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It is necessary to confirm the appropriate processing parameters for recycled-Be/2024Al composites before hot processing. Therefore, hot compression experiments were conducted on 40 and 50 vol% recycled-Be/2024Al composites prepared by pressure infiltration method. Meanwhile, the constitutive equations were established. The activation energy increased with the volume fraction of reinforcement, which means the increasing difficulty for composites to deform. However, different from ceramic reinforcements, Be is able to deform with matrix coordinately. This characteristic makes recycled-Be/2024Al composites more prone to deformation than ceramic reinforced Al composites with the same volume fraction of reinforcements. The processing maps of 40 and 50 vol% recycled-Be/2024Al composites have been drawn, and the appropriate processing parameters for 40 and 50 vol% recycled-Be/2024Al composites were determined as 495–525 °C,0.0006–0.0016 s−1 and 500–530 °C,0.016–0.04 s−1, respectively. The microstructures of samples hot compressed with various parameters were observed to identify the accuracy of processing maps.

Replant diseases (RDs), intraspecific negative plant–soil feedback, often stem from nutrient deficiency, allelopathy, or pathogen accumulation. However, the RDs of certain crops are long-lasting and their causes remain unknown. We examined Panax quinquefolius RD in a space-for-time soil sequence representing crop rotation restoration over 1, 10, and 20 years using multiomics and bioassays. Compared with the soils with no ginseng cultivation history, we found 110 significant potential factors related to RD, surprisingly, 53 of which remained unrestored after 20 years. Soil pH and the levels of organic nutrients (amino acids, carbohydrates, and alditols), allelopathic-promoting metabolites (phenolic acids, amines, pyridines, etc.), and beneficial bacteria (Sphingomonas, Burkholderia-Caballeronia-Paraburkholderia, and Terrabacter) and fungi (Acremonium, Penicillium, and Naganishia) decreased, while the levels of allelochemicals (pyruvic and fatty acids) increased. The expression of all metabolic pathways was significantly down-regulated, with the exception of the up-regulated fatty acid-related metabolic pathways. We confirmed that decreased organic nutrient levels and increased levels of allelochemicals impaired P. quinquefolius growth. Soil metabolic factors rather than microbial factors were dominant by network analysis. In conclusion, we found that the overall changes in nutrient levels and metabolic and microbial factors contributed to short-term RD (1–10 year) persistence, whereas long-term RD (after 20 years) primarily resulted from disordered soil metabolite levels and pathways. This research will help deepen our understanding of the relationship between RD and potential changes in the factors influencing RD that are caused by soil legacy effects of valuable plants and provide theoretical guidance for effective soil quality improvement.

The steel and aluminum alloy tubes were successfully joined by magnetic pulse welding (MPW). Part of the joints fractured at the interface, yet part of them fractured at the base metal (BM) of aluminum alloy. The tensile test results revealed a fluctuation of the mechanical properties of the steel/Al MPW joints, demonstrating the microstructure inhomogeneity of the MPW joints. The typical wavy interfacial morphology could be observed at the interface of the MPW joints. The element transition zone composed of elements Fe and Al were detected while no obvious intermetallic compound (IMC) layer could be traced. The good mechanical properties of steel/Al MPW joints could be attributed to the longer effective bonding length and larger element transition area. Besides, the grain refinement was observed at the interface of the MPW joint, which explained its microhardness increase.

Serological detection of hepatitis B virus markers plays a vital role in the diagnosis, treatment, prognosis, and therapeutic surveillance of hepatitis B. To compare the diagnostic performance of Autolumo A2000Plus and Abbott Architect i2000 systems in the detection of hepatitis B infection markers. A total of 6 HBV seroconversion panels and 743 participants were enrolled in this study, including 383 HBV-infected patients and 360 healthy adults. Clinical diagnostic information, laboratory results, and HBV genotyping were collected to evaluate the diagnostic performance of the A2000Plus and i2000 systems in detecting HBV infection markers. The results showed that the total percent agreement of HBV markers was all >90 % in both detection systems among the six seroconversion panels and 743 serum samples from the population. The χ2 values of the Chi-square test among hepatitis B virus serological markers in both analyzers were between 550.7 and 743.0, p

Summary: Background: Azvudine and nirmatrelvir/ritonavir are approved to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with a high risk for progression to severe infection. We sought to compare the antiviral effectiveness and clinical outcomes of elderly severe patients with COVID-19 receiving these two antiviral agents. Methods: In this observational study, we identified 249 elderly patients with severe COVID-19 infection who were admitted to the Second Medical Center of the People's Liberation Army General Hospital from December 2022 to January 2023, including 128 azvudine recipients, 66 nirmatrelvir/ritonavir recipients and 55 patients not received antiviral treatments. We compared the cycle threshold (Ct) value dynamic change of all three groups. The primary outcome was a composite outcome of disease progression, including all-cause death, intensive care unit admission, and initiation of invasive mechanical ventilation. The outcomes of all enrolled patients were followed up from the electronic medical record system. Kaplan–Meier and Cox risk proportional regression analyses were used to compare the clinical outcomes of all three groups. To more directly compare the effectiveness of the two antiviral drugs, we performed propensity-score matching between the two antiviral groups and compared antiviral efficacy and clinical outcomes in the matched population. Findings: Among 249 patients (mean age, 91.41 years), 77 patients died during the follow-up period. When compared to patients who did not receive any antivirals, neither nirmatrelvir/ritonavir nor azvudine demonstrated a survival benefit. The Cox analysis of the all-cause death of the three groups showed that the risk of death was 0.730 (0.423–1.262) in the azvudine group 0.802 (0.435–1.480) and in the nirmatrelvir/ritonavir group compared with the non-antiviral group. After propensity score matching, we included 58 azvudine recipients and 58 nirmatrelvir/ritonavir recipients. The fitted curve of the Ct value after matching illustrated that the rate of viral decline in the early stage of nirmatrelvir/ritonavir treatment seems to surpass that of azvudine, but there was no statistical significance. Azvudine was seemly associated with a lower risk of composite outcomes (HR:1.676, 95% CI:0.805–3.488) and short-term all-cause death (HR: 1.291, 95%CI: 0.546–3.051). Interpretation: Patients who received azvudine have a similar antiviral effectiveness and survival curve trend compared to nirmatrelvir/ritonavir. In this limited series, antiviral treatment was not associated with a significant clinical benefit. This lack of clinical benefit might be attributed to potential bias. Funding: This study was supported by the “National Key R&D Program of China” (Funding No. 2020YFC2008900) and the National Defense Science and Technology Innovation Special Zone Project (223-CXCY-N101-07-18-01).

