Discovery of N-(phenylsulfonyl)thiazole-2-carboxamides as potent α-glucosidase inhibitors.

In a search for novel nonsugar α-glucosidase inhibitors for diabetes treatment, a series of N-(phenylsulfonyl)thiazole-2-carboxamide derivatives were designed and synthesized, the α-glucosidase inhibitory activities were then evaluated. Several compounds with promising α-glucosidase inhibitory effects were identified. Among these, compound W24 which shows low cytotoxicity and good α-glucosidase inhibitory activity with an IC50 value of 53.0 ± 7.7 µM, is more competitive compared with the commercially available drug acarbose (IC50 = 228.3 ± 9.2 µM). W24 was identified as a promising candidate in the development of α-glucosidase inhibitors. Molecular docking studies and molecular dynamics simulation were also performed to reveal the binding pattern of the active compound to α-glucosidase, and the binding free energy of the best compound W24 was 36.3403 ± 3.91 kcal/mol.

Safety and efficacy of Pucotenlimab (HX008) - a humanized immunoglobulin G4 monoclonal antibody in patients with locally advanced or metastatic melanoma: a single-arm, multicenter, phase II study.

BACKGROUND: Pucotenlimab is a novel recombinant humanized anti-PD-1 (Programmed death-1) monoclonal antibody, which belongs to the human IgG4/kappa subtype, and can selectively block the binding of PD-1 with its ligands PD-L1 and PD-L2. METHODS: In this phase 2 trial, patients with locally advanced or metastatic melanoma who had failed conventional treatment (chemotherapy, targeted therapy, interferon, IL-2, et al.) were recruited. The patients were administrated with Pucotenlimab of 3 mg/kg every 3 weeks until disease progression, intolerable toxicity, or treatment discontinuation for any other reasons. The primary endpoint was the overall response rate (ORR). The secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: One-hundred and nineteen patients were enrolled and followed up for 19.32 (ranging from 15.901 to 24.608) months by the cutoff date of July 30th, 2021. The ORR was 20.17% (24/119, 95% CI, 13.370%-28.506%) based on both independent review committee (IRC) and the investigator's assessment per RECIST v1.1. The median PFS were 2.89 (95% CI, 2.037-4.074) months and 2.46 (95% CI, 2.004-4.008) months based on IRC and investigator's assessment, respectively, per RECIST v1.1. The median OS was 16.59 (95% CI, 13.963-26.973) months. Treatment-related adverse events (TRAEs) occurred in 77.3% (92/119) of the patients. The incidence of Grade ≥ 3 TRAEs was 15.1% (18/119). In addition, none of the patients died because of TRAEs. As for biomarker analysis, Eotaxin (CCL11) and MCP-1 (CCL2) were related to treatment response, while TNF-α and VEGF were related to treatment failure. CONCLUSIONS: Pucotenlimab as a ≥ 2nd line therapy showed promising efficacy and tolerable toxicity for patients with locally advanced or metastatic melanoma. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04749485 (registered retrospectively on 11/02/2021).

New Insight into CO2 Reduction to Formate by In Situ Hydrogen Produced from Hydrothermal Reactions with Iron.

To reveal the nature of CO2 reduction to formate with high efficiency by in situ hydrogen produced from hydrothermal reactions with iron, DFT calculations were used. A reaction pathway was proposed in which the formate was produced through the key intermediate species, namely iron hydride, produced in situ in the process of hydrogen gas production. In the in situ hydrogenation of CO2, the charge of H in the iron hydride was -0.135, and the Fe-H bond distance was approximately 1.537 Å. A C-H bond was formed as a transition state during the attack of Hδ- on Cδ+. Finally, a HCOO species was formed. The distance of the C-H bond was 1.107 Å. The calculated free energy barrier was 16.43 kcal/mol. This study may provide new insight into CO2 reduction to formate in hydrothermal reactions with metal.

Academician Wen-Rui Hu - Eminent Pioneer and Prominent Leader of Microgravity Science in China.

