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Uncertainty exists about whether lowering systolic blood pressure to less than 120 mm Hg is superior to that of less than 140 mm Hg, particularly in patients with diabetes and patients with previous stroke.

During the pathogenesis of heart failure with preserved ejection fraction (HFpEF), fibroblasts are activated and express the fibroblast activation protein (FAP). Targeted imaging of FAP can qualitatively and quantitatively assess the fibroblast activity. This study aimed to use [18F]AlF-NOTA-FAPI-04 (AlF = aluminum fluoride; NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid; FAPI = FAP inhibitor) positron emission tomography/computed tomography (PET/CT) imaging to detect activated fibroblasts in a rat HFpEF model. The rat HfpEF model was established by feeding a high-fat diet plus l-NAME (Nω-nitro-l-arginine methyl ester) for 10 weeks. Blood pressure, echocardiography, and [18F]AlF-NOTA-FAPI-04 PET/CT were used to assess the progression of HfpEF. The biodistribution of [18F]AlF-NOTA-FAPI-04 in healthy rats was obtained. Cardiac tissue sections were also analyzed using Masson’s, hematoxylin and eosin (H&E), and FAP immunohistochemistry (IHC) staining. The echocardiography and blood pressure data indicated that the rat HfpEF model was successfully established. [18F]AlF-NOTA-FAPI-04 PET/CT imaging showed obvious radiotracer accumulation in the left ventricular wall of the HfpEF rats from the seventh week. A biodistribution test showed that the tracer was cleared mainly via renal and intestinal excretion. Percentage of injected dose per gram tissue (% ID) of the heart and its surrounding organs was lower in normal rats, which was conducive to image analysis. Masson’s and H&E stainings showed large areas of vascular and interstitial fibrosis in the HfpEF rat hearts. IHC staining also confirmed the presence of FAP-positive cardiac fibroblasts of the HfpEF rat hearts, with a good correlation with FAPI PET. Thus, [18F]AlF-NOTA-FAPI-04 PET/CT is a promising and non-invasive method to assess the progression of fibrosis in HfpEF to facilitate the clinical management.

Breast cancer treatment has been challenging all the time because cancer cells have multiple signaling pathways; so, breast cancer still remains a threat to the lives and health of many patients. While common single drug therapies inhibit only one pathway, the combination of multiple mechanisms offers the potential to simultaneously suppress multiple targets and pathways to kill cancer cells more effectively. It is reported that autophagy caused by autophagy inducers and apoptosis caused by some chemotherapeutic drugs can promote ferroptosis to some extent; herein, we combined these three pathways and constructed a multifunctional dual-responsive release nanosystem of Rap@mFe3O4–DOX–HA that achieved the ferroptosis–autophagy–apoptosis synergistic effect for cancer treatment. Mesoporous Fe3O4(mFe3O4) was set as the carrier and can also release Fe ions for ferroptosis, the autophagy inducer rapamycin (Rap) was wrapped in the carrier to trigger autophagy, and the chemotherapeutic drug doxorubicin (DOX) was used as the apoptosis inducer. At the tumor site, the prepared Rap@mFe3O4–DOX–HA nanoparticles split and released DOX/Rap in response to H+/GSH. From in vivoand in vitrostudies, it was found that Rap@mFe3O4–DOX–HA nanoparticles effectively inhibited the migration of 4T1 cells, furthermore, they struck cancer cells through multiple pathways and greatly improved the anti-tumor effect. Therefore, the strategy of multi-mechanism combination achieved a therapeutic effect of 1 + 1 > 2.