Background: The irreversible progression of autosomal dominant polycystic kidney disease (ADPKD) to end-stage renal disease (ESRD) is delayed by tolvaptan. Therefore, we aim to systematically estimate and evaluate the efficacy and safety of tolvaptan in the treatment of ADPKD. Methods: Two reviewers independently searched all published randomized controlled trials studies in PubMed, EMBASE, Web of Science and Cochrane databases, extracted data, assessed bias risk and rated the quality of evidence. Data were analyzed by the RevMan software. Results: We identified 8 trials including 2135 patients. Both of the decline of estimated glomerular filtration rate (eGFR) [MD = 1.89, 95% CI (0.74, 3.04), P = 0.001] and total kidney volume (TKV) [MD = −3.32, 95% CI (−4.57, −2.07), P

The microstructure and mechanical properties of Sn–Bi solder alloys with various Ag and In addition are comparatively investigated. The results illustrate that the tensile strength and ductility of the solder alloy could be dramatically enhanced with negligible loss of the plasticity. Especially, the Sn–Bi solder alloy with 0.4 wt. % Ag and 1.5 wt. % In exhibits the maximum tensile strength and elongation of 79.7 MPa and 45.9%, respectively. The microstructure of the Sn–Bi solder alloys is mainly composed of Bi-rich and β-Sn phases. With the addition of elements Ag and In, the microstructure is significantly refined, and the lamellar eutectic structure with thinner interlayer spacing could be detected. Element Ag tends to form Ag3Sn phase while element In solutes in the Sn matrix. The mechanical properties of the as-prepared Sn–Bi solder alloy are improved attributed to the precipitated-phase strengthening of the fined Ag3Sn phase and the refinement effect of In on coarse Bi-rich phase.

This report involves a 54-year-old female patient diagnosed with diffuse large B-cell lymphoma who developed interstitial pneumonia (IP) during treatment. The patient presented to the ward with enlarged lymph nodes in the neck and was treated with the standard regimen, which included rituximab, cyclophosphamide, doxorubicin liposomes, vincristine, and prednisone (R-CDOP regimen). After 3 cycles, the treatment was assessed as effective. However, following the 4th cycle, the patient experience shortness of breath after physical activity. A repeat lung computer tomography indicated IP, which completely recovered after receiving “full coverage” treatment. Subsequently, the patient underwent 2 cycles of cyclophosphamide, doxorubicin liposomes, vincristine, and prednisone (CDOP), followed by local radiotherapy. Currently, the patient is now being followed up with regular reviews.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

The clarification of the type of the ferrite formed owing to the melting of the Al–Si coating into the weld metal plays a significant role in the improvement of the mechanical properties of the laser welded joint. The results obtained by optical microscope (OM) and scanning electron microscope (SEM) in the regions near the ferrite before and after thermal simulation clearly demonstrate the negligible change in microstructure morphology, even for the ferrite with the size around 2 μm. In addition, simulated by JMatPro software, it can be found that the content of the α-ferrite decreases with the increase of the cooling rate. Based on the ultra-high cooling rate during laser welding and negligible change in the morphology of the ferrite by decreasing the cooling rate, the type of the ferrite formed in the WM is clarified as the δ-ferrite, without the formation of α-ferrite. The differences in the formation condition between the δ-ferrite and α-ferrite can affect the control of their size, morphology and distribution.

Rational chemical fertilizer application, especially combined with manure or straw amendment, serves as a key strategy for facilitating soil organic carbon (SOC) sequestration and soil fertility improvement. However, the effects of fertilization managements on the SOC priming induced by straw return remains unclear. Here, a microcosm was conducted to clarify the mechanisms of 13C-labeled maize straw addition effects on priming effect (PE) in two 29-year fertilized soils (Urumqi, UQ; Gongzhuling, GZL) subjected to four fertilization regimes (no fertilizer, CK; chemical fertilizers, NPK; combined application of NPK with straw, NPKS; combined application of NPK with manure, NPKM). Results showed that straw addition strongly increased native SOC decomposition by 15–44%, inducing positive PEs across sites and fertilization treatments. Compared to CK treatment, the NPK and NPKS treatments significantly increased PE by 26% and 98%, respectively, in the UQ soil, but had little effect on the PE in the GZL soil. The NPKM treatment strongly decreased PE by 51–55%, mainly due to the increased proportion of mineral-associated organic carbon (MAOC) and N availability, and decreased fungal abundances, as compared to the CK treatment in UQ and GZL soils. The PE intensities were significantly lower in GZL soil (5.1–11.7 mg CO2-C/g SOC) relative to UQ soil (13.7–54.8 mg CO2-C/g SOC), primarily due to the higher MAOC/SOC ratio and N availability in the former across fertilization regimes. Overall, manure application has the potential to mitigate soil C loss via priming, mainly resulting from enhanced SOC stabilization via mineral protection and increased N availability, thus facilitating SOC sequestration in agroecosystems.

The goal of digital dress body animation is to produce the most realistic dress body animation possible. Although a method based on the same topology as the body can produce realistic results, it can only be applied to garments with the same topology as the body. Although the generalization-based approach can be extended to different types of garment templates, it still produces effects far from reality. We propose GSNet, a learning-based model that generates realistic garment animations and applies to garment types that do not match the body topology. We encode garment templates and body motions into latent space and use graph convolution to transfer body motion information to garment templates to drive garment motions. Our model considers temporal dependency and provides reliable physical constraints to make the generated animations more realistic. Qualitative and quantitative experiments show that our approach achieves state-of-the-art 3D garment animation performance.

Summary: The organization and dynamics of chromatin fiber play crucial roles in regulating DNA accessibility for gene expression. Here we combine cryoelectron tomography (cryo-ET), sub-volume averaging, and 3D segmentation to visualize the in vitro and in vivo chromatin fibers folding by linker histone. We discover that an increased nucleosome repeat length and prolonged fiber length do not change the two-start helical architecture in reconstituted chromatin of homogeneous composition. Additionally, an isolated chromatin fiber with heterogeneous composition was observed, which includes short-range regions compatible with two-start helix. In vivo, sub-volume averaging reveals similar subunits of two-start helical architecture in transcriptionally inactive chromatin in frog erythrocyte nuclei. Strikingly, unambiguous DNA trajectories that displayed a zigzag pattern universally between alternate N/N+2 nucleosomes were further determined by cryo-ET with voltage phase plate. Therefore, these structural similarities suggest a general folding mode of chromatin induced by linker histone, and heterogeneous compositions mainly affect local conformation rather than changing the overall architecture.