In 2021, the scientific community celebrated the 85th anniversary of the Chinese scientist Academician Wen-Rui Hu. In addition to his innovative contributions to cosmic magnetohydrodynamics (MHD) during his early scientific career, he has initiated microgravity science research in China from the middle of 1980s, and made many pioneering contributions to microgravity fluid physics. He has also promoted researches in China in the fields of space material science, space biotechnology, space fundamental physics, and relevant applications. He is respected as the founder of microgravity science in China because of his eminent pioneering contributions and prominent leadership. This article tries to provide a brief historical perspective of the tireless explorations of Academician Wen-Rui Hu in the field of microgravity science and other relevant disciplines till today based on personal views of his former students and colleagues.

Chlorinated Paraffins in Human Milk from Urban Sites in China, Sweden, and Norway.

Short-, medium-, and long-chain chlorinated paraffins (SCCPs, MCCPs, and LCCPs) were analyzed in human milk from the Yangtze River Delta (YRD) and Scandinavia. Individual samples were collected from Shanghai, Jiaxing, and Shaoxing (China), Stockholm (Sweden), and Bodø (Norway) between 2010 and 2016. Mean concentrations (range) of SCCPs, MCCPs, and LCCPs in samples from the YRD were 124 [

Removal Efficacy of Opportunistic Pathogens and Bacterial Community Dynamics in Two Drinking Water Treatment Trains.

Drinking water treatment processes (DWTPs) impact pathogen colonization and microbial communities in finished water; however, their efficacies against opportunistic pathogens are not fully understood. In this study, the effects of treatment steps on the removal of Legionella spp., Legionella pneumophila, nontuberculous mycobacteria, Mycobacterium avium, and two amoeba hosts (Vermamoeba vermiformis, Acanthamoeba) are evaluated in two parallel trains of DWTPs equipped with different pretreatment units. Quantitative polymerase chain reaction analysis demonstrates significantly reduced numbers of total bacteria, Legionella, and mycobacteria during ozonation, followed by a rebound in granular activated carbon (GAC) filtration, whereas sand filtration exerts an overarching effect in removing microorganisms in both treatment trains. V. vermiformis is more prevalent in biofilm (34%) than water samples (7.7%), while Acanthamoeba is not found in the two trains of DWTPs. Illumina sequencing of bacterial 16S rRNA genes reveals significant community shifts at different treatment steps, as well as distinct bacterial community structures in water and biofilm samples in parallel units (e.g., ozonation, GAC, sand filtration) between the two trains (analysis of similarities (ANOSIM), p < 0.05), implying the potential influence of different pretreatment steps in shaping the downstream microbiome. Overall, the results provide insights to mitigation of opportunistic pathogens and engineer approaches for managing bacterial communities in DWTPs.

Tissue-Specific Accumulation, Sexual Difference, and Maternal Transfer of Chlorinated Paraffins in Black-Spotted Frogs.

The restriction on usage of short-chain chlorinated paraffins (SCCPs) under Stockholm Convention may promote the production and application of medium chain chlorinated paraffins (MCCPs) and long chain chlorinated paraffins (LCCPs) as substitutes. This study focused on the tissue-specific exposure to SCCPs, MCCPs, and LCCPs in black-spotted frog, a prevalent amphibian species in the Yangtze River Delta, China. The total CP concentrations in frog liver, muscle, and egg samples ranged of 35-1200, 6.3-97, and 6.8-300 ng/g wet weight (ww), respectively. Livers and eggs contained primary SCCPs (on average 78%) while MCCPs (43%) together with SCCPs (41%) were dominant in muscles. A significantly negative correlation was observed between hepatosomatic index and CPs concentration in liver ( p < 0.01), indicating that CP exposure may lower survival rates of frogs by suppressing the energy storage in liver. Additionally, maternal transfer, an important uptake pathway for CPs, was evaluated for the first time by calculating the ratios of CP levels in eggs to those in their paired liver tissues. The ratio of egg to liver for CP congener groups raised with the increasing of log Kow values, indicating mother to egg transport of CPs was related to the lipophilicity of the chemicals.

Rational Design of Cancer-Targeted Selenadiazole Derivative as Efficient Radiosensitizer for Precise Cancer Therapy.