Although tumor starvation therapy has been proven to be an excellent method for tumor therapy, its efficiency may be weakened by autophagy, a self-protection mechanism exerted by tumors under starvation stress. Interestingly, over-activated autophagy not only improves the efficacy of starvation therapy, but also induces autophagic death. Herein, we report cascade nanozymes for enhanced starvation therapy by inducing over-activated autophagy. First, glucose oxidase (GOx) modified metal–organic frameworks (NH2-MIL88, MOF) were constructed (MOF-GOx). After loading with curcumin (Cur), Cur@MOF-GOx was further decorated with tumor-targeting hyaluronic acid (HA) to obtain Cur@MOF-GOx/HA nanozymes. GOx can catalyze glucose into H2O2and gluconic acid, which not only leads to tumor starvation, but also provides reactants for the Fenton reaction mediated by the MOF to generate hydroxyl radicals (OH) for chemo-dynamic therapy. Most importantly, protective autophagy caused by tumor starvation can be over-activated by Cur to convert autophagy from pro-survival to pro-death, realizing augmented anticancer therapy efficacy. With these cascade reactions, the synergistic action of starvation, autophagy and chemo-dynamic therapy was realized. Generally, the introduction of Cur@MOF-GOx/HA into tumor cells leads to a “butterfly effect”, which induces enhanced starvation therapy through subsequent autophagic cell death to completely break the self-protective mechanism of cancer cells, and generate OH for chemo-dynamic therapy. Precise design allows for the use of cascade nanozymes to realize efficient cancer treatment and restrain metastasis.

ABSTRACTWe prospectively investigated the neurological development in infants born from mothers treated with telbivudine (LdT) in the third trimester for prevention of hepatitis B virus (HBV) mother-to-infant transmission. Mothers with high HBV load were assigned to either the LdT group (n= 81, 600 mg of LdT each day from gestational week 28 to delivery) or the Control group (n= 39, untreated). Their infants were followed for 36 months to assess physical and neurological developments with Gesell Developmental Schedule tools. At 12 months after birth, the mean scores in the LdT group for gross motor, fine motor, adaptive, linguistic, and personal social domains were similar to those in the Control group. At 36 months, infants in the LdT group had higher mean scores for gross motor than the Control group (98.42 ± 9.69 vs. 94.54 ± 7.48, P= 0.03). In the LdT group, the rates of normal development were higher for gross motor (96.30% vs. 82.05% P= 0.01) and lower for adaptive (74.07% vs. 92.31% P= 0.02). Multivariate regression analyses showed that exposure to LdT during pregnancy was independently associated with infant’s development in gross motor (OR 6.49, 95% CI 1.37–30.20, P= 0.02) and adaptive (OR 0.18, 95% CI 0.05–0.71, P= 0.01) at 36 months. These results suggest that prenatal LdT exposure might affect neurological development in long-term observation.Abbreviations: LdT: telbivudine; HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; HBeAg: hepatitis Be antigen; HbsAb: hepatitis B surface antibody; ALT: alanine aminotransferase; NA: nucleoside/nucleotide analog; LAM: lamivudine; MTCT: mother-to-child transmission; GDS: Gesell Developmental Schedule; OR: odds ratio; CI: confidence interval; DQ: developmental quotient; RMB: renminbi; BMI: body mass Index; HBIG: hepatitis B immunoglobulin.

Acute kidney injury (AKI) is a critical medical condition characterized by high morbidity and mortality rates. The pathogenesis of AKI potentially involves bursts of reactive oxygen species (ROS) bursts and elevated levels of inflammatory mediators. Developing nanoparticles (NPs) that downregulate ROS and inflammatory mediators is a promising approach to treat AKI. However, such NPs would be affected by the glomerular filtration barrier (GFB). Typically, NPs are too large to penetrate the glomerular system and reach the renal tubules─the primary site of AKI injury. Herein, we report the development of ultrasmall carbon dots-gallic acid (CDs-GA) NPs (∼5 nm). These NPs exhibited outstanding biocompatibility and were shown not only to efficiently eliminate ROS and alleviate oxidative stress but also to suppress the activation of the NF-κB signaling pathway, leading to a reduction in the release of inflammatory factors. Importantly, CDs-GA NPs were shown to be able to rapidly accumulate rapidly in the renal tissues without the need for intricate targeting strategies. In vivo studies demonstrated that CDs-GA NPs significantly reduced the incidence of cisplatin (CDDP)-induced AKI in mice, surpassing the efficacy of the small molecular drug, N-acetylcysteine. This research provides an innovative strategy for the treatment of AKI.