Understanding the characteristics and influences of various factors on phosphorus (P) fractions is of significance for promoting the efficiency of soil P. Based on long-term experiments on black soil, fluvo-aquic soil, and loess soil, which belong to Phaeozems, Cambisols, and Anthrosols in the World Reference Base for Soil Resources (WRB), respectively, five fertilization practices were selected and divided into three groups: no P fertilizer (CK/NK), balanced fertilizer (NPK/NPKS), and manure plus mineral fertilizer (NPKM). Soil inorganic P (Pi) fractions and soil properties were analyzed to investigate the characteristics of the Pi fractions and the relationships between Pi fractions and various soil properties. The results showed that the proportion of Ca10-P in the sum of total Pi fractions was the highest in the three soils, accounting for 33.5% in black soil, 48.8% in fluvo-aquic soil, and 44.8% in loess soil. Long-term fertilization practices resulted in periodic changes in soil Pi accumulation or depletion. For black soil and fluvo-aquic soil, the Pi accumulation was higher in the late period (10–20 years) of fertilization than in the early period (0–10 years) under NPK/NPKS and NPKM, whereas the opposite result was found in loess soil. The Pi accumulation occurred in all Pi fractions in black soil; mainly in Ca8-P, Fe-P, and Ca10-P in fluvo-aquic soil; and in Ca2-P, Ca8-P, and O-P in loess soil. Under CK/NK, the soil Pi was depleted mainly in the early period in each of the three soils. In addition to the labile Pi (Ca2-P) and moderately labile Pi (Ca8-P, Fe-P, Al-P), the Ca10-P in black soil and fluvo-aquic soil and O-P in loess soil could also be used by crops. Redundancy analysis showed that soil properties explained more than 90% of the variation in the Pi fractions in each soil, and the explanatory percentages of soil organic matter (SOM) were 43.6% in black soil, 74.6% in fluvo-aquic, and 38.2% in loess soil. Consequently, decisions regarding the application of P fertilizer should consider the accumulation rate and the variations in Pi fractions driven by soil properties in non-acidic soils.

Summary: Urinary tract infection (UTI) is a pervasive health problem worldwide. Patients with a history of UTIs suffer increased risk of recurrent infections, a major risk of antibiotic resistance. Here, we show that bladder infections induce expression of Ezh2 in bladder urothelial cells. Ezh2 is the methyltransferase of polycomb repressor complex 2 (PRC2)—a potent epigenetic regulator. Urothelium-specific inactivation of PRC2 results in reduced urine bacterial burden, muted inflammatory response, and decreased activity of the NF-κB signaling pathway. PRC2 inactivation also facilitates proper regeneration after urothelial damage from UTIs, by attenuating basal cell hyperplasia and increasing urothelial differentiation. In addition, treatment with Ezh2-specific small-molecule inhibitors improves outcomes of the chronic and severe bladder infections in mice. These findings collectively suggest that the PRC2-dependent epigenetic reprograming controls the amplitude of inflammation and severity of UTIs and that Ezh2 inhibitors may be a viable non-antibiotic strategy to manage chronic and severe UTIs.

Backgrounds: Thyroid function was associated with depression and psychotic symptoms; however, little research has focused on its role in coexisting psychotic symptoms in adolescents with depressive disorder. This study aimed to explore the association between thyroid function and psychotic symptoms among depression adolescents. Methods: A total of 679 adolescent patients (aged 12–18) diagnosed as depressive disorder were recruited. Their socio-demographic, clinical data and thyroid function parameters were collected. The severity of psychotic symptoms was measured according to the assessment measure in DSM-5. Based on the severity of psychotic symptoms, patients were distributed into psychotic depression (PD) and non-psychotic depression (NPD) subgroups, respectively. Results: The prevalence rate of PD was 52.7% among adolescents with depressive disorder in this study. PD patients were younger (p

Both natural ginsenoside F2 and unnatural ginsenoside 3β,20S-Di-O-Glc-DM were reported to exhibit anti-tumor activity. Traditional approaches for producing them rely on direct extraction from Panax ginseng, enzymatic catalysis or chemical synthesis, all of which result in low yield and high cost. Metabolic engineering of microbes has been recognized as a green and sustainable biotechnology to produce natural and unnatural products. Hence we engineered the complete biosynthetic pathways of F2 and 3β,20S-Di-O-Glc-DM in Saccharomyces cerevisiae via the CRISPR/Cas9 system. The titers of F2 and 3β,20S-Di-O-Glc-DM were increased from 1.2 to 21.0 mg/L and from 82.0 to 346.1 mg/L at shake flask level, respectively, by multistep metabolic engineering strategies. Additionally, pharmacological evaluation showed that both F2 and 3β,20S-Di-O-Glc-DM exhibited anti-pancreatic cancer activity and the activity of 3β,20S-Di-O-Glc-DM was even better. Furthermore, the titer of 3β,20S-Di-O-Glc-DM reached 2.6 g/L by fed-batch fermentation in a 3 L bioreactor. To our knowledge, this is the first report on demonstrating the anti-pancreatic cancer activity of F2 and 3β,20S-Di-O-Glc-DM, and achieving their de novo biosynthesis by the engineered yeasts. Our work presents an alternative approach to produce F2 and 3β,20S-Di-O-Glc-DM from renewable biomass, which lays a foundation for drug research and development.

Although returning crop residue to fields is a recommended measure for improving soil carbon (C) stocks in agroecosystems, the response of newly formed soil C (NFC) to the integrated supply of residue and nutrients and the microbial mechanisms involved in NFC are not fully understood. Therefore, an 84-day incubation experiment was conducted to ascertain the microbial mechanisms that underpin the NFC response to inputs of residue and nitrogen (N), phosphorus (P), and sulfur (S) in two black (Phaeozem) soils from experimental plots at Gongzhuling, Jilin Province and Hailun, Heilongjiang Province, China. The results showed that adding residue alone accelerated microbial nutrient mining, which was supported by decreases of 8–16% in the ratios of C:N and C:P enzyme activities, relative to soils with nutrient inputs. The NFC amounts increased from 1 156 to 1 722 mg kg−1 in Gongzhuling soil and from 725 to 1 067 mg kg−1 in Hailun soil as the levels of nutrient supplementation increased. Boosted regression tree analysis suggested that β-glucosidase (BG), acid phosphatase (AP), microbial biomass C (MBC), and Acidobacteria accounted for 27.8, 18.5, 14.7, and 8.1%, respectively, of the NFC in Gongzhuling soil and for 25.9, 29.5, 10.1, and 13.9%, respectively, of the NFC in Hailun soil. Path analysis determined that Acidobacteria positively influenced NFC both directly and indirectly by regulating BG, AP, and MBC, in which MBC acquisition was regulated more by AP. The amount of NFC was lower in Hailun soil than in Gongzhuling soil and was directly affected by AP, indicating the importance of soil properties such as SOC and pH in determining NFC. Overall, our results reveal the response of NFC to supplementation by N, P, and S, which depends on Acidobacteria and Proteobacteria, and their investment in BG and AP in residue-amended soil.

Investigating the dynamics and distribution of soil phosphorus (P) fractions can provide a basis for enhancing P utilization by crops. Four treatments from a 29-year long-term experiment in black soil with maize cropping were involved in this study: no fertilizer (CK), inorganic nitrogen and potassium (NK), inorganic nitrogen, phosphorus, and potassium (NPK), and NPK plus manure (NPKM). We analyzed soil P fractions in different soil layers using a modified Hedley sequential method. The long-term NPKM treatment significantly increased total P by 0.6–1.6 times in the different soil layers. The Olsen-P concentration far exceeded the environmental threshold for soil Olsen-P (50.6 mg kg−1) in the NPKM treatment in the 0–60 cm soil profile. Moreover, the concentrations and proportion of labile and partially labile inorganic P (Pi) fractions (i.e., NaHCO3-extracted Pi, NaOH-extracted Pi, and dilute HCl-extracted Pi) to the sum of all P fractions (Pt) in the 0–60 cm soil profile were higher in the NPKM treatment than in the NPK treatment, indicating that manure could promote the transformation of non-labile into more labile forms of P in soil, possibly by manure reducing P fixation by soil particles. Soil organic matter, Mehlich-3 extractable iron (Fe), and organic-bound aluminum were increased by fertilization, and were the main factors influencing the differences in the P fractions in the 0–20 cm soil layer. Soil mineral components, i.e., free Fe oxide and CaCO3, were the main factors influencing the P fractions in the subsoil. The soil P transformation process varied with soil layer and fertilization. Application of manure fertilizer can increase the labile (Olsen) P concentrations of the various soil layers, and thus should reduce the mineral P fertilizer requirement for crop growth and reduce potential environmental damage.

