breast cancer MDA-MB-231 cells, and the target genes were determined by qRT-PCR. The results showed that the survival rate of MDA-MB-231 cells was reduced by 27.33% after 400 μg/mL EE treatment. The results of qRT-PCR showed that EE down-regulated target genes in breast cancer cells, which was consistent with our predicted results. Moreover, our results indicated that EE may have impact on the transcription and translation of BLCA cells by targeting ADCY2, ADCY5 and JUN. In BRCA, we identified three targets for EE. In addition, EE affected DNA repair and the development of BRCA by affecting the expression of RAD51. In LUAD, we identified 9 targets for EE, 8 of which were related to DNA repair. EE inhibited PRAD by targeting ADCY8. Our research was the first report on the targets and mechanisms of EE for suppressing cancer combined with clinical data. Our research also provides theoretical support for using EE to suppress cancer.

Background: Antibody-mediated humoral immune response is involved in the damage process in Hashimoto’s thyroiditis (HT). Although the traditional Chinese medicine (TCM) formula bupleurum inula flower soup (BIFS) is often used in HT treatment, it has not been evaluated through high-quality clinical research. Rigorously designed randomized, double-blind, prospective clinical studies are urgently needed to evaluate BIFS for intervening in the HT immune damage process, and to improve clinical prognosis and patient quality of life.Methods: A prospective randomized, double-blind, placebo-controlled trial was used to evaluate the efficacy of BIFS. Fifty participants diagnosed with HT with hypothyroidism were randomly assigned at a 1:1 ratio to the BIFS (levothyroxine with BIFS) or control (levothyroxine with placebo) group. Participants received 8 weeks of treatment and were followed for 24 weeks. They were monitored for: levels of thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), and thyroid stimulating hormone (TSH); scores for depression, anxiety, and health-related quality of life (HRQoL); thyroid volume; safety indicators including routine blood tests, liver and kidney functions, and electrocardiogram; and levothyroxine dose.Results: Forty-eight participants completed the study and were included in the final analysis. At baseline, there were no significant between-group differences in the observed indicators (p > 0.05). Post-treatment, compared with the control group, the BIFS group had significantly lower levels of TPOAb (275.77 ± 132.98 vs. 441.78 ± 195.50, p = 0.001), TgAb (385.92 ± 281.91 vs. 596.17 ± 282.26, p = 0.013), and TSH (6.57 ± 3.73 vs. 9.63 ± 5.34, p = 0.001). Compared with the control group, the BIFS group’s scores improved significantly for depression (47.00 ± 5.12 vs. 51.04 ± 3.22, p = 0.002), anxiety (43.21 ± 4.22 vs. 48.08 ± 2.81, p = 0.005), and HRQoL physical (62.08 ± 5.97 vs. 57.96 ± 4.71, p = 0.011) and psychological (60.17 ± 5.94 vs. 55.75 ± 7.09, p = 0.024) subscores. At 24-week follow-up, levothyroxine combined with TCM allowed a significantly reduced levothyroxine dose (0.58 ± 0.43 vs. 1.02 ± 0.45, p = 0.001). The post-treatment clinical efficacy rates differed significantly (p = 0.03), with 75% (18/24) for the BIFS group and 46% (11/24) for the control group. There were no significant between-group differences in thyroid volume or safety indicators after eight treatment weeks or at the 24-week follow-up (p > 0.05).Conclusion: The TCM BIFS can effectively reduce thyroid titer, relieve clinical and emotional symptoms, and improve HRQoL in patients with HT.Clinical Trial Registration:https://www.chictr.org.cn/, identifier ChiCTR1900020987

Molecular imaging visualizes, characterizes, and measures biological processes at the molecular and cellular level. In oncology, molecular imaging is an important technology to guide integrated and precise diagnosis and treatment. Photoacoustic imaging is mainly divided into three categories: photoacoustic microscopy, photoacoustic tomography and photoacoustic endoscopy. Different from traditional imaging technology, which uses the physical properties of tissues to detect and identify diseases, photoacoustic imaging uses the photoacoustic effect to obtain the internal information of tissues. During imaging, lasers excite either endogenous or exogenous photoacoustic contrast agents, which then send out ultrasonic waves. Currently, photoacoustic imaging in conjunction with targeted photoacoustic contrast agents is frequently employed in the research of tumor molecular imaging. In this study, we will examine the latest advancements in photoacoustic imaging technology and targeted photoacoustic contrast agents, as well as the developments in tumor molecular imaging research.