In the dynamic global trade environment, accurately predicting trade values of diverse commodities is challenged by unpredictable economic and political changes. This study introduces the Meta-TFSTL framework, an innovative neural model that integrates Meta-Learning Enhanced Trade Forecasting with efficient multicommodity STL decomposition to adeptly navigate the complexities of forecasting. Our approach begins with STL decomposition to partition trade value sequences into seasonal, trend, and residual elements, identifying a potential 10-month economic cycle through the Ljung–Box test. The model employs a dual-channel spatiotemporal encoder for processing these components, ensuring a comprehensive grasp of temporal correlations. By constructing spatial and temporal graphs leveraging correlation matrices and graph embeddings and introducing fused attention and multitasking strategies at the decoding phase, Meta-TFSTL surpasses benchmark models in performance. Additionally, integrating meta-learning and fine-tuning techniques enhances shared knowledge across import and export trade predictions. Ultimately, our research significantly advances the precision and efficiency of trade forecasting in a volatile global economic scenario.

Hydrogels are often used as synthetic extracellular matrices (ECMs) for biomedical applications. Natural ECMs are viscoelastic and exhibit partial stress relaxation. However, commonly used hydrogels are typically elastic. Hydrogels developed from ECM-based proteins are viscoelastic, but they often have weak mechanical properties. Here, biocompatible viscoelastic hydrogels with excellent mechanical performance are fabricated by an all aqueous process at body or room temperature. These hydrogels offer obvious stress relaxation and tunable mechanical properties and gelation kinetics. Their compressive modulus can be controlled between 2 kPa and 1.2 MPa, covering a significant portion of the properties of native tissues. Investigation of the gelation mechanism revealed that silk fibroin gelation is caused by the synergistic effects of hydrophobic interaction and hydrogen bonding between silk fibroin molecules. Newly formed crystals serve as the cross-link sites and form a network endowing the hydrogel with stable structure, and the flexible noncrystalline silk nanofibers connect disparate silk fibroin crystals, endowing hydrogels with viscoelastic properties. The all aqueous gelation process avoids complex chemical and physical treatments and is beneficial for encapsulating cells or biomolecules. Encapsulation of chondrocytes results in high initial survival rate (95% ± 1%). These silk fibroin-based viscoelastic hydrogels, combined with superior biocompatible and tunable mechanical properties, represent an exciting option for tissue engineering and regenerative medicine.

ABSTRACTLong noncoding RNAs (lncRNAs) have been reported to participate in the progression of various cancers, including oral squamous cell carcinoma (OSCC). This study aims to find out whether lncRNA LINC01207 regulates the progression of OSCC. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to evaluate gene expression in OSCC cells and tissues. Cell viability, proliferation, migration, apoptosis, and autophagy were detected using Cell Counting Kit-8 (CCK-8), colony formation, Transwell assays, flow cytometry, and western blot analysis. Luciferase reporter and RNA immunoprecipitation (RIP) assays were conducted to assess the interactions among genes. We found that LINC01207 was overexpressed in OSCC cells and tissues. LINC01207 silencing inhibited OSCC cell proliferation and migration but promoted apoptosis and autophagy, and LINC01207 overexpression had an opposite result. LINC01207 interacted with microRNA-1301-3p (miR-1301-3p) while lactate dehydrogenase isoform A (LHDA) was targeted by miR1301-3p. Effects caused by LINC01207 downregulation on OSCC cells were reversed by overexpression of LDHA. Overall, LINC01207 promotes OSCC progression via the miR-1301-3p/LDHA axis

Mesenchymal Stem Cells (MSCs) exhibit enormous therapeutic potential because of their indispensable regenerative, reparative, angiogenic, anti-apoptotic, and immunosuppressive properties. MSCs can best differentiate into mesodermal cell lineages, including osteoblasts, adipocytes, muscle cells, endothelial cells and chondrocytes. Specific differentiation of MSCs could be induced through limited conditions. In addition to the relevant differentiation factors, drastic changes also occur in the microenvironment to conduct it in an optimal manner for particular differentiation. Recent evidence suggests that the mitochondria participate in the regulating of direction and process of MSCs differentiation. Therefore, our current review focuses on how mitochondria participate in both osteogenesis and adipogenesis of MSC differentiation. Besides that, in our current review, we try to provide a further understanding of the relationship between the behavior of mitochondria and the direction of MSC differentiation, which could optimize current cellular culturing protocols for further facilitating tissue engineering by adjusting specific conditions of stem cells.