Summary: Pancreatic amyloid deposits composed of a fibrillar form of the human islet amyloid polypeptide (hIAPP) are the pathological hallmark of type 2 diabetes (T2D). Although various cryo-EM structures of polymorphic hIAPP fibrils were reported, the underlying polymorphic mechanism of hIAPP remains elusive. Meanwhile, the structure of hIAPP fibrils with all residues visible in the fibril core is not available. Here, we report the full-length structures of two different polymorphs of hIAPP fibrils, namely slim form (SF, dimer) and thick form (TF, tetramer), formed in a salt-free environment, which share a similar ζ-shaped protofilament but differ in inter-protofilament interfaces. In the absence of salt, electrostatic interactions were found to play a dominant role in stabilizing the fibril structure, suggesting an antagonistic effect between electrostatic and hydrophobic interactions in different salt concentrations environments. Our results shed light on understanding the mechanism of amyloid fibril polymorphism.

10-Deacetylbaccatin III (10-DAB) C10 acetylation is an indispensable procedure for Taxol semi-synthesis, which often requires harsh conditions. 10-Deacetylbaccatin III-10-β-O-acetyltransferase (DBAT) catalyzes the acetylation but acetyl-CoA supply remains a key limiting factor. Here we refactored the innate biosynthetic pathway of acetyl-CoA in Escherichia coli and obtained a chassis with acetyl-CoA productivity over three times higher than that of the host cell. Then, we constructed a microbial cell factory by introducing DBAT gene into this chassis for efficiently converting 10-DAB into baccatin III. We found that baccatin III could be efficiently deacetylated into 10-DAB by DBAT with CoASH and K+ under alkaline condition. Thus, we fed acetic acid to the engineered strain both for serving as a substrate of acetyl-CoA biosynthesis and for alleviating the deacetylation of baccatin III. The fermentation conditions were optimized and the baccatin III titers reached 2, 3 and 4.6 g/L, respectively, in a 3-L bioreactor culture when 2, 3 and 6 g/L of 10-DAB were supplied. Our study provides an environment-friendly approach for the large scale 10-DAB acetylation without addition of acetyl-CoA in the industrial Taxol semi-synthesis. The finding of DBAT deacetylase activity may broaden its application in the structural modification of pharmaceutically important lead compounds.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by excessive proliferation of fibroblasts and excessive accumulation of extracellular matrix (ECM). Ferroptosis is a novel form of cell death characterized by the lethal accumulation of iron and lipid peroxidation, which is associated with many diseases. Our study addressed the potential role played by ferroptosis and iron accumulation in the progression of pulmonary fibrosis. We found that the inducers of pulmonary fibrosis and injury, namely, bleomycin (BLM) and lipopolysaccharide (LPS), induced ferroptosis of lung epithelial cells. Both the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) alleviated the symptoms of pulmonary fibrosis induced by bleomycin or LPS. TGF-β stimulation upregulated the expression of transferrin receptor protein 1 (TFRC) in the human lung fibroblast cell line (MRC-5) and mouse primary lung fibroblasts, resulting in increased intracellular Fe2+, which promoted the transformation of fibroblasts into myofibroblasts. Mechanistically, TGF-β enhanced the expression and nuclear localization of the transcriptional coactivator tafazzin (TAZ), which combined with the transcription factor TEA domain protein (TEAD)-4 to promote the transcription of TFRC. In addition, elevated Fe2+ failed to induce the ferroptosis of fibroblasts, which might be related to the regulation of iron export and lipid metabolism. Finally, we specifically knocked out TFRC expression in fibroblasts in mice, and compared with those in the control mice, the symptoms of pulmonary fibrosis were reduced in the knockout mice after bleomycin induction. Collectively, these findings suggest the therapeutic potential of ferroptosis inhibitors and iron chelators in treating pulmonary fibrosis.

The engineering of devices with various functional molecules in a high-efficient and convenient manner is crucial for biosensors towards biomedical applications. In this study, a multi-channel surface acoustic wave (SAW) device was rapid engineered with bitter receptors prepared from a cell-free protein expression system for the development of biomimetic biosensors for the detection of bitter substances. The novelty of this study mainly attributed to the utilization of DNA-directed immobilization (DDI) method to achieve high-efficient and controllable immobilization of bitter receptors onto sensitive area of SAW device. SAW device is employed as a transducer to monitor the specific interactions between bitter receptors and their ligands, which is a mass-sensitive device that can monitor tiny mass changes by recording the changes in the phase shift of SAW. The obtained results indicated that this biomimetic biosensor was able to respond to different bitter substances by generating various responsive signals, which show good stability. In addition, the distinct responsive patterns could be used to discriminating different bitter substances. It was successfully used to detect and discriminate 10 μM MgSO4, 0.1 μM denatonium, 0.1 μM D-(−)-Salicin, and 0.1 μM quinine. This biomimetic biosensor has great potential to be used as a novel tool for chemical sensing as well as for the research of mechanisms of bitter receptor interacting with their ligands.

Despite its prominent therapeutic efficacy, chemotherapy has raised serious concerns due to the severe adverse effects and multidrug resistance evoked, which propels the search for safe and green therapeutic agents. BAMLET (bovine α-lactalbumin made lethal against tumor cell) is a well-known protein-based anticancer agent of selective tumoricidal activity. Here, we prepared oleic acid-modified mesoporous silica nanoparticles (OA-MSNs) conjugated with bovine α-lactalbumin, a lipoprotein complex resembling BAMLET formed on the surface of MSNs (MSN-BAMLET) to load the anticancer drug of docetaxel (DTX). Compared to that of OA-MSNs/DTX, the obtained MSN-BAMLET/DTX with a sustained and pH-responsive drug release behaviors exhibited good biocompatibility and enhanced cytotoxic effect against cancer cells. Moreover, the presence of lipoprotein complex in MSN-BAMLET contributed to the improved dispersion of the composite in solution and the inhibitory effect on the migration of cancer cells. Furthermore, the adsorption profiles of protein corona on the obtained nanoparticles were analyzed. It was found that the marked low amount and abundance of plasma proteins were adsorbed on the α-lactalbumin coated siliceous composite demonstrated its long circulation property. Finally, in vivo study showed that MSN-BAMLET/DTX contributed to the effective cancer ablation and the prolonged survival. Therefore, the constructed MSN-BAMLET of the mesoregular structure and peculiar tumoricidal effect provides a manipulable nanoplatform as drug nanocarrier for therapeutic applications.

