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The chemical mechanisms responsible for rapid sulfate production, an important driver of winter haze formation in northern China, remain unclear. Here, we propose a potentially important heterogeneous hydroxymethanesulfonate (HMS) chemical mechanism. Through analyzing field measurements with aerosol mass spectrometry, we show evidence for a possible significant existence in haze aerosols of organosulfur primarily as HMS, misidentified as sulfate in previous observations. We estimate that HMS can account for up to about one-third of the sulfate concentrations unexplained by current air quality models. Heterogeneous production of HMS by SO2 and formaldehyde is favored under northern China winter haze conditions due to high aerosol water content, moderately acidic pH values, high gaseous precursor levels, and low temperature. These analyses identify an unappreciated importance of formaldehyde in secondary aerosol formation and call for more research on sources and on the chemistry of formaldehyde in northern China winter.

In this paper, we investigate the radius of robust feasibility of system of uncertain convex inequalities by the Minkowski function. We firstly establish an upper bound and a lower bound for radius of robust feasibility of the system of uncertain convex inequalities. Exact formulas of radius of robust feasibility of the system are derived under the nonsymmetric and symmetric assumptions of the uncertain sets. We also obtain a characterization on the positiveness of radius of robust feasibility for the system. Lastly, explicit tractable formulas for computing the radius of robust feasibility of the system are presented when the uncertain sets are ellipsoids, polytopes, boxes and unit ball, respectively.

Multi-source Weber problem (MSWP) is a classical nonconvex and NP-hard model in facility location. A well-known method for solving MSWP is the location–allocation algorithm which consists of a location phase to locate new facilities and an allocation phase to allocate customers at each iteration. This paper considers the more general and practical case of MSWP called the constrained multi-source Weber problem (CMSWP), i.e., locating multiple facilities with the consideration of the gauge for measuring distances and locational constraints on new facilities. According to the favorable structure of the involved location subproblems after reformulation, an alternating direction method of multipliers (ADMM) type method is contributed to solving these subproblems under different distance measures in a uniform framework. Then a new ADMM-based location–allocation algorithm is presented for CMSWP and its local convergence is theoretically proved. Some preliminary numerical results are reported to verify the effectiveness of proposed methods.

The roots of Sophora flavescens (SF) are clinically used as a traditional Chinese medicine for the treatment of various lung diseases. In this study, we investigated the mechanism by which SF inhibits proliferation and induces apoptosis in non-small-cell lung cancer (NSCLC) cells. A new compound, kushenol Z (KZ), and 14 known flavonoids were isolated from SF. KZ, sophoraflavanone G, and kushenol A demonstrated potent cytotoxicity against NSCLC cells in a dose- and time-dependent manner; KZ showed a wide therapeutic window. We also found that KZ induced NSCLC cell apoptosis by increasing the Bax/Bcl-2 ratio and by activating caspase-3 and caspase-9 leading to mitochondrial apoptosis, and upregulated CHOP and activatedcaspase-7 and caspase-12, which triggered the endoplasmic reticulum stress pathway. After KZ treatment, we observed cAMP accumulation, which reflected the inhibition of cAMP-phosphodiesterase (PDE), along with the increase in PKA activity; additionally, phospho-p70 S6 kinase was downregulated. KZ also attenuated the phosphorylation of Akt and PRAS40, which was partially rescued by an Akt activator. This suggested that KZ mediated the antiproliferative activity in NSCLC cells by inhibiting the mTOR pathway through the inhibition of cAMP-PDE and Akt. These findings suggested that KZ may be used as a promising cAMP-PDE and Akt inhibitor in targeted chemotherapeutic drug development.

Germline mutations in the NF1 gene disrupt neurofibromin function, leading to autosomal-dominant neurofibromatosis type I (NF1). As a tumor suppressor, neurofibromin negatively regulates the RAS signaling. NF1 presents notable phenotypic variability, progressive symptoms with age, and potential malignant transformation. Early screening, diagnosis, and necessary interventions are essential for improving patient outcomes. Here, sixteen NF1 variants were identified at Henan Provincial People’s Hospital. Among them, 75.0% were de novo mutations, and two novel variants, c.547_548delAT p.(Ile183Glnfs*17) and c.4721dupC p.(Thr1574Thrfs*2), were revealed. These two novel variants, located in the RAS-GTPase domain, manifested cutaneous café-au-lait macules at birth; the former even exhibited motor delays. A retrospective analysis of 49 clinical trials over the past 20 years revealed that NF1 therapies predominantly target neurofibromin’s GTPase function. Gene therapies aiming to restore neurofibromin by transducing the truncated NF1-GRD gene have been developed but faced pre-clinical challenges, including cloning capacity, transduction efficiency, and immunogenicity caused by gene delivery. Two novel NF1 variants expanded the variation spectrum for the NF1 gene, facilitating the diagnosis, genetic counseling, and clinical management of patients. Therapeutic approaches targeting GTPase and improved gene therapy may dawn a new therapeutic era for NF1.