Understanding the in vivobehavior of experimental therapeutic cells is fundamental to their successful development and clinical translation. Iodine-124 has the longest half-life (4.2 days) among the clinically used positron emitters. Consequently, this isotope offers the longest possible tracking time for directly labeled cells using positron emission tomography (PET). Herein, we have radiosynthesized and evaluated two iodine-124/fluorescein-based dual PET and fluorescent labeling reagents, namely 124I-FIT-Mal and 124I-FIT-(PhS)2Mal for cell surface thiol bioconjugation. 124I-FIT-(PhS)2Mal labeled cells significantly more effectively than 124I-FIT-Mal. It conjugated to various cell lines in 22%–62% labeling efficiencies with prolonged iodine-124 retention. 124I-FIT-(PhS)2Mal mainly conjugated on the cell membrane, which was confirmed by high-resolution fluorescence imaging. The migration of 124I-FIT-(PhS)2Mal labeled Jurkat cells was visualized in NSG mice with excellent target-to-background contrast using PET/CT over 7 days. These data demonstrate that 124I-FIT-(PhS)2Mal can dynamically track cell migration in vivousing PET/CT over a clinically relevant time frame.

Background:Follicular lymphoma (FL) is a chronic and incurable disease requiring multiple lines of therapy for patients (pts) with relapsed/refractory (R/R) disease. Covalent Bruton tyrosine kinase inhibitors (cBTKi) have transformed the management of select B-cell malignancies, in particular chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, despite the transformative impact in CLL and MCL, the efficacy of single-agent cBTKi has been limited in pts with R/R FL, with an overall response rate (ORR) of 20.9% to 37.5% (Gopal et al, J Clin Oncol, 2018; Bartlett et al, Blood, 2018). Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency and has a favorable oral pharmacology that enables continuous BTK inhibition throughout the once-daily dosing interval. Pirtobrutinib has demonstrated promising efficacy and tolerability in pts with poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here, we report the safety and efficacy of pirtobrutinib in a cohort of pts with R/R FL from the BRUIN study (NCT03740529).

Epitaxial heterostructures based on organic-inorganic hybrid perovskites and two-dimensional materials hold great promises in optoelectronics, but they have been prepared only viasolid-state methods that restricted their practical applications. Herein, we report cubic-phased MAPbBr3(MA=CH3NH3+) nanocrystals were epitaxially deposited on trigonal/hexagonal-phased MoS2nanosheets in solution by facilely tuning the solvation conditions. In spite of the mismatched lattice symmetry between the square MAPbBr3(001) overlayer and the hexagonal MoS2(001) substrate, two different aligning directions with lattice mismatch of as small as 1% were observed based on the domainmatching epitaxy. This was realized most likely due to the flexible nature and absence of surface dangling bonds of MoS2nanosheets. The formation of the epitaxial interface affords an effective energy transfer from MAPbBr3to MoS2, and as a result, paper-based photodetectors facilely fabricated from these solution-dispersible heterostructures showed better performance compared to those based on MoS2or MAPbBr3alone. In addition to the improved energy transfer and light adsorption, the use of MoS2nanosheets provided flexible and continuous substrates to connect the otherwise discrete MAPbBr3nanocrystals and achieved the better film forming ability. Our work suggests that the scalable preparation of heterostructures based on organic-inorganic hybrid perovskites and 2D materials viasolution-phase epitaxy may bring about more opportunities for expanding their optoelectronic applications. 基于外延异质结构的有机-无机杂化钙钛矿/二维纳米片复合材料在光电领域具有很好的应用前景, 但目前使用的固相制备方法大大限制了这一目标的实现. 我们通过精细调节溶剂环境, 成功利用外延沉积的方式实现了在三角/六方相MoS2纳米片表面生长立方相MAPbBr3(MA=CH3NH3+)钙钛矿纳米晶. 虽然MAPbBr3与MoS2存在较大的晶格不匹配度, 但是由于MoS2纳米片性质柔软且表面缺失悬挂键, 可以在两条不同方向上观察到较高容忍度(∼1%错位)的外延生长关系. 这种外延界面的形成有利于MAPbBr3与MoS2之间有效的能量转移, 因此基于MAPbBr3/MoS2异质结的纸质器件与MAPbBr3或MoS2器件相比具有更优异的光电性能. 此外, 除了提高光吸收能力和能量传递, MoS2纳米片的存在还为离散的MAPbBr3纳米晶提供柔性和连续的基底, 从而改善了MAPbBr3纳米晶粒的成膜能力. 这种液相外延法可用于高性能的有机无机杂化钙钛矿与二维材料的异质结构材料的大规模制备, 将推动异质结构材料在光电领域的广泛使用.