Background: LXYL-P1-2 is the first reported glycoside hydrolase that can catalyze the transformation of 7-β-xylosyl-10-deacetyltaxol (XDT) to 10-deacetyltaxol (DT) by removing the d-xylosyl group at the C-7 position. Successful synthesis of paclitaxel by one-pot method combining the LXYL-P1-2 and 10-deacetylbaccatin III-10-β-O-acetyltransferase (DBAT) using XDT as a precursor, making LXYL-P1-2 a highly promising enzyme for the industrial production of paclitaxel. The aim of this study was to investigate the catalytic potential of LXYL-P1-2 stabilized on magnetic nanoparticles, the surface of which was modified by Ni2+-immobilized cross-linked Fe3O4@Histidine. Results: The diameter of matrix was 20–40 nm. The Km value of the immobilized LXYL-P1-2 catalyzing XDT (0.145 mM) was lower than that of the free enzyme (0.452 mM), and the kcat/Km value of immobilized enzyme (12.952 mM s−1) was higher than the free form (8.622 mM s−1). The immobilized form maintained 50% of its original activity after 15 cycles of reuse. In addition, the stability of immobilized LXYL-P1-2, maintained 84.67% of its initial activity, improved in comparison with free form after 30 d storage at 4°C. Conclusions: This investigation not only provides an effective procedure for biocatalytic production of DT, but also gives an insight into the application of magnetic material immobilization technology. How to cite: Zou S, Chen TJ, Li DY, et al. LXYL-P1-2 immobilized on magnetic nanoparticles and its potential application in paclitaxel production. Electron J Biotechnol 2021;50.https://doi.org/10.1016/j.ejbt.2020.12.005

A major challenge in radically alleviating the threats posed by Cd-contaminated paddy fields to human health is to reduce the Cd levels in both soils and rice grains. In this study, the microbial extraction (ME) treatment using a mixotrophic acidophilic consortium was used for the bioremediation of Cd-contaminated soils. The results showed that the ME treatment enhanced the total Cd (40%) and diethylenetriamine pentaacetic acid-soluble Cd (DTPA-Cd, 64%) removal efficiencies in contaminated soils. In addition, ME treatment decreased the levels of Cd acid-soluble and reducible fractions and thereby reduced Cd uptake in rice tissues. Microbial community analysis indicated that the indigenous soil microbial diversity and composition were not changed after the ME treatment, but the relative abundance of functional microbes associated with Cd removal was improved. Notably, soil available nutrient levels were elevated upon inoculation with mixotrophic acidophiles, resulting in an increase in rice growth and grain weight. This study provides a scientific basis for the potential application and evaluation of ME treatment in the field for remediating Cd-contaminated paddy soils.

Summary: Bergamotenes are bicyclo[3.1.1]heptane sesquiterpenes found abundantly in plants and fungi. Known bergamotene derivatives all possess (2S,6S)-bergamotene backbone. In this study, two (+)-α-trans-bergamotene derivatives (1 and 2) with unusual (2R,6R) configuration were isolated and elucidated from marine fungus Nectria sp. HLS206. The first (+)-α-trans-bergamotene synthase NsBERS was characterized using genome mining and heterologous expression-based strategies. Based on homology search, we characterized another (+)-α-trans-bergamotene synthase LsBERS from Lachnellula suecica and an (+)-α-bisabolol synthase BcBOS from Botrytis cinerea. We proposed that the cyclization mechanism of (+)-α-trans-bergamotene involved endo-anti cyclization of left-handed helix farnesyl pyrophosphate by (6R)-bisabolyl cation, which was supported by molecular docking. The biosynthesis-based volatiles (3–6) produced by heterologous fungal expression systems elicited significant electroantennographic responses of Helicoverpa armigera and Spodoptera frugiperda, respectively, suggesting their potential in biocontrol of these pests. This work enriches diversity of sesquiterpenoids and fungal sesquiterpene synthases, providing insight into the enzymatic mechanism of formation of enantiomeric sesquiterpenes.

Meplazumab is an anti-CD147 humanized IgG2 antibody. The purpose of this study was to characterize the nonclinical safety, tolerance and efficacy evaluation of meplazumab treating chloroquine resistant Plasmodium falciparum. Meplazumab was well tolerated in repeat-dose toxicology studies in cynomolgus monkeys. No observed adverse effect level was 12 mg/kg. No difference between genders in the primary toxicokinetic parameters after repeat intravenous injection of meplazumab. No increased levels of drug exposure and drug accumulation were observed in different gender and dose groups. Meplazumab had a low cross-reactivity rate in various tissues and did not cause hemolysis or aggregation of red blood cells. The biodistribution and excretion results indicated that meplazumab was mainly distributed in the plasma, whole blood, and hemocytes, and excreted in the urine. Moreover, meplazumab effectively inhibited the parasites from invading erythrocytes in humanized mice in a time-dependent manner and the efficacy is superior to that of chloroquine. All these studies suggested that meplazumab is safe and well tolerated in cynomolgus monkeys, and effectively inhibits P. falciparum from invading into human red blood cells. These nonclinical data facilitated the initiation of an ongoing clinical trial of meplazumab for antimalarial therapy.

Soil productivity (SP) without external fertilization influence is an important indicator for the capacity of a soil to support crop yield. However, there have been difficulties in estimating values of SPs for soils after various long-term field treatments because the treatment without external fertilization is used but is depleted in soil nutrients, leading to erroneous estimation. The objectives of this study were to estimate the change of SP across different cropping seasons using pot experiments, and to evaluate the steady SP value (which is defined by the basal contribution of soil itself to crop yield) after various long-term fertilization treatments in soils at different geographical locations. The pot experiments were conducted in Jinxian of Jiangxi Province with paddy soil, Zhengzhou of Henan Province with fluvo-aquic soil, and Gongzhuling of Jilin Province with black soils, China. Soils were collected after long-term field fertilization treatments of no fertilizer (control; CK-F), chemical fertilizer (NPK-F), and combined chemical fertilizer with manure (NPKM-F). The soils received either no fertilizer (F0) or chemical fertilizer (F1) for 3–6 cropping seasons in pots, which include CK-P (control; no fertilizer from long-term field experiments for pot experiments), NPK-P (chemical fertilizer from long-term field experiments for pot experiments), and NPKM-P (combined chemical and organic fertilizers from long-term field experiments for pot experiments). The yield data were used to calculate SP values. The initial SP values were high, but decreased rapidly until a relatively steady SP was achieved at or after about three cropping seasons for paddy and fluvo-aquic soils. The steady SP values in the third cropping season from CK-P, NPK-P, and NPKM-P treatments were 37.7, 44.1, and 50.0% in the paddy soil, 34.2, 38.1, and 50.0% in the fluvo-aquic soil, with the highest value observed in the NPKM-P treatment for all soils. However, further research is required in the black soils to incorporate more than three cropping seasons. The partial least squares path mode (PLS-PM) showed that total N (nitrogen) and C/N ratio (the ratio of soil organic carbon and total N) had positive effects on the steady SP for all three soils. These findings confirm the significance of the incorporation of manure for attaining high soil productivity. Regulation of the soil C/N ratio was the other main factor for steady SP through fertilization management.