PM2.5 and PM10 samples were collected simultaneously in each season in Beijing, Tianjin and Shijiazhuang to identify the characteristics of water-soluble ion compositions in the North China Plain. The water-soluble ions displayed significant seasonal variation. The dominant ions were NO3(-), SO4(2-), NH4(+) and Cl(-), accounting for more than 90% and 86% to the mass of total water-soluble ions in PM2.5 and PM10, respectively. The anion/cation ratio indicated that the ion acidity of each city varied both between sites and seasonally. Over 50% of the ion species were enriched in small particles ≤1 µm in diameter. The [NO3(-)]/[SO4(2-)] ratio indicated that vehicles accounted for the majority of the particulate pollution in Beijing. Shijiazhuang, a city highly reliant on coal combustion, had a higher SO4(2-) concentration.

Soluble glucose regulated protein 78 (sGRP78) has long been suggested as a mediator resolution of inflammation. We previously reported that sGRP78 induced the rapid endocytosis of TLR4 with defective TLR4 signaling. To elucidate the underlying mechanisms, in this study, we investigated how sGRP78 influenced the behavior and trafficking of TLR4 in myeloid cells. It was found that sGRP78 promoted LPS endocytosis with monomeric TLR4. This internalized monomeric TLR4 formed complexes with p62–LC3, and was degraded in autolysosomes. Furthermore, the sGRP78-enhanced autophagy-dependent TLR4 degradation caused apoptosis and ferroptosis in myeloid cells, contributing to the sGRP78-mediated resolution of inflammation. These reports establish innovative mechanisms for endotoxin clearance and immune regulation by TLR4 degradation, linking innate immunity with multiple ancient processes, including autophagy, apoptosis, and ferroptosis, together through a shared resolution-associated molecular pattern (RAMP)—sGRP78.

Aspernolide A, a butyrolactone secondary metabolite, was purified from the endophytic fungus Cladosporium cladosporioides derived from roots of Camptotheca acuminata Decne. In this study, the antitumor activity and mechanisms of aspernolide A on human laryngeal cancer Hep-2 and TU212 cells were studied by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, morphological observation and Western blotting. The results showed that aspernolide A significantly inhibited the proliferation of Hep-2 and TU212 cells in dose- and time-dependent manners. Morphological changes of apoptotic cells could be observed under an inverted microscope, such as irregular margins, decreased adherence ability and chromatin condensation. The expressions of Bax, Caspase-9, Caspase-3 and PARP (poly ADP-ribose polymerase) increased with the increase of dosage while Bcl-2 decreased, suggesting that the apoptotic mechanism might be related to the mitochondrial apoptotic pathway. Moreover, the expression of the phosphorylation of STAT3 decreased with the increase of dosage, suggesting that the apoptotic mechanism might be related to the STAT3 signaling pathway. All these conclusions indicated that aspernolide A has the potential anti-laryngocarcinoma effects.

BackgroundBreast cancer is the leading cause of cancer-related deaths among women globally. Tumor-secreted proteins foster an immunosuppressive environment, enabling immune evasion and reducing the effectiveness of antitumor immunity. Interleukin (IL)-10, an immune-regulatory cytokine, is upregulated in breast cancer (BRCA), but the underlying mechanism remains unclear.MethodsIn silico analysis was used to identify candidate genes associated with IL-10 expression. Mouse model of BRCA and in vitro co-culture assays were conducted to identify immune cells responsible for IL-10 upregulation. The efficacy of galectin-3 (Gal-3) inhibition combined with chemotherapy was also evaluated.ResultsTumor-secreted Gal-3 served as a key immunosuppressive factor in BRCA. Gal-3 promoted IL-10 production in B cells, thus impairing antitumor immunity. Mechanistically, Gal-3 triggered CD45 polymerization, reducing its phosphatase activity and subsequently activating STAT3 to promote IL-10 production. Knockdown of STAT3 or its blockade abrogated Gal-3-induced IL-10 upregulation. Furthermore, Gal-3 inhibition combined with chemotherapy significantly reduced tumor growth and enhanced antitumor immunity.ConclusionsGal-3 is a crucial regulator of immune evasion in BRCA. Targeting Gal-3 may improve the efficacy of BRCA therapies.

Severe water shortage is unacceptable for water-supply reservoir operation. For avoiding single periods of catastrophic water shortage, this paper proposes a multi-reservoir operating policy for water supply by combining parametric rule with hedging rule. In this method, the roles of parametric rule and hedging rule can be played at the same time, which are reducing the number of decision variables and adopting an active reduction of water supply during droughts in advance. In order to maintain the diversity of the non-dominated solutions for multi-objective optimization problem and make them get closer to the optimal trade-off surfaces, the multi-population mechanism is incorporated into the non-dominated sorting particle swarm optimization (NSPSO) algorithm in this study to develop an improved NSPSO algorithm (I-NSPSO). The performance of the I-NSPSO on two benchmark test functions shows that it has a good ability in finding the Pareto optimal set. The water-supply multi-reservoir system located at Taize River basin in China is employed as a case study to verify the effect of the proposed operating policy and the efficiency of the I-NSPSO. The operation results indicate that the proposed operating policy is suitable to handle the multi-reservoir operation problem, especially for the periods of droughts. And the I-NSPSO also shows a good performance in multi-objective optimization of the proposed operating policy.