Newborn microglia rapidly replenish the whole brain after selective elimination of most microglia (>99%) in adult mice. Previous studies reported that repopulated microglia were largely derived from microglial progenitor cells expressing nestin in the brain. However, the origin of these repopulated microglia has been hotly debated. In this study, we investigated the origin of repopulated microglia by a series of fate-mapping approaches. We first excluded the blood origin of repopulated microglia via parabiosis. With different transgenic mouse lines, we then demonstrated that all repopulated microglia were derived from the proliferation of the few surviving microglia (<1%). Despite a transient pattern of nestin expression in newly forming microglia, none of repopulated microglia were derived from nestin-positive non-microglial cells. In summary, we conclude that repopulated microglia are solely derived from residual microglia rather than de novo progenitors, suggesting the absence of microglial progenitor cells in the adult brain.

Single-mode laser is realized in a cesium lead halide perovskite submicron sphere at room temperature. All-inorganic cesium lead halide (CsPbX3, X = Cl, Br, I) microspheres with tunable sizes (0.2–10 μm) are first fabricated by a dual-source chemical vapor deposition method. Due to smooth surface and regular geometry structure of microspheres, whispering gallery resonant modes make a single-mode laser realized in a submicron sphere. Surprisingly, a single-mode laser with a very narrow line width (∼0.09 nm) was achieved successfully in the CsPbX3spherical cavity at low threshold (∼0.42 μJ cm–2) with a high cavity quality factor (∼6100), which are the best specifications of lasing modes in all natural nano/microcavities ever reported. By modulating the halide composition and sizes of the microspheres, the wavelength of a single-mode laser can be continuously tuned from red to violet (425–715 nm). This work illustrates that the well-controlled synthesis of metal cesium lead halide perovskite nano/microspheres may offer an alternative route to produce a widely tunable and greatly miniaturized single-mode laser.

The effects of adding the alloy element Sc to Al alloys on strengthening, recrystallization and modification of the grain microstructure have been investigated. The combination of Sc and Zr alloying not only produces a remarkable synergistic effect of inhibition of recrystallization and refinement of grain size but also substantially reduce the amount of high-cost additional Sc. In this work, the microstructures and corrosion behavior of a new type of Al-Cu-Mg-Sc-Zr alloy with Sc/Zr ratio of 1/2 were investigated. The experimental results showed that the Sc and Zr additions to Al-Cu-Mg alloy could strongly inhibit recrystallization, refine grain size, impede the segregation of Cu element along the grain boundary and increase the spacing of grain boundary precipitates. In addition, adding Sc and Zr to Al-Cu-Mg alloy effectively restricts the corrosion mechanism conversion associated with Al 2 CuMg particles, which resulted in the change of the cross-section morphology of inter-granular corrosion from an undercutting to an elliptical shape. The susceptibility to inter-granular corrosion was significantly decreased with increasing Sc and Zr additions to the Al-Cu-Mg alloy. The relationships between microstructures evolution and inter-granular corrosion mechanism of Al-Cu-Mg-Sc-Zr alloys were also discussed. [ABSTRACT FROM AUTHOR]