This study provides a viable path to save energy by means of e-commerce development. Taking the national e-commerce demonstration cities (NEDC) pilots policy implemented in China as a quasi-natural experiment, based on the city panel data from 2006 to 2019, this study applies the multi-period difference-in-difference (DID) method to evaluate the effect of NEDC on energy saving in pilot cities. The empirical results suggest that the NEDC policy obviously contributes to energy conservation. The treated cities reduced energy consumption by 14.2% as a result of the implementation of NEDC, relative to the untreated cities. The conclusions remain valid after conducting robustness tests such as placebo test, instrumental variables regression, propensity score matching-difference-in-difference (PSM-DID), and synthetic difference-in-difference (SDID). The NEDC achieves energy-saving effects through technological innovation, industrial restructuring, and economic agglomeration. Furthermore, the heterogeneity analysis indicates that, in cities with high levels of human capital, well-developed information infrastructure, non-resource-based cities, and favorable business environments, the impact of NEDC on energy saving is more significant. Analysis of spatial effects shows that the implementation of NEDC has negative externalities, increasing energy consumption in the surrounding area. In the context of the digital economy, this paper presents new insights on the relationship between e-commerce and energy consumption and provides policy direction for countries looking for energy-saving solutions.

IntroductionResistin is a small secretory adipokine which is implicated to obesity and associated diseases. Recently, plenty of research papers have been conducted to explore the association between peripheral resistin and the severity of acute pancreatitis (AP). However, the results were controversial. In this study, we aimed to confirm the effect of peripheral resistin and the development of acute pancreatitis.MethodsA comprehensive online search was performed using the PubMed, Embase, Web of Science, CNKI, and Wanfang databases up through January 20, 2022. The retrieved records and their references were screened to identify additional studies. Data were extracted to calculate the pooled Hedges' g and its 95% CI, which were selected to assess peripheral resistin levels and the severity of acute pancreatitis. Subgroup analyses, sensitivity analyses, meta-regression, and publication bias tests were also undertaken based on obtained information.ResultsA total of eleven studies with 892 acute pancreatitis patients were enrolled in the study. Peripheral resistin levels were significantly increased in severe acute pancreatitis compared with mild acute pancreatitis (Hedges' g = 2.092, 95% CI: 0.994–3.190, P < 0.001). Subgroup analyses based on sample types and ethnicity also showed similar results. A single study did not affect our results, which was verified by sensitivity analysis. Meta-regression analyses revealed that age, gender of the included subjects, sample size, and publication year did not moderate effects on the present results.ConclusionIn our study, peripheral resistin levels were significantly elevated in patients with severe AP compared with patients with mild AP. Abnormal resistin levels may provide us some new insights in predicting the severity of AP.

Drought is a major environmental threat that limits crop growth, development, and productivity worldwide. Improving drought resistance with genetic engineering methods is necessary to tackle global climate change. It is well known that NAC (NAM, ATAF and CUC) transcription factors play a critical role in coping with drought stress in plants. In this study, we identified an NAC transcription factor ZmNAC20, which regulates drought stress response in maize. ZmNAC20 expression was rapidly upregulated by drought and abscisic acid (ABA). Under drought conditions, the ZmNAC20-overexpressing plants had higher relative water content and survival rate than the wild-type maize inbred B104, suggesting that overexpression of ZmNAC20 improved drought resistance in maize. The detached leaves of ZmNAC20-overexpressing plants lost less water than those of wild-type B104 after dehydration. Overexpression of ZmNAC20 promoted stomatal closure in response to ABA. ZmNAC20 was localized in the nucleus and regulated the expression of many genes involved in drought stress response using RNA-Seq analysis. The study indicated that ZmNAC20 improved drought resistance by promoting stomatal closure and activating the expression of stress-responsible genes in maize. Our findings provide a valuable gene and new clues on improving crop drought resistance.

