A positive (or negative) chameleon: A nanogel that is negatively charged at physiological pH values and activated to be positively charged at tumor extracellular pH values was internalized ...efficiently by tumor cells both in vitro and in vivo (see illustration). Intracellular drug release was also enhanced, probably as a result of a decrease in the interaction between the drug and the nanogel in its protonated state.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Objective
The current study evaluated the diagnostic performance of serum (1,3)-beta-D Glucan (BDG) in differentiating PJP from
P. jirovecii
-colonization in HIV-uninfected patients with
P. ...jirovecii
PCR-positive results.
Methods
This was a single-center retrospective study between 2019 and 2021. The diagnosis of PJP was based on the following criteria: detection of
P. jirovecii
in sputum or BAL specimen by qPCR or microscopy; Meet at least two of the three criteria: (1) have respiratory symptoms of cough and/or dyspnea, hypoxia; (2) typical radiological picture findings; (3) receiving a complete PJP treatment. After exclusion, the participants were divided into derivation and validation cohorts. The derivation cohort defined the cut-off value of serum BDG. Then, it was verified using the validation cohort.
Results
Two hundred and thirteen HIV-uninfected patients were enrolled, with 159 PJP and 54
P. jirovecii
-colonized patients. BDG had outstanding specificity, LR, and PPV for PJP in both the derivation (90.00%, 8.900, and 96.43%) and the validation (91.67%, 9.176, and 96.30%) cohorts at ≥ 117.7 pg/mL. However, it had lower sensitivity and NPV in the derivation cohort (89.01% and 72.97%), which was even lower in the validation cohort (76.47% and 57.89%). Of note, BDG ≥ 117.7 pg/mL has insufficient diagnostic efficacy for PJP in patients with lung cancer, interstitial lung disease (ILD) and nephrotic syndrome. And although lymphocytes, B cells, and CD4
+
T cells in PJP patients were significantly lower than those in
P. jirovecii
-colonized patients, the number and proportion of peripheral blood lymphocytes did not affect the diagnostic efficacy of serum BDG.
Conclusions
Serum BDG ≥ 117.7 pg/mL could effectively distinguish
P. jirovecii
-colonization from infection in qPCR-positive HIV-uninfected patients with infectious diseases, solid tumors (excluding lung cancer), autoimmune or inflammatory disorders, and hematological malignancies. Of note, for patients with lung cancer, ILD, and nephrotic diseases, PJP should be cautiously excluded at BDG < 117.7 pg/mL.
Familial hypercholesterolemia (FH) is an inherited metabolic disorder with a high level of low-density lipoprotein cholesterol and the worse prognosis. The triglyceride-glucose (TyG) index, an ...emerging tool to reflect insulin resistance (IR), is positively associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) in healthy individuals, but the value of TyG index has never been evaluated in FH patients. This study aimed to determine the association between the TyG index and glucose metabolic indicators, insulin resistance (IR) status, the risk of ASCVD and mortality among FH patients.
Data from National Health and Nutrition Examination Survey (NHANES) 1999-2018 were utilized. 941 FH individuals with TyG index information were included and categorized into three groups: < 8.5, 8.5-9.0, and > 9.0. Spearman correlation analysis was used to test the association of TyG index and various established glucose metabolism-related indicators. Logistic and Cox regression analysis were used to assess the association of TyG index with ASCVD and mortality. The possible nonlinear relationships between TyG index and the all-cause or cardiovascular death were further evaluated on a continuous scale with restricted cubic spline (RCS) curves.
TyG index was positively associated with fasting glucose, HbA1c, fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR) index (all p < 0.001). The risk of ASCVD increased by 74% with every 1 unit increase of TyG index (95%CI: 1.15-2.63, p = 0.01). During the median 114-month follow-up, 151 all-cause death and 57 cardiovascular death were recorded. Strong U/J-shaped relations were observed according to the RCS results (p = 0.0083 and 0.0046 for all-cause and cardiovascular death). A higher TyG index was independently associated with both all-cause death and cardiovascular death. Results remained similar among FH patients with IR (HOMA-IR ≥ 2.69). Moreover, addition of TyG index showed helpful discrimination of both survival from all-cause death and cardiovascular death (p < 0.05).
TyG index was applicable to reflect glucose metabolism status in FH adults, and a high TyG index was an independent risk factor of both ASCVD and mortality.
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Brain metastasis (BM) is a leading cause of mortality in patients with non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying BM of NSCLC remain largely ...unknown because of the lack of models to accurately investigate such a dynamic and complex process. Here we developed a multi-organ microfluidic chip as a new methodological platform to study BM. The chip consisted of two bionic organ units – an upstream “lung” and a downstream “brain” characterized by a functional “blood–brain barrier (BBB)” structure, allowing real-time visual monitoring of the entire BM process, from the growth of primary tumor to its breaking through the BBB, and finally reaching the brain parenchyma. The chip was verified by lung cancer cell lines with differing metastatic abilities and then applied for the BM research where we first demonstrated that the protein expression of Aldo-keto reductase family 1 B10 (AKR1B10) was significantly elevated in lung cancer BM. Silencing AKR1B10 in brain metastatic tumor cells suppressed their extravasation through the BBB in the in vitro Transwell model, in our ex vivo microfluidic chip, as well as the in vivo model of brain metastasis in nude mice. Moreover, AKR1B10 downregulated the expression of matrix metalloproteinase (MMP)-2 and MMP-9 via MEK/ERK signaling in metastatic lung cancers. These data suggest that our multi-organ microfluidic chip is a practical alternative to study BM pathogenesis, and AKR1B10 is a diagnostic biomarker and a prospective therapeutic target for NSCLC BM.