Sun and Dean proposed an approach for finding A-optimal and A-efficient discrete choice designs without a large computational effort, for estimating orthonormal contrasts, and for both balanced and unbalanced profile utilities. Their method was based on the “contribution” made by each choice set to the contrasts being estimated, and was illustrated for the setting of two-level attributes and orthonormal main effect and interaction contrasts. In this article, the use of the Sun and Dean methodology is extended to encompass pairwise comparisons. The methodology is illustrated for the construction of A-efficient designs for attributes having different numbers of levels and where contrasts of interest are either orthonormal factorial contrasts or pairwise comparisons in the attribute levels. When the designs are large, issues involved with finding smaller subdesigns are discussed briefly.

In the tumor microenvironment (TME), the extracellular matrix (ECM) produced by cancer-associated fibroblasts (CAFs) forms a dense barrier that prevents nanodrugs from penetrating into deep tumor sites, leading to unsatisfactory therapeutic effects. Recently, it has been found that ECM depletion and using small-sized nanoparticles are effective strategies. Herein, we reported a detachable dual-targeting nanoparticle (HA-DOX@GNPs-Met@HFn) based on reducing ECM for enhancing penetration. When these nanoparticles reached the tumor site, the nanoparticles were divided into two parts in response to matrix metalloproteinase-2 overexpressed in TME, causing a decrease in the nanoparticle size from about 124 to 36 nm. One part was Met@HFn, which was detached from the surface of gelatin nanoparticles (GNPs), which effectively targeted tumor cells and released metformin (Met) under acidic conditions. Then, Met downregulated the expression of the transforming growth factor β by the adenosine monophosphate-activated protein kinase pathway to inhibit the activity of CAFs, thereby suppressing the production of ECM including α-smooth muscle actin and collagen I. The other was the small-sized hyaluronic acid-modified doxorubicin prodrug with autonomous targeting ability, which was gradually released from GNPs and internalized into deeper tumor cells. Intracellular hyaluronidases triggered the release of doxorubicin (DOX), which killed tumor cells by inhibiting DNA synthesis. The combination of size transformation and ECM depletion enhanced the penetration and accumulation of DOX in solid tumors. Therefore, the tumor chemotherapy effect was greatly improved.

The paper deals with one important topic in impact engineering - the lateral compression behavior of thin-walled tubes. To study the lateral collapse modes and energy absorption behaviors of equilateral triangular tubes, quasi-static compression experiments were carried out. Crushing modes were revealed by the experiments. Three typical crushing stages characterize the lateral deformation plateaus of equilateral triangular tubes. In simulation, perfect tubes have symmetrical crushing modes. Strengths of the tubes were correctly predicted by the competition between yielding and buckling. Based on the observed crushing modes, plastic models were proposed for each stage to predict the lateral crushing behaviors theoretically. Equilateral triangular tubes have unified energy absorbing mechanisms, including five plastic hinges and one traveling plastic hinge. Plastic models have been constructed to predict the mean crushing forces and evaluate the energy absorption efficiency of the equilateral triangular tubes.

Alkaline pretreatment is an effective technology to disintegrate sewage sludge, where alkali dosage and sludge concentration are two important factors. pH value or alkali concentration is usually adjusted in order to determine a proper dosage of alkali. Our work has found that this is not a good strategy. A new parameter, the ratio of alkali to sludge (Ra/s), is more sensitive in controlling the alkali dosage. The sludge concentration Csand retention time tare two other important factors to consider. The validity of these arguments is confirmed with modeling and experiments. The individual effect of Ra/s, Csand twas studied separately. Then the combined effect of these three factors was evaluated. The sludge disintegration degree of 44.7% was achieved with the optimized factors. Furthermore, an alkaline-microwave combined pretreatment process was carried out under these optimized conditions. A high disintegration degree of 62.3% was achieved while the energy consumption of microwave was much lower than previously reported.