Magnesium alloys have narrow available slip result from close-packed hexagonal structure that limit their processing properties. In the recent work, the Mg-2Zn-0.46Y-0.5Nd, as materials for degradable stents, was applied to produce as-extruded micro-tube with an outer diameter of 3.0 mm and a wall thickness of 0.35 mm by hot extrusion with an extrusion ratio of 105:1 at 653 K and rapid cooling. The fine microstructure of the dynamic recrystallization of as-extruded micro-tube could be preserved by rapid cooling such as water-cooled, resulting in more excellent mechanical properties relative to air-cooled micro-tube. The addition of rare earth elements Y and Nd results in continuous dynamic recrystallization dominated the dynamic recrystallization mechanism. During the hot extrusion process, the activation of the non-basal slip system, especially the pyramidal 〈c + a〉 slip, could significantly weaken the texture strength, and the as-extruded micro-tube exhibits weak “RE” texture components 〈011¯1〉∥ED and 〈1¯21¯1〉∥ED. Hence, the magnesium alloy micro-tube prepared by the rapid cooling has fine microstructure and weak texture, which is favorable for further process and governance.

Magnesium alloys were considered to be used as biodegradable implants due to their biocompatibility, biodegradability and nontoxicity. However, under the simultaneous action of corrosive environment and mechanical loading in human body, magnesium alloys are easy to be affected by corrosion fatigue and stress corrosion cracking. In this work, the fatigue behavior of the extruded Mg–Zn–Y–Nd alloy used for vascular stents was studied both in air and in simulated body fluid (SBF). It was revealed that the fatigue limit of as-extruded Mg–Zn–Y–Nd alloy in air is about 65 MPa at 107 cycles, while there is no limit in SBF and shows a linear relationship between the fatigue life and stress amplitudes. The fatigue crack source in air was formed by the inclusions and defects. However, the stress corrosion and hydrogen embrittlement are the main reasons for the formation of the fatigue initial crack source in SBF. Keywords: Biodegradable magnesium alloy, Corrosion fatigue, Simulated body fluid, Fatigue crack source

Abstract Background The Health Research Council of New Zealand is the first major government funding agency to use a lottery to allocate research funding for their Explorer Grant scheme. This is a somewhat controversial approach because, despite the documented problems of peer review, many researchers believe that funding should be allocated solely using peer review, and peer review is used almost ubiquitously by funding agencies around the world. Given the rarity of alternative funding schemes, there is interest in hearing from the first cohort of researchers to ever experience a lottery. Additionally, the Health Research Council of New Zealand wanted to hear from applicants about the acceptability of the randomisation process and anonymity of applicants. Methods This paper presents the results of a survey of Health Research Council applicants from 2013 to 2019. The survey asked about the acceptability of using a lottery and if the lottery meant researchers took a different approach to their application. Results The overall response rate was 39% (126 of 325 invites), with 30% (76 of 251) from applicants in the years 2013 to 2018, and 68% (50 of 74) for those in the year 2019 who were not aware of the funding result. There was agreement that randomisation is an acceptable method for allocating Explorer Grant funds with 63% (n = 79) in favour and 25% (n = 32) against. There was less support for allocating funds randomly for other grant types with only 40% (n = 50) in favour and 37% (n = 46) against. Support for a lottery was higher amongst those that had won funding. Multiple respondents stated that they supported a lottery when ineligible applications had been excluded and outstanding applications funded, so that the remaining applications were truly equal. Most applicants reported that the lottery did not change the time they spent preparing their application. Conclusions The Health Research Council’s experience through the Explorer Grant scheme supports further uptake of a modified lottery.

Klippel-Trenaunay syndrome (KTS) was demonstrated as a mosaic activating PIK3CA mutations related overgrowth syndrome. We present the first case of primary pleural angiosarcoma in a 17-year-old woman with a history of KTS. The combined targeted DNA and RNA sequencing revealed an activating mutation in PIK3CA in the tumor tissue. Our case suggested an association and perhaps a causal link between the two different PIK3CA-related genetic diseases.