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of targeted therapies for personalized cancer medicine. Herein, cancer targeting RGD peptide has been covalently conjugated to selenadiazole derivative (RGD-SeD) to improve its cancer selectivity. The RGD decoration significantly enhances the anticancer efficacy of RGD-SeD in αVß3 integrin-overexpressing HepG2 liver cancer cells but not in normal liver cells. Cellular uptake assay and fluorescent imaging confirmed the selectivity of RGD-SeD to integrin-overexpressing cancer cells. RGD-SeD strongly sensitizes HepG2 cells to clinically used X-ray radiotherapy through ROS overproduction, which triggers DNA damage-mediated apoptosis and G2/M cell cycle arrest. This X-ray-responsive DNA damage activates p53 signaling pathways by phosphorylation of ATM/ATR and γ-H2A.X. Furthermore, in a HepG2 nude mice xenograft model, the combined treatment of RGD-SeD and X-ray demonstrates potent in vivo antitumor efficacy via induction of apoptotic cell death but shows no toxicity on the functions of major organs. In summary, this study provides a strategy to design a selenium-based cancer targeting radiosensitizer for precise cancer therapy.

Short-, Medium-, and Long-Chain Chlorinated Paraffins in Wildlife from Paddy Fields in the Yangtze River Delta.

Short-chain chlorinated paraffins (SCCPs) were added to Annex A of the Stockholm Convention on Persistent Organic Pollutants in April, 2017. As a consequence of this regulation, increasing production and usage of alternatives, such as medium- and long-chain chlorinated paraffins (MCCPs and LCCPs, respectively), is expected. Little is known about the environmental fate and behavior of MCCPs and LCCPs. In the present study, SCCPs, MCCPs, and LCCPs were analyzed in nine wildlife species from paddy fields in the Yangtze River Delta, China, using atmospheric pressure chemical ionization-quadrupole time-of-flight mass spectrometry. SCCPs, MCCPs, and LCCPs were detected in all samples at concentrations ranging from <91-43 000, 96-33 000, and 14-10 000 ng/g lipid, respectively. Most species contained primarily MCCPs (on average 44%), with the exception of collared scops owl and common cuckoo, in which SCCPs (43%) accumulated to a significantly (i.e., p < 0.05) greater extent than MCCPs (40%). Cl6 groups were dominant in most species except for yellow weasel and short-tailed mamushi, which contained primarily Cl7 groups. Principal components analysis, together with CP concentrations and carbon stable isotope analysis showed that habitat and feeding habits were key factors driving CP accumulation and congener group patterns in wildlife. This is the first report of LCCP exposure in wildlife and highlights the need for data on risks associated with CP usage.

Catalytic wet oxidation of high concentration pharmaceutical wastewater with Fe3+ as catalyst.

Catalytic wet oxidation of high concentration pharmaceutical wastewater with Fe3+ as catalyst was carried out in a batch reactor. Results showed that the degradation of pharmaceutical wastewater was enhanced significantly by Fe3+. The effects of reaction parameters, such as the catalyst dose, reaction temperature, time, and initial oxygen pressure, were discussed. The chemical oxygen demand (COD) removal increased with the increases of catalyst dose, temperature, time and oxygen supply. With the initial COD 34,000-35,000 mg/L, approximately 70% COD removal can be achieved under the conditions of catalyst 1.0 g and oxygen pressure 1.0 MPa at 250 °C after 60 min. The results of kinetic studies showed that two reaction steps existed in this oxidation process, which followed an apparent first-order rate law. This process provides an effective approach for the pretreatment of high concentration pharmaceutical wastewater.

Using environmental DNA to assess population-wide spatiotemporal reserve use.

Scientists increasingly rely on protected areas to assist in biodiversity conservation, yet the efficacy of these areas is rarely systematically assessed, often because of underfunding. Still, adaptive management strategies to maximize conservation success often rely on understanding the temporal and spatial dynamism of populations therein. Examination of environmental DNA (eDNA) is a time and cost-effective way to monitor species' distribution, and quantitative polymerase chain reaction (qPCR) provides information on organismal abundance. To date, however, such techniques remain underused for population assessments in protected areas. We determined eDNA concentration of the critically endangered Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) to describe its occurrence, range, and use of the Tian e-Zhou National Nature Reserve in Hubei, China, across seasons and hydrological depths. Despite the observation that total eDNA concentrations were highest in surface waters in summer, finless porpoise eDNA concentrations were significantly higher in deeper waters than in surface waters in summer. During the breeding season (spring), eDNA signals were site specific and restricted to the core area of the reserve. However, postbreeding eDNA concentrations were widespread across the reserve, encompassing sites previously thought to be unfrequented by the species. Our results suggest spatiotemporal idiosyncrasies in site, depth, and seasonal use of the reserve and a propensity for postbreeding population dispersal. With eDNA and qPCR we were able to assess an entire population's use of a protected area. Illuminating nuances in habitat use via eDNA could be valuable to set pragmatic conservation goals for this, and other, species.