As a subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex, GATA zinc finger domain containing 2B (GATAD2B) plays a vital role in chromatin modification and transcriptional regulation. To further investigate the role of GATAD2B in cell fate determination of human ESCs, we generated two GATAD2B homozygous knockout human ESC lines by CRISPR/Cas9 technology. The cell line exhibits normal karyotype and typical stem cell morphology, following the high expression of pluripotent genes and differentiation potential in vitro. These cell lines will provide cell resources to investigate epigenetic regulation in extensive biological processes as menthioned above.

Cardiovascular diseases (CVD) are a significant cause of human health harm. In the past, stem cell therapy was reported to have functional defects, such as immune rejection, tumorigenicity, and infusion toxicity. Exosomes are extracellular vesicles with lipid bilayer membrane structure, containing proteins, lipids, mRNA, miRNA, DNA, and other molecules, which can mediate various biological functions such as immune response, inflammatory response, cell migration, and differentiation intercellular communication. Exosomal miRNAs have outstanding advantages in disease diagnosis and curative effect prediction. Likewise, paracrine factors could also mediate the main therapeutic effect of mesenchymal stem cells. Research has shown that mesenchymal stem cell-derived micro-exosomes, which may come from stem cells, accumulate in the ischemic tissue and regulate cell proliferation, apoptosis, inflammation, and angiogenesis sites of myocardial injury after being transplanted. This review reviewed the molecular mechanisms of exosomes and internal microRNAs derived from mesenchymal stem cells in cardiac ischemic injury repair.

Summary: Activation of nucleic acid sensing Toll-like receptors (TLRs) in B cells is involved in antiviral responses by promoting B cell activation and germinal center responses. In order to take advantage of this natural pathway for vaccine development, synthetic pathogen-like antigens (PLAs) constructed of multivalent antigens with encapsulated TLR ligands can be used to activate B cell antigen receptors and TLRs in a synergistic manner. Here we report a PLA-based coronavirus disease 2019 (COVID-19) vaccine candidate designed by combining a phage-derived virus-like particle carrying bacterial RNA as TLR ligands with the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein as the target antigen. This PLA-based vaccine candidate induces robust neutralizing antibodies in both mice and non-human primates (NHPs). Using a NHP infection model, we demonstrate that the viral clearance is accelerated in vaccinated animals. In addition, the PLA-based vaccine induces a T helper 1 (Th1)-oriented response and a durable memory, supporting its potential for further clinical development.

Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease with worldwide high prevalence. Although AS is strongly associated with HLA-B27 MHC-I antigen presentation, the role played by αβ T cells in AS remains elusive. Methods: Utilizing TCRβ repertoire sequencing and bioinformatics tools developed in house, we analyzed overall TCR repertoire structures and antigen-recognizing CDR3 motifs in AS patients with different disease activities. Findings: We found that disease progression is associated with both CD4+ and CD8+ T cell oligo-clonal expansion, which suggests that αβ T cell activation may mediate AS disease progression. By developing a bioinformatics platform to dissect antigen-specific responses, we discovered a cell population consisting of both CD4+ and CD8+ T cells expressing identical TCRs, herein termed CD4/8 T cells. CD4/8 clonotypes were highly enriched in the spondyloarthritic joint fluid of patients, and their expansion correlated with the activity of disease. Interpretation: These results provide evidence on the T cell clone side to reveal the potential role of CD4/8 T cells in the etiology of AS development. Keywords: Ankylosing spondylitis, Autoimmune disease, T cells, TCR repertoire, Human, Complementarity determining region 3

Taxol is a “blockbuster” antitumor drug produced by Taxus species with extremely low amount, while its analogue 7-β-xylosyl-10-deacetyltaxol is generally much higher in the plants. Both the fungal enzymes LXYL-P1−1 and LXYL-P1−2 can convert 7-β-xylosyl-10-deacetyltaxol into 10-deacetyltaxol for Taxol semi-synthesis. Of them, LXYL-P1−2 is twice more active than LXYL-P1−1, but there are only 11 significantly different amino acids in terms of the polarity and acidic-basic properties between them. In this study, single and multiple site-directed mutations at the 11 sites from LXYL-P1−1 to LXYL-P1−2 were performed to define the amino acids with upward bias in activities and to acquire variants with improved catalytic properties. Among all the 17 mutants, E12 (A72T/V91S) was the most active and even displayed 2.8- and 3-fold higher than LXYL-P1−2 on β-xylosidase and β-glucosidase activities. The possible mechanism for such improvement was proposed by homology modeling and molecular docking between E12 and 7-β-xylosyl-10-deacetyltaxol. The recombinant yeast GS115-P1E12-7 was constructed by introducing variant E12, the molecular chaperone gene pdi and the bacterial hemoglobin gene vhb. This engineered yeast rendered 4 times higher biomass enzyme activity than GS115-3.5K-P1−2 that had been used for demo-scale fermentation. Thus, GS115-P1E12-7 becomes a promising candidate to replace GS115-3.5K-P1−2 for industrial purpose. KEY WORDS: β-Glycosidases, Combinatorial mutation, Improved catalytic property, Molecular docking, Engineered yeast, Taxol

COVID-19 is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early reported symptoms include fever, cough, and respiratory symptoms. There were few reports of digestive symptoms. However, with COVID-19 spreading worldwide, symptoms such as vomiting, diarrhoea, and abdominal pain have gained increasing attention. Research has found that angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, is strongly expressed in the gastrointestinal tract and liver. Whether theoretically or clinically, many studies have suggested a close connection between COVID-19 and the digestive system. In this review, we summarize the digestive symptoms reported in existing research, discuss the impact of SARS-CoV-2 on the gastrointestinal tract and liver, and determine the possible mechanisms and aetiology, such as cytokine storm. In-depth exploration of the relationship between COVID-19 and the digestive system is urgently needed.

Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Currently, many methods have been proposed by researchers for the prevention and treatment of CVD; among them, stem cell-based therapies are the most promising. As the cells of origin for various mature cells, stem cells have the ability to self-renew and differentiate. Stem cells have a powerful ability to regenerate biologically, self-repair, and enhance damaged functional tissues or organs. Allogeneic stem cells and somatic stem cells are two types of cells that can be used for cardiac repair. Theoretically, dilated cardiomyopathy and acute myocardial infarction can be treated with such cells. In addition, stem cell transplantation procedures, including intravenous, epicardial, cardiac, and endocardial injections, have been reported to provide significant benefits in clinical practice; however, there are still a number of issues that need further study and consideration, such as the form and quantity of transplanted cells and post-transplantation health. The goal of this analysis was to summarize the recent advances in stem cell-based therapies and their efficacy in cardiovascular regenerative medicine.