We present our fifth set of results from our mid-infrared imaging survey of Milky Way Giant H ii (GH ii ) regions with our detailed analysis of DR7 and K3-50. We obtained 20/25 and 37 μ m imaging maps of both regions using the FORCAST instrument on the Stratospheric Observatory For Infrared Astronomy. We investigate the multiscale properties of DR7 and K3-50 using our data in conjunction with previous multiwavelength observations. Near- to far-infrared spectral energy distributions of individual compact infrared sources were constructed and fitted with massive young stellar object (MYSO) models. We find eight out of the ten (80%) compact sources in K3-50 and three out of the four (75%) sources in DR7 are likely to be MYSOs. We derived luminosity-to-mass ratios of the extended radio subregions of DR7 and K3-50 to estimate their relative ages. The large spread in evolutionary state for the subregions in K3-50 likely indicates that the star-forming complex has undergone multiple star-forming events separated more widely in time, whereas the smaller spread in DR7 likely indicates the star formation subregions are more co-eval. DR7 and K3-50 have Lyman continuum photon rates just above the formal threshold criterion for being categorized as a GH ii region (10 ^50 photons s ^−1 ) but with large enough errors that this classification is uncertain. By measuring other observational characteristics in the infrared, we find that K3-50 has properties more akin to previous bona fide GH ii regions we have studied, whereas DR7 has values more like those of the non-GH ii regions we have previously studied.

Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading microbes, plays an essential role for the functions of both classical (CP) and lectin (LP) complement pathways. Complement C4 is the most polymorphic protein in complement system. A plethora of research data demonstrated that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders. In this review, we will discuss the diversity of complement C4 proteins and its genetic structures. In addition, the current development of the regulation of complement C4 activation and its activation derivatives will be reviewed. Moreover, the review will provide the updates on the molecule interactions of complement C4 under the circumstances of bacterial and viral infections, as well as autoimmune diseases. Lastly, more evidence will be presented to support the paradigm that links microbial infections and autoimmune disorders under the condition of the deficiency of complement C4. We provide such an updated overview that would shed light on current research of complement C4. The newly identified targets of molecular interaction will not only lead to novel hypotheses on the study of complement C4 but also assist to propose new strategies for targeting microbial infections, as well as autoimmune disorders.

Background Context: The association between low back pain and lumbar disc degeneration is not fully characterized. One potentially overlooked factor of this process is the lumbar multifidus, which plays a role in segmental stabilization and locomotion. Previous reports have shown multifidus degeneration to be associated with disc degeneration. The goal of this study was to develop a mouse model of advanced lumbar disc degeneration to recapitulate the pathology of the human multifidus in patients with lumbar disc degeneration and low back pain. Methods: C57BL/6 mice underwent a left anterolateral approach to the lumbar spine and disc puncture with a micro scalpel at L5/6 and L6/S1. Mice underwent behavioral analysis and functional gait testing. A subset of mice underwent 14T T2-weighted MRI to assess disc degeneration and paraspinal muscle quality. At 6 and 15 weeks, mice were sacrificed, and the multifidus muscles were harvested and divided into proximal and distal segments relative to disc injury. Histological analysis was performed to assess muscle degeneration, fiber type, and macrophage density. Fibroadipogenic progenitors (FAPs) were isolated for gene expression analysis with qPCR. Results: MRI demonstrated decreased intervertebral disc signal and paraspinal muscle atrophy at 6 weeks, with progressive degeneration and atrophy at 15 weeks. Disc injury resulted in delayed functional recovery and impaired gait. Histology demonstrated progressive multifidus fibrofatty degeneration between 6 and 15 weeks. CD68+ macrophage density was increased at 6 weeks but not 15 weeks. FAPs exhibited increased fibrotic and adipogenic gene expression at 6 weeks compared to sham with less of a difference in gene expression by 15 weeks. Conclusions: We have developed a mouse model of disc injury-mediated paraspinal muscle degeneration that recapitulates features of degenerative muscle pathology observed in patients with lumbar disc degeneration, and highlights the role of FAPs in mediating fibrofatty muscle degeneration after disc injury.