Tests for dispersion effects in replicated two-level factorial experiments assuming a location-dispersion model are presented. The tests use individual measures of dispersion that remove the location effects and also provide an estimate of pure error. Empirical critical values for two such tests are given for two-level full or regular fractional factorial designs with 8, 16, 32, and 64 runs. The powers of the tests are examined under normal, exponential, and Cauchy distributed errors. Our recommended test uses dispersion measures calculated as deviations of the data values from their cell medians, and this test is illustrated via an example.

It has been reported that the mammalian target of rapamycin (mTOR) pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE), and increasing evidence has shown the effect of mTOR-targeted therapies with sirolimus in SLE. The objective of this study was to report the successful treatment of sirolimus in a Chinese patient with refractory lupus nephritis (LN) and anti-phospholipid antibody syndrome (APS). A 44-year-old female with a previous diagnosis of autoimmune hemolytic anemia (AIHA) and APS secondary to SLE presented with lupus nephritis refractory to cyclophosphamide and mycophenolate. Renal biopsy met the criteria of WHO class III LN complicated by acute tubular injury and immunofluorescence confirmed the activation of the mTOR pathway. Treatment with the mTOR inhibitor sirolimus was initiated in this patient. Complete remission (CR) was achieved after 6 months, and flare-free remission was maintained for the next 3.5 years. The literature on the efficacy of sirolimus in patients with LN was reviewed. Although the available evidence is limited to retrospective studies with small sample sizes, sirolimus appeared to be efficacious in some patients with refractory LN. Well-designed clinical trials are warranted, and pathology-guided precision medicine might assist in guiding physicians’ treatment decisions.

AbstractThis paper compares two metamodel-based methodologies for multi-criteria simulation optimization (SO), using the injection molding of a disposable camera front housing as a case study. The first methodology uses linear regression metamodels and data envelopment analysis (DEA) to iteratively identify potential Pareto solutions, while the second one uses a Gaussian process metamodel and calculates an expected improvement to determine the new input runs sequentially. A one-to-one comparison of the approaches is presented using two optimization examples. The first example involves two process outputs and the second involves three. The approaches are evaluated using the same number of simulations, and are compared in terms of the quality of the obtained Pareto front, based on the hypervolume indicator. Advantages and disadvantages of both methods are discussed.

Utilizing the dramatic accelerating effect of 2‐aminophenols, we developed a copper‐catalyzed system for the selective synthesis of di‐ and triphenylamines. In addition, N‐ and O‐arylation could be achieved in coupling reactions between 2‐aminophenol and nitroaryl halides.

The principles guiding the diurnal organization of biological pathways remain to be fully elucidated. Here, we perturb the hepatic transcriptome through nutrient regulators (high-fat diet and mTOR signaling components) to identify enduring properties of pathway organization. Temporal separation and counter-regulation between pathways of energy metabolism and inflammation/proliferation emerge as persistent transcriptome features across animal models, and network analysis identifies the G0s2and Rgs16genes as potential mediators at the metabolism-inflammation interface. Mechanistically, G0s2and Rgs16are sequentially induced during the light phase, promoting amino acid oxidation and suppressing overall mitochondrial respiration. In their absence, sphingolipids and diacylglycerides accumulate, accompanied by hepatic inflammation and hepatocyte proliferation. Notably, the expression of G0s2and Rgs16is further induced in obese mouse livers, and silencing of their expression accentuates hepatic fibrosis. Therefore, diurnal regulation of energy metabolism alleviates inflammatory and proliferative stresses under physiological and pathological conditions.

The type I interferon (IFN) pathway is a key component of innate immune response upon invasion of foreign pathogens. It is also under precise control to prevent excessive upregulation and undesired inflammation cascade. In the present study, we report that Riok3, an atypical kinase, negatively regulates retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) sensing-induced type I IFN signaling. Riok3 deficiency selectively inhibits RNA viral replication in vitro, resulting from an upregulated type I IFN pathway. Mice with myeloid-specific Riok3 knockout also show a more robust induction of type I IFN upon RNA virus infection and are more resistant to RNA virus-induced pathogenesis. Mechanistically, Riok3 recruits and interacts with the E3 ubiquitin ligase TRIM40, leading to the degradation of RIG-I and melanoma differentiation-associated gene-5 (MDA5) via K48- and K27-linked ubiquitination. Collectively, our data reveal the mechanism that Riok3 employs to be a negative regulator of antiviral innate immunity.