Congenital heart disease, particularly cyanotic congenital heart disease (CCHD), may lead to a neurodevelopmental delay through central nervous system injury, more unstable central nervous system development, and increased vulnerability of the nervous system. Neurodevelopmental disease is the most serious disorder of childhood, affecting the quality of life of children and their families. Therefore, the monitoring and optimization of nerve damage treatments are important. The factors contributing to neurodevelopmental disease are primarily related to preoperative, intraoperative, postoperative, genetic, and environmental causes, with intraoperative causes being the most influential. Nevertheless, few studies have examined these factors, particularly the influencing factors during early postoperative care. Children with congenital heart disease may experience brain damage during early heart intensive care due to unstable haemodynamics and total body oxygen transfer, particularly early postoperative inflammatory reactions in the brain, blood glucose levels, and other factors that potentially influence long-term neural development. This study analyses the forms of structural and functional brain damage in the early postoperative period, along with the recent evolution of research on its contributing factors.

Hypoxia, the decline of tissue oxygen stress, plays a role in mediating cellular processes. Cardiovascular disease, relatively widespread with increased mortality, is closely correlated with oxygen homeostasis regulation. Besides, hypoxia-inducible factor-1(HIF-1) is reported to be a crucial component in regulating systemic hypoxia-induced physiological and pathological modifications like oxidative stress, damage, angiogenesis, vascular remodeling, inflammatory reaction, and metabolic remodeling. In addition, HIF1 controls the movement, proliferation, apoptosis, differentiation and activity of numerous core cells, such as cardiomyocytes, endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages. Here we review the molecular regulation of HIF-1 in cardiovascular diseases, intended to improve therapeutic approaches for clinical diagnoses. Better knowledge of the oxygen balance control and the signal mechanisms involved is important to advance the development of hypoxia-related diseases.

Background: Colorectal cancer (CRC) has a high incidence and mortality rate worldwide. Colitis-associated CRC (CAC) is used for describing the relationship between inflammation and CRC. No chemopreventive agents have been found to be both effective and safe in CRC. Therefore, the prevention and treatment of CAC are extremely urgent. Wu Mei Wan (WMW) has been used for the clinical treatment of enteritis with a remarkable efficacy. Here, we aim to investigate the underlying mechanism of WMW in the prevention of CAC. Methods: The AOM/DSS-induced CAC mouse model was used, and the mice were divided into normal control (NC), AOM/DSS model control (MC), and AOM/DSS plus WMW (WMW). The weight of mice, the score of DAI, survival rate, number of tumors and sample collection were performed at the end of the 14th week. Histopathological examination was performed using Hematoxylin–Eosin (HE) staining. Tumor cell proliferation was indicated by the expression of PCNA, and p65 and p-STAT3 were detected by immunohistochemistry. Serum IL-6 levels were detected by enzyme-linked immunosorbent assay (ELISA). The expression of p65, IL-6 and p-STAT3 in the colon was detected by Western Blot. Intestinal flora was analyzed by 16S rDNA sequencing. Results: WMW improved the survival rate of mice in the MC group and also attenuated CAC symptoms such as abnormal clinical colitis and pathological changes to intestinal tissue by reducing DAI score, tumor formation, tumor volume, and grade of tumorigenesis. WMW also reduced the proliferation of tumor cells in colon tissues. WMW decreased the expression of p65, IL-6, and p-STAT3 in colon tumors of CAC mice. WMW decreased Bacteroidetes and increased Firmicutes at the phylum level, while decreasing bacteroidales_s24-7_group and increasing the number of Lachnospiraceae at the family level. Conclusion: WMW attenuates CAC by regulating the balance between “tumor-promoting bacteria” and “tumor-suppressing bacteria” and the NF-kB/IL-6/STAT3 pathway. WMW has the potential to be a safe and effective chemopreventive drug but further clinical evidence is necessary.

Patients with cancer survivors are at increased risk of cardiovascular disease(CVD). Cardio-oncology has developed as a new discipline with the advances in cancer treatment. There are many new challenges for the clinician and a new frontier for research and investigation. There is an urgent need for further study on the prevention of cardiovascular toxicity. Imperatorin (IMP) is a natural form of coumarin and extract from several plants with diver’s pharmacokinetic effects, including antioxidant and anti-inflammatory properties. This review focus on the molecular mechanisms and pharmacological effects of Imperatorin maybe provide potential cancer and cardiovascular protection that targets IMP. Further studies are required to elucidate the entire spectrum of cytotoxic activities of these compounds to validate and expand their preclinical and clinical applications and to clarify the potential role of IMP.

Black soil is one of the most precious soil resources on earth because it has abundant carbon stocks and a relatively high production capacity. However, decreasing organic matter after land reclamation, and the effects of long-term inputs of organic carbon have made it less fertile black soil in Northeast China. Straw return could be an effective method for improving soil organic carbon (SOC) sequestration in black soils. The objective of this study was to evaluate whether straw return effectively increases SOC sequestration. Long-term field experiments were conducted at three sites in Northeast China with varying latitudes and SOC densities. Study plots were subjected to three treatments: no fertilization (CK); inorganic fertilization (NPK); and NPK plus straw return (NPKS). The results showed that the SOC stocks resulting from NPKS treatment were 4.0 and 5.7% higher than those from NPK treatment at two sites, but straw return did not significantly affect the SOC stocks at the third site. Furthermore, at higher SOC densities, the NPKS treatment resulted in significantly higher soil carbon sequestration rates (CSR) than the NPK treatment. The equilibrium value of the CSR for the NPKS treatment equated to cultivation times of 17, 11, and 8 years at the different sites. Straw return did not significantly increase the SOC stocks in regions with low SOC densities, but did enhance the C pool in regions with high SOC densities. These results show that there is strong regional variation in the effects of straw return on the SOC stocks in black soil in Northeast China. Additional cultivations and fertilization practices should be used when straw return is considered as an approach for the long-term improvement of the soil organic carbon pool.

CD147 is highly expressed on the surface of numerous tumor cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated as an effective approach for lung and liver cancer therapy. In the immune system, CD147 is recognized as a co-stimulatory receptor and impacts the outcome of thymic selection. Using T cell-specific deletion, we showed here that in thymus CD147 is indispensable for the stable αβ T cell lineage commitment: loss of CD147 biases both multipotent DN (double negative) and fully committed DP (double positive) cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11b, a master transcription factor in determining T cell identity. In addition, functional blocking of CD147 by antibody phenocopies genetic deletion to enrich NK-like cells in the periphery. Furthermore, using a melanoma model and orthotopic liver cancer transplants, we showed that the augmentation of NK-like cells strongly associates with resistance against tumor growth upon CD147 suppression. Therefore, besides its original function in tumorigenesis, CD147 is also an effective surface target for immune modulation in tumor therapy.