Spaceflight is a special abiotic stress condition. In recent years, it has been confirmed that the spaceflight caused the stress response of rice seeds, and the protein level, transcription level, and methylation level will change during the planting process after returning to the ground. However, the changes at the metabolome level are not very clear. In this study, two kinds of rice seeds, Dongnong423 (DN3) and Dongnong416 (DN6), were carried on the ShiJian-10 retractable satellite (SJ-10) for 12.5 days in orbit, returned to the ground and planted in the field until the three-leaf (TLP) and tillering stage (TS). The results of antioxidant enzyme activity, soluble sugar, and electron leakage rate revealed that the spaceflight caused the stress response of rice. The TLP and TS of DN3 identified 110 and 57 different metabolites, respectively, while the TLP and TS of DN6 identified 104 and 74 different metabolites, respectively. These metabolites included amino acids, sugars, fatty acids, organic acids and secondary metabolites. We used qRT-PCR technology to explore the changes of enzyme genes in the tricarboxylic acid cycle (TCA) and amino acid metabolism pathway. Combined with the results of metabolomics, we determined that during the TLP, the TCA cycle rate of DN3 was inhibited and amino acid metabolism was activated, while the TCA cycle rate of DN6 was activated and amino acid metabolism was inhibited. In TS, the TCA cycle rate of DN3 was inhibited, and amino acid metabolism was not significantly changed, while the TCA cycle rate of DN6 was activated and amino acid metabolism was inhibited. These results suggested that the response mechanisms of the two different rice strains to spaceflight stress are different, and these differences may be reflected in energy consumption and compound biosynthesis of rice in different growth and development stages. This study provided new insights for further exploring the effects of spaceflight.

Carbon dioxide emissions and air pollution are often assessed on a national or regional level, but little is known about the role of trade structures. Here, a combination of models shows that trade restrictions can lead to massive reduction of gross domestic product in most countries, but also to a reduction of emissions and pollution.

Air pollution has become a major health risk in China. Here Zhang et al. report that maternal and neonatal exposure to particulate matter increases the risk of neonatal jaundice based on the study of 25,782 newborns born in China between 2014 and 2017.

The accurate estimation of ammonia emission is essential for quantifying secondary inorganic aerosol formation and reactive nitrogen deposition. During the last decades, both fertilizer type and the total amount of nitrogen fertilizer in China have changed, while the resulting changes in ammonia emissions and their spatio-temporal variations are unclear. In this study, we compile a long-term (2005–2020) high-resolution ammonia emission inventory for synthetic fertilizer in China with bottom-up method. We parameterized emissions factors (EFs) considering the impacts of soil properties, method of fertilizer application, fertilizer type, crop type, ambient temperature and wind speed. Meanwhile, the monthly nitrogen fertilizer application is calculated by detailed information on crop-specific fertilizer application practices. For the spatial distribution, the ammonia emissions from fertilizer mostly concentrate in eastern and southwestern China, coincident with the high density of agriculture activity and population in these regions. For the seasonal variation, the ammonia emissions from fertilizer application peak in spring and summer because of dense fertilizer application and high ambient temperature. For the long-term trend, we estimate that the emissions from synthetic fertilizer increased from 5.38 Tg in 2005 to 5.53 Tg in 2008 and remained nearly unchanged during 2008–2012, then decreased to 3.96 Tg in 2020. Urea, ammonium bicarbonate (ABC) and nitrogenous compound fertilizer are major fertilizer types used in China. Despite the increased use of nitrogen fertilizer, ammonia emissions remained stable throughout 2008–2012 with the declined use of ABC. This stable period also reflects ammonia emission increases in western China, offsetting the decreases in eastern China. Furthermore, our emission inventory provides a monthly estimation at a spatial resolution of 0.1 degrees, which can be applied to global and regional atmospheric chemistry model simulations.