Photodegradation of 4-tert-butylphenol in aqueous solution by UV-C, UV/H2O2 and UV/S2O8(2-) system.

The photolytic degradation of 4-tert-butylphenol (4-t-BP) in aqueous solution was investigated using three kinds of systems: UV-C directly photodegradation system, UV/H2O2 and UV/S2O8(2-) system. Under experimental conditions, the degradation rate of 4-t-BP was in the order: UV/S2O8(2-) > UV/H2O2 > UV-C. The reaction kinetics of UV/S2O8(2-) system were thoroughly investigated. The increase of S2O8(2-) concentration enhanced the 4-t-BP degradation rate, which was inhibited when the concentration of S2O8(2-) exceeded 4.0 mM. The highest efficacy in 4-t-BP degradation was obtained at pH 6.5. The oxidation rate of 4-t-BP could be accelerated by increasing the reaction temperature and irradiation intensity. The highest rate constant (kobs = 8.4 × 10(-2) min(-1)) was acquired when the reaction temperature was 45 °C. The irradiation intensity was measured by irradiation distance, and the optimum irradiation distance was 10 cm. Moreover, the preliminary mechanism of 4-t-BP degradation was studied. The bond scission of the 4-t-BP molecule occurred by the oxidation of SO4(•-), which dimerized and formed two main primary products. Under the conditions of room temperature (25 °C ± 1 °C) and low concentration of K2S2O8 (0.5 mM), 35.4% of total organic carbon (TOC) was removed after 8.5-h irradiation. The results showed that UV/S2O8(2-) system was effective for the degradation of 4-t-BP.

Construction and application of the Synechocystis sp. PCC6803-ftnA in microbial contamination control in a coupled cultivation and wastewater treatment.

Inspired by iron fertilization experiments in HNLC (high-nitrate, low-chlorophyll) sea areas, we proposed the use of iron-rich engineered microalgae for microbial contaminant control in iron-free culture media. Based on the genome sequence and natural transformation system of Synechocystis sp. PCC6803, ftnA (encoding ferritin) was selected as our target gene and was cloned into wild-type Synechocystis sp. PCC6803. Tests at the molecular level confirmed the successful construction of the engineered Synechocystis sp. PCC6803-ftnA. After Fe(3+)-EDTA pulsing, the intracellular iron content of Synechocystis sp. PCC6803-ftnA was significantly enhanced, and the algae was used in the microbial contamination control system. In the coupled Synechocystis sp. PCC6803-ftnA production and municipal wastewater (MW, including Scenedesmus obliquus and Bacillus) treatment, Synechocystis sp. PCC6803-ftnA accounted for all of the microbial activity and significantly increased from 70% of the microbial community to 95%. These results revealed that while the stored iron in the Synechocystis sp. PCC6803-ftnA cells was used for growth and reproduction of this microalga in the MW, the growth of other microbes was inhibited because of the iron limitation, and these results provide a new method for microbial contamination control during a coupling process.

microRNA-377 suppresses the proliferation of human osteosarcoma MG-63 cells by targeting CDK6.

MicroRNAs (miRNAs) are essential to the progression of osteosarcoma. Previous research using osteosarcoma samples confirmed that miR-377 expression is less than that observed in normal human osteoblast expression. These data suggest a role for miR-377 in osteosarcoma that warrants investigation. To address this concept, we measured miR-377 expression in two cell models, and we also observed that miR-377 was less expressed in osteosarcoma MG-63 cells compared to the hFOB1.19 human fetal osteoblastic cell line. Moreover, miR-377 overexpression reduced cell proliferation and suppressed invasion of MG-63 cells but had no effect on MG-63 cell apoptosis. Because cyclin-dependent kinase 6 (CDK6) may be a potential target of miR-377 in osteosarcoma cells, we overexpressed CDK6 and observed that overexpression attenuated tumor suppressive effects of miR-377 on cell proliferation. Our data suggest that miR-377 can suppress proliferation in MG-63 cells in part by targeting CDK6.