Regulatory dendritic cell (DCregs)-based immunotherapy is a potential therapeutic tool for transplant rejection. We generated DCregs from murine induced pluripotent stem cells (iPSCs), which could remain in a “stable immature stage” even under strong stimulation. Harnessing this characteristic, we hypothesized that iPS-DCregs worked as a negative vaccine to generate regulatory T cells (Tregs), and induced donor-specific allograft acceptance. We immunized naive CBA (H-2Kk) mice with B6 (H-2Kb) iPS-DCregs and found that Tregs (CD4+CD25+FOXP3+) significantly increased in CBA splenocytes. Moreover, immunized CBA recipients permanently accepted B6 cardiac grafts in a donor-specific pattern. We demonstrated mechanistically that donor-type iPS-DCregs triggered transforming growth factor β1 secretion, under which the donor-antigen peptides directed naive CD4+ T cells to differentiate into donor-specific FOXP3+ Tregs instead of into effector T cells in vivo. These findings highlight the potential of iPS-DCregs as a key cell therapy resource in clinical transplantation.

The combined use of chemical and organic fertilizers is considered a good method to sustain high crop yield and enhance soil organic carbon (SOC), but it is still unclear when and to what extent chemical fertilizers could be replaced by organic fertilizers. We selected a long-term soil fertility experiment in Gongzhuling, Northeast China Plain to examine the temporal dynamics of crop yield and SOC in response to chemical nitrogen, phosphorus, and potassium (NPK) fertilizers and manure, applied both individually and in combination, over the course of three decades (1980–2010). We aimed to test 1) which fertilizer application is the best for increasing both maize yield and SOC in this region, and 2) whether chemical fertilizers can be replaced by manure to maintain high maize yield and enhance SOC, and if so, when this replacement should be implemented. We observed that NPK fertilizers induced a considerable increase in maize yield in the first 12 years after the initiation of the experiment, but manure addition did not. In the following years, the addition of both NPK fertilizers and manure led to an increase in maize yield. SOC increased considerably in treatments with manure but remained the same or even declined with NPK treatments. The increase in maize yield induced by NPK fertilizers alone declined greatly with increasing SOC, whereas the combination of NPK and manure resulted in high maize yield and a remarkable improvement in SOC stock. Based on these results we suggested that NPK fertilizers could be at least partially replaced by manure to sustain high maize yield after SOC stock has reached 41.96 Mg C ha−1 in the Northeast China Plain and highly recommend the combined application of chemical fertilizers and manure (i.e., 60 Mg ha−1).

The embryonic process of forming a complex structure such as the heart remains poorly understood. Here, we show that Six2 marks a dynamic subset of second heart field progenitors. Six2-positive (Six2+) progenitors are rapidly recruited and assigned, and their descendants are allocated successively to regions of the heart from the right ventricle (RV) to the pulmonary trunk. Global ablation of Six2+ progenitors resulted in RV hypoplasia and pulmonary atresia. An early stage-specific ablation of a small subset of Six2+ progenitors did not cause any apparent structural defect at birth but rather resulted in adult-onset cardiac hypertrophy and dysfunction. Furthermore, Six2 expression depends in part on Shh signaling, and Shh deletion resulted in severe deficiency of Six2+ progenitors. Collectively, these findings unveil the chronological features of cardiogenesis, in which the mammalian heart is built sequentially by temporally distinct populations of cardiac progenitors, and provide insights into late-onset congenital heart disease.

Carvedilol, a third generation beta blocker, is in clinical use for heart failure patients. However, besides adrenergic receptor blockade, the pharmacological effects of carvedilol on cardiomyocytes remain unknown. AMP-activated protein kinase (AMPK) is an emerging target recognized for heart failure treatment. The mechanical properties and intracellular Ca2+ properties were measured in isolated cardiomyocyte contractile functions in response to ischemic stress. Treatment of cardiomyocytes with carvedilol augmented phosphorylation of AMPK and downstream acetyl CoA carboxylase (ACC), and ameliorated hypoxia-induced impairment in maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt), and the impaired peak height and peak shortening (PS) amplitude caused by hypoxia. Carvedilol treatment improved calcium homeostasis with rescuing the peak Ca2+ signal, the maximum rate of Ca2+ change during contraction (+dF/dt) and the maximum rate of Ca2+ change during relaxation (-dF/dt) under hypoxia conditions. In mouse hearts perfused ex vivo with carvedilol, the function of post-ischemia left ventricle was improved and an augmentation in myocardial glucose uptake and glucose oxidation, and inhibition of fatty acid oxidation during ischemia and reperfusion. The protective effect of carvedilol was further supported in an in vivo regional ischemia model by ligation of left anterior descending coronary artery (LAD), mice treated with carvedilol followed by LAD occlusion and reperfusion showed significant size reduction in infarcted myocardium and improved cardiac functions. Therefore, Carvedilol as a clinical drug can modulate cardiac AMPK signaling pathway to reduce ischemic insults by ischemia and reperfusion.

Ginsenoside Re (GS-Re), which is a major monomeric member of the ginseng trialcohol saponin family, is one of the main active components of ginseng and plays an important role in protecting the cardiovascular system. Here, we report a novel function by which GS-Re regulates the eNOS/NO/cGMP pathway, which affects the platelet-derived growth factor-BB (PDGF-BB)-induced proliferation of vascular smooth muscle cells (VSMCs). GS-Re inhibited PDGF-BB-induced VSMC proliferation in a concentration-dependent manner without cytotoxicity, and the endothelial nitric oxide synthase (eNOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) antagonized the antiproliferative effect of GS-Re. The flow cytometry analysis suggested that GS-Re regulates VSMC proliferation by influencing the cell cycle transition from G0/G1 to S phase and decreasing the expression of G0/G1-specific regulatory proteins, including proliferating cell nuclear antigen (PCNA), cyclin D1, and CDK4, in PDGF-BB-treated VSMCs, consequently upregulating the protein expression of p21. After GS-Re treatment, the levels of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) and the phos-eNOS Ser1177/eNOS protein ratio were obviously increased. In addition, treatment with L-NAME blocked the eNOS/NO/cGMP signaling pathway, and the protein levels of PCNA, cyclin D1, and CDK4 were markedly increased in GS-Re-treated VSMCs, while p21 expression was decreased in PDGF-BB-induced VSMCs. Overall, these findings reveal that GS-Re can inhibit the proliferation of VSMCs through G0/G1 cell cycle arrest, which is closely related to eNOS/NO/cGMP pathway activation. The present results provide basic pharmacological evidence of the potential prevention and treatment of cardiovascular diseases by GS-Re.

Summary: Reprogramming somatic cells to pluripotency by Oct4, Sox2, Klf4, and Myc represent a paradigm for cell fate determination. Here, we report a combination of Jdp2, Jhdm1b, Mkk6, Glis1, Nanog, Essrb, and Sall4 (7F) that reprogram mouse embryonic fibroblasts or MEFs to chimera competent induced pluripotent stem cells (iPSCs) efficiently. RNA sequencing (RNA-seq) and ATAC-seq reveal distinct mechanisms for 7F induction of pluripotency. Dropout experiments further reveal a highly cooperative process among 7F to dynamically close and open chromatin loci that encode a network of transcription factors to mediate reprogramming. These results establish an alternative paradigm for reprogramming that may be useful for analyzing cell fate control. : Wang et al. report a 7F reprogramming system for iPSC generation and the underlying mechanism for inducing pluripotency through a TF network, opening an alternative path for reprogramming cell fate.