The metabolomics approach has proved to be promising in achieving non-targeted screening for those unknown and unexpected (U&U) contaminants in foods, but data analysis is often the bottleneck of the approach. In this study, a novel metabolomics analytical method via seeking marker compounds in 50 pharmaceutical and personal care products (PPCPs) as U&U contaminants spiked into lettuce and maize matrices was developed, based on ultrahigh-performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS) output results. Three concentration groups (20, 50 and 100 ng mL−1) to simulate the control and experimental groups applied in the traditional metabolomics analysis were designed to discover marker compounds, for which multivariate and univariate analysis were adopted. In multivariate analysis, each concentration group showed obvious separation from other two groups in principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) plots, providing the possibility to discern marker compounds among groups. Parameters including S-plot, permutation test and variable importance in projection (VIP) in OPLS-DA were used for screening and identification of marker compounds, which further underwent pairwise t-test and fold change judgement for univariate analysis. The results indicate that marker compounds on behalf of 50 PPCPs were all discovered in two plant matrices, proving the excellent practicability of the metabolomics approach on non-targeted screening of various U&U PPCPs in plant-derived foods. The limits of detection (LODs) for 50 PPCPs were calculated to be 0.4~2.0 µg kg−1 and 0.3~2.1 µg kg−1 in lettuce and maize matrices, respectively.

Mycoplasma bovis is a significant bacterial pathogen which is able to persist in cattle and cause chronic diseases. This phenomenon may relate to M. bovis evading the immune system of the host. Immunoglobulin-binding proteins are widely distributed in a variety of pathogenic bacteria, including some Mycoplasma species. These proteins are considered to help the bacteria evade the immune response of the host. Here we found M. bovis strain PG45 can bind to IgG from several animals. MBOVPG45_0375 encodes a putative membrane protein, has strong amino acid sequence similarity with Immunoglobulin G-binding protein in Mycoplasma mycoides subsp. capri. Hence, we constructed recombinant MBOVPG45_0375 (r0375) in the Escherichia coli expression system and demonstrated that r0375 can bind to IgG non-immunologically rather than specific binding similar to interaction of antigen and antibody. Moreover, r0375 can bind to the Fab fragment of IgG. Also, the binding of r0375 and IgG inhibits the formation of antigen-antibody union. Furthermore, MBOVPG45_0376 encodes an IgG-cleaving protein of M. bovis strain PG45. Nevertheless, r0375 binding to IgG is required for the cleavage activity of recombinant 0376 (r0376). The activity of r0376 is also affected by incubation time and temperature. In addition, we found both MBOVPG45_0375 and MBOVPG45_0376 are membrane proteins of M. bovis strain PG45. These results about MBOVPG45_0375 as an IgG-binding protein and MBOVPG45_0376 as an IgG-cleaving protein offer a new insight into the interaction between M. bovis and its host.

With the advancement of science and technology, humans are chronically exposed to ionizing radiation. It is crucial to look for efficient and low-toxic anti-radiation agents. Through preliminary screening, we found that Acanthopanax senticosus polysaccharide (ASPS) played a major role in regulating immune damage caused by radiation. The objective of this study was to apply the Caenorhabditis elegans—P. aeruginosa (PA14) infection model to illuminate the mechanism of ASPS increasing the pathogen resistance of radiation-damaged nematodes. Results indicated that ASPS (1 mg/mL) significantly enhanced the pathogen resistance of radiation-damaged nematodes by directly elevating the immune response of nematodes rather than by affecting the bacterial activity. Through further research on the p38 MAPK signaling pathway and related mutants, we found that ASPS functioned by the p38 MAPK pathway in the intestine, and SKN-1, ATF-7 as the downstream targets of PMK-1 participated the regulation of ASPS. In addition, ASPS markedly alleviated the stress status of damaged nematodes by regulating oxidative stress. Collectively, our findings suggest that ASPS enhances the pathogen resistance of radiation-damaged nematodes through the intestinal p38MAPK-SKN-1/ATF-7 pathway and stress response.