A Correction to this paper has been published: https://doi.org/10.1038/s41593-018-0090-8.

To instruct optimal design of sandwich panel with cutout, stress/strain concentration factor (SCF) and failure envelope of composite lattice-core sandwich panel (LSP) with circular cutout under multi-axial in-plane loads were investigated by numerical simulations and verified by digital image correlation (DIC) technique. SCF of the laminated composite skin is much higher than the orthotropic lattice core. Under different loading cases, skin layers with different orientations have different SCFs. SCF is also sensitive to the relation between the cutout diameter and the lattice cell dimension. Intersection of the lattices always produces a local peak value of SCF. Lower SCF can be designed by optimizing the diameter and location of the cutout. Strengthening effects of the strengthening range and strengthening material were discussed to reduce the SCF of the LSP.

No relevant conflicts of interest to declare.

Nutrients stimulate the anabolic synthesis of proteins and lipids, but selective insulin resistance in obesity biases the anabolic program toward lipogenesis. Here, we report the identification of a DNAJB9-driven program that favors protein synthesis and energy production over lipid accumulation. We show there are two pools of DNAJB9 cochaperone. DNAJB9 in the ER lumen promotes the degradation of the lipogenic transcription factor SREBP1c through ERAD, whereas its counterpart on the ER membrane promotes the assembly of mTORC2 in the cytosol and stimulates the synthesis of proteins and ATP. The expression of Dnajb9is induced by nutrients and downregulated in the obese mouse liver. Restoration of hepatic DNAJB9 expression effectively improves insulin sensitivity, restores protein synthesis, and suppresses food intake, accompanied by reduced hepatic steatosis and adiposity in multiple mouse models of obesity. Therefore, targeting the anabolic balance may provide a unique opportunity to tackle obesity and diabetes.

Background: Infection remains a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). This study aimed to establish a clinical prediction model for the 3-month all-cause mortality of invasive infection events in patients with SLE in the emergency department.Methods: SLE patients complicated with invasive infection admitted into the emergency department were included in this study. Patient’s demographic, clinical, and laboratory characteristics on admission were retrospectively collected as baseline data and compared between the deceased and the survivors. Independent predictors were identified by multivariable logistic regression analysis. A prediction model for all-cause mortality was established and evaluated by receiver operating characteristic (ROC) curve analysis.Results: A total of 130 eligible patients were collected with a cumulative 38.5% 3-month mortality. Lymphocyte count <800/ul, urea >7.6mmol/l, maximum prednisone dose in the past ⩾60 mg/d, quick Sequential Organ Failure Assessment (qSOFA) score, and age at baseline were independent predictors for all-cause mortality (LUPHAS). In contrast, a history of hydroxychloroquine use was protective. In a combined, odds ratio-weighted LUPHAS scoring system (score 3–22), patients were categorized to three groups: low-risk (score 3–9), medium-risk (score 10–15), and high-risk (score 16–22), with mortalities of 4.9% (2/41), 45.9% (28/61), and 78.3% (18/23) respectively. ROC curve analysis indicated that a LUPHAS score could effectively predict all-cause mortality [area under the curve (AUC) = 0.86, CI 95% 0.79–0.92]. In addition, LUPHAS score performed better than the qSOFA score alone (AUC = 0.69, CI 95% 0.59–0.78), or CURB-65 score (AUC = 0.69, CI 95% 0.59–0.80) in the subgroup of lung infections (n= 108).Conclusions: Based on a large emergency cohort of lupus patients complicated with invasive infection, the LUPHAS score was established to predict the short-term all-cause mortality, which could be a promising applicable tool for risk stratification in clinical practice.

Copper‐catalyzed selective N‐arylation and N,N‐diarylation of o‐aminophenol derivatives with aryl halides is smoothly achieved using the self‐accelerating effect of o‐aminophenols.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.