A review: factors affecting excess sludge anaerobic digestion for volatile fatty acids production.

This paper presents a review of methods that improve the production of volatile fatty acids (VFA) from excess sludge during the anaerobic digestion process. These methods are mainly divided into two approaches. The first approach is located in the pre-treatment methods, which change the properties of the substrates, such as thermal pre-treatment, alkaline pre-treatment, microwave pre-treatment and ultrasonic pre-treatment. The other approach is found in the fermentation process control methods, which influence the environment of anaerobic digestion for the production of VFA, such as pH, temperature, mixing, additives and solids retention time control. In the text recent research studies of each method are listed and analyzed in detail. Comparably, microwave and ultrasonic pre-treatment methods are considered emerging and promising technologies due to their efficiency and environmentally friendly characteristics. However, the microwave pre-treatment has high electricity demand, which might make the process economically unfeasible. In order to calculate optimal operation, further studies still need to be done.

Effects of low-concentration Cr(VI) on the performance and the membrane fouling of a submerged membrane bioreactor in the treatment of municipal wastewater.

The effects of low-concentration Cr(VI) (0.4 mg l(-1)) on the performance of a submerged membrane bioreactor (SMBR) in the treatment of municipal wastewater, as well as membrane fouling were investigated. Compared with the SMBR for control municipal wastewater, the SMBR for Cr(VI)-containing municipal wastewater had a higher concentration of soluble microbial products (SMP) with lower molecular weights, and smaller sludge particle sizes. Furthermore, low-concentration Cr(VI) induced membrane fouling, especially irreversible membrane pore blocking, which markedly shortened the service life of the membrane.

Enhanced heavy metal stabilization and phosphorus retention during the hydrothermal carbonization of swine manure by in-situ formation of MgFe2O4.

Hydrothermal carbonization is an efficient technique for the disposal of livestock manure, enabling its harmless treatment, quantity reduction, and resourceful utilization. Co-hydrothermal of modified materials facilitates the production of more valuable carbonaceous materials. However, further exploration is needed to understand their potential impact on the environmental risks associated with livestock manure disposal and the application of products derived from it. Therefore, the carbonization degree, heavy metals stabilization, and phosphorus retention during the hydrothermal treatment of swine manure were systematically investigated in this study under the influence of in-situ formed MgFe2O4. The results revealed that the in-situ formation of MgFe2O4 improved the dehydration and decarboxylation of organic components in swine manure, thereby improving its carbonization degree. Furthermore, both hydrothermal carbonization and MgFe2O4 modified hydrothermal carbonization resulted in an enhanced stabilization of heavy metals, leading to a significant reduction in their soluble/exchangeable fraction and reducible fraction. Phosphorus was predominantly retained in the hydrochars, with the highest retention rate reaching 88%, attributed to the significant decrease in soluble and exchangeable phosphorus fractions facilitated by the in-situ formation of MgFe2O4. Moreover, MgFe2O4 modified hydrochars exhibited remarkable adsorption capacity for Pb(II) and Cu(II) without any leaching of heavy metals. Overall, the findings indicated that the in-situ formation of MgFe2O4 positively influenced the hydrothermal of swine manure, improving certain economic benefits in its practical application.

Causal relationship between immune cells and prostate cancer: a Mendelian randomization study.