Fibrillins are microfibril-associated macro glycoproteins found in connective tissues and structurally related to latent TGF-β-binding proteins (LTBPs). The special cellular immunity and blocking glycoprotein receptors IIb and IIIa of fibrillins are emerging topics in recent years. In this study, Nile Tilapia type IIcollagen (NTCII) was extracted and purified from the skull cartilages by a pepsin-soluble method. Amino acid analysis indicated that NTCII consisted of 315/1000 glycine residues, 72/1000 hydroxyproline residues and 108/1000 proline residues. SDS-PAGE analysis showed that NTCII was composed of three identical 130 kDa α-chains. The results of glycoprotein/carbohydrate assay indicated that the total polysaccharide content of NTCII was 5.6–19.0%. The IR spectrum of NTCII displayed five characteristic peaks of amide I, II, III, A, B. NTCII at 10–100 μg/mL concentration downregulated the content of cytokines in the presence or absence of LPS, especially the secretion of cytokines IL-6, IL-1β and TNF-α. Interestingly, NTCII promoted the secretion of Fas/Apo-1 compared to the control group and 25 μg/mL of NTCII resulted in a higher Fas/Apo-1 secretion level in CD8+ T cells. FITC-TCII fluorescence images confirmed that NTCII could bind to the membrane surface of CD8+ T cells, leading to the induction of rigidity. NTCII could bind to the membrane surface of CD8+ T cells that leads to the induction of rigidity, as evidenced by the FITC-NTCII fluorescence images. The qRT-PCR gene expression analysis of caspase-8 collected with Fas/Apo-1 was upregulated significantly in the 1 and 50 μg/mL NTCII-treated groups compared with the control group. Overall, the results conclude that the rigidity did not lead to an increase in inflammatory factors in CD8+ T cells treated with NTCII. The oral administration of NTCII 3 mg/kg dosage caused more prominent repair of damaged ankle cartilage than the 1 mg/kg dosage in Freund’s adjuvant-induced model of arthritis in rats. Therefore, this study disclosed the immunological and anti-arthritic effect of fibrillar collagen, which could be a potential biomaterial for practical applications with lower toxicity.

Diet and antibiotic strongly affect human health by modulating gut microbiota (GM) composition. To investigate how Lycium barbarum (LB) relieves GM dysbiosis and enhances colonic barrier function, C57BL/6 mice were chronically exposed to sub-therapeutic antibiotic dosages or not (control), and fed a 1.5% LB diet for 10 weeks. HiSeq sequencing of 16S rDNA revealed that oral antibiotics distinctly lowered the microbial diversity and richness, Bacteroidetes, Firmicutes, Bacteroidales_S24-7_group, Lachnospiraceae, Ruminococcaceae, Lachnospiraceae_NK4A136_group, Lachnoclostridium, Akkermansia, Anaerotruncus, and Odoribacter, as well as increased Proteobacteria, Enterobacteriaceae, Enterococcaceae, Escherichia-Shigella, Morganella, and Enterococcus. Compared with the antibiotic-treated group, dietary LB reversed the variations in these bacteria, improved the abundance of certain short-chain fatty acid (SCFA)-producing bacteria, SCFA concentrations, and decreased fecal ammonia and pH value. Accordingly, this promoted the expression of tight junction proteins, immune barrier, sequentially improved barrier function, histomorphology, and development in the intestine. The results show that dietary LB can partially mitigate antibiotics-induced dysbiosis.

Absract Background Paraspinal muscles are crucial for vertebral stabilization and movement. These muscles are prone to develop fatty infiltration (FI), fibrosis, and atrophy in many spine conditions. Fibro‐adipogenic progenitors (FAPs), a resident muscle stem cell population, are the main contributors of muscle fibrosis and FI. FAPs are involved in a complex interplay with satellite cells (SCs), the primary myogenic progenitor cells within muscle. Little is known about the stem cell composition of the multifidus. The aim of this study is to examine FAPs and SCs in the multifidus in disc herniation patients. Multifidus muscle samples were collected from 10 patients undergoing decompressive spine surgery for lumbar disc herniation. Hamstring muscle was collected from four patients undergoing hamstring autograft ACL reconstruction as an appendicular control. Multifidus tissue was analyzed for FI and fibrosis using Oil‐Red‐O and Masson's trichrome staining. FAPs and SCs were visualized using immunostaining and quantified with fluorescence‐activated cell sorting (FACS) sorting. Gene expression of these cells from the multifidus were analyzed with reverse transcription‐polymerase chain reaction and compared to those from hamstring muscle. FI and fibrosis accounted for 14.2%± 7.4% and 14.8%±4.2% of multifidus muscle, respectively. The multifidus contained more FAPs (11.7%±1.9% vs 1.4%±0.2%; P