Introduction: Despite the abundance of research indicating the participation of immune cells in prostate cancer development, establishing a definitive cause-and-effect relationship has proven to be a difficult undertaking. Methods: This study employs Mendelian randomization (MR), leveraging genetic variables related to immune cells from publicly available genome-wide association studies (GWAS), to investigate this association. The primary analytical method used in this study is inverse variance weighting (IVW) analysis. Comprehensive sensitivity analyses were conducted to assess the heterogeneity and horizontal pleiotropy of the results. Results: The study identifies four immune cell traits as causally contributing to prostate cancer risk, including CD127- CD8+ T cell %CD8+ T cell (OR = 1.0042, 95%CI:1.0011-1.0073, p = 0.0077), CD45RA on CD39+ resting CD4 regulatory T cell (OR = 1.0029, 95%CI:1.0008-1.0050, p = 0.0065), CD62L- Dendritic Cell Absolute Count (OR = 1.0016; 95%CI:1.0005-1.0026; p = 0.0039), CX3CR1 on CD14+ CD16- monocyte (OR = 1.0024, 95%CI:1.0007-1.0040, p = 0.0060). Additionally, two immune cell traits are identified as causally protective factors: CD4 on monocyte (OR = 0.9975, 95%CI:0.9958-0.9992, p = 0.0047), FSC-A on plasmacytoid Dendritic Cell (OR = 0.9983, 95%CI:0.9970-0.9995, p = 0.0070). Sensitivity analyses indicated no horizontal pleiotropy. Discussion: Our MR study provide evidence for a causal relationship between immune cells and prostate cancer, holding implications for clinical diagnosis and treatment.

Tracking the carbon flows in municipal waste management in China.

Municipal solid waste (MSW), a carbon-intensive waste stream, may create both instant and indirect impacts onto environmental and climate management. Despite multiple studies made for greenhouse gases (GHGs) emissions of municipal waste, this research aims to achieve a comprehensive assessment for the carbon cycle by exploring evolution of waste composition and temporal-spatial disparities in waste management. Carbon flows embodied in MSW have been estimated across 31 provinces in Mainland China in the period 2000-2018. This improved estimation could be 15-40% smaller than the conventional estimation employing a constant waste composition. Aggregately some 578 ± 117 megatonnes carbon (MtC) were contained in MSW, including 239 ± 60 Mt of fossil carbon and 339 ± 58 Mt of degradable organic carbon. After treatment, 299 ± 66 MtC were possibly deposited in landfills and dumps. 279 ± 51 MtC were released to the atmosphere, creating net GHGs emissions equivalent to1870 ± 334 megatonnes of CO2 (MtCO2e). MSW generation in China nearly doubled during the period, net GHGs emissions increased by 1.8×, whereas fossil carbon grew by a factor of 3.5, mainly propelled by an increasing content of waste plastic in MSW. More rapid growth was witnessed in provinces in southern China than in northern. Distinct spatial-temporal evolution of waste and carbon metabolism was driven by increment, composition, and management effects. In the long run, the increment and composition effects may drop off. Enhanced practices of waste management integrating the circular economy are needed to fully recycle carbon flows, minimize emissions, and manage carbon deposits in aging landfills and dumps.

Comparison of sedimentary PAHs in the rivers of Ammer (Germany) and Liangtan (China): differences between early- and newly-industrialized countries.

As a proxy to trace the impact of anthropogenic activity, sedimentary polycyclic aromatic hydrocarbons (PAHs) are compared between the early industrialized and newly industrialized countries of Germany and China, respectively. Surface sediment samples in the Ammer River of Germany and the Liangtan River of China were collected to compare concentration levels, distribution patterns, and diagnostic plots of sedimentary PAHs. Total concentrations of 16 PAHs in Ammer sediments were significantly higher by a factor of ~4.5 than those in Liangtan. This contrast agrees with an extensive literature survey of PAH levels found in Chinese versus European sediments. Distribution patterns of PAHs were similar across sites in the Ammer River, whereas they were highly varied in the Liangtan River. Pyrogenic sources dominated in both cases. Strong correlations of the sum of 16 PAHs and PAH groups with TOC contents in the Liangtan River may indicate coemission of PAHs and TOC. Poor correlations of PAHs with TOC in the Ammer River indicate that other factors exert stronger influences. Sedimentary PAHs in the Ammer River are primarily attributed to input of diffuse sources or legacy pollution, while sediments in the Liangtan River are probably affected by ongoing point source emissions. Providing further evidence of a more prolonged anthropogenic influence are the elevated black carbon fractions in sedimentary TOC in the Ammer compared to the Liangtan. This implies that the Liangtan River, like others in newly industrialized regions, still has a chance to avoid legacy pollution of sediment which is widespread in the Ammer River and other European waterways.