Brain metastasis (BM) of non-small cell lung cancer (NSCLC) is a complex cascade, and in particular, the process of lung cancer cells penetrating the blood–brain barrier (BBB) is very unique. However, due to the lack of reliable models that can faithfully mimic the dynamic process of BBB breaking, its molecular mechanisms have not well elucidated so far. In addition, although Aldo-keto reductase family 1 B10 (AKR1B10) has been implicated to the tumor development of liver cancer and many other cancers, little is known on its roles in the BM. Here, we established a multi-organ microfluidic bionic chip platform to recapitulate the entire BM process, and applied it to the BM pathology research, especially BBB extravasation. By using the chip and traditional models synergistically, we first demonstrated that AKR1B10 was significantly elevated in lung cancer BM, and defined the value of AKR1B10 as a diagnostic serum biomarker for lung cancer patients suffering from BM. Further, we investigated the role and mechanisms of AKR1B10 in BM that it promotes the extravasation of cancer cells through the BBB.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cyanobacterial blooms (CBs) in eutrophic lakes can cause various harmful issues to both humans and animals, disturb drinking water supply, and devastate lake ecosystems. Although great progresses ...have been made in many lakes from China and abroad on CBs prevention, mitigation and control, systematic research on the influencing factors of CBs in hypereutrophic plateau Lake Dianchi over a long time span is so far unavailable. This study comprehensively generalized both meteorological and water quality changes in Lake Dianchi during 1990–2015 on both yearly and monthly basis, separated Caohai from Waihai of Lake Dianchi regarding water quality variations, and investigated the individual and joint influencing meteorological and water quality factors on CBs using Spearman correlation, principal component analysis, and multivariate linear stepwise regression. Four specific lake regions, i.e. Caohai, northern Waihai, central Waihai, and southern Waihai, were respectively analyzed due to significant water quality heterogeneity. Results indicated that mild temperatures, low wind velocities, and hypereutrophic water conditions all favor CBs in Lake Dianchi, and the significant temperature rising trend may exacerbate severer CBs in the future. Despite configuration differences, the first principal components on CBs in the four sub-regions of Lake Dianchi were all consisted of meteorological factors, while water quality parameters especially total phosphorus concentrations contributed to the second principal component. Quantification of joint meteorological and water quality influencing factors on CBs needs further improvement, and largely relies on the accuracy of future weather forecasts, in order to set the goal of water quality improvement in each specific lake region for effective CBs management.
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•Meteorological and water quality changes in Lake Dianchi (1990–2015) were analyzed.•The lake was divided into four sub-regions based on water quality heterogeneity.•In all regions, meteorological factors were the first principal component on CBs.•Meanwhile, water quality especially nutrients were the second principal component.•Accurate weather forecast helps to set the water quality standards across the lake.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Globally intensified hazardous algal blooms (HABs) can and have already threatened public health and ecosystem services. For the hypereutrophic plateau Lake Dianchi in China, although comprehensive ...measures have been made regarding nutrients reduction and HABs biomass mitigation in the past decades, massive HABs are still frequently observable. HABs management strategies could hardly be successful unless relationships between the surrounding rivers’ water quality and HABs inside the lake are taken into serious consideration. This study characterized the river-lake water quality differences during 2010–2015, explored the relationships of riverine pollutants loading to lake water quality, and investigated the correlations of single and joint riverway water quality parameters to lacustrine HABs respectively via Spearman correlation analysis and multiple stepwise linear regression. Results indicated that surrounding inflow rivers displayed greater fluctuations than the lake in terms of water quality, and pollutants especially CODCr and nutrients were generally of higher concentrations in rivers that flow into Caohai and northern Waihai, than at the nearby state controlling sampling sites in the lake. Comparing to the rest of the lake, HABs in northern Waihai was much more influenced by the water quality of inflow rivers. Water temperature (WT) and SS were uniformly recognized as significant positive correlation factors between riverine water quality and lacustrine HABs, while DO as negative factor. When multiple factors were considered, WT was the predominant positive contributor to lacustrine HABs among most of the inflow rivers. Impact of riverine nutrients, however, was equivocal, due to the fact that nutrients concentrations in both rivers and the lake were already way beyond the hyper-eutrophication criteria. Taking into account multiple factors that may influence the threshold of nutrients to trigger HABs, the target nutrients limits for inflow rivers as well as Lake Dianchi itself was suggested to be much lower than previously recommended, and years of nutrients reduction efforts together with other remediation projects are required to ultimately mitigate HABs inside the lake.
•River-lake water quality differences of Dianchi Basin in 2010–2015 were analyzed.•Relationship between rivers' pollutants loading and lake water quality was explored.•Correlation of riverway water quality to HABs inside the lake was investigated.•Contribution of joint riverway water quality factors to in-lake HABs was quantified.•Stricter nutrients reduction and additional remediation efforts were suggested.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Heteroatom doping could markedly enhance the properties of carbon materials. For the precursor with nitrogen (N) heteroatom, it is difficult to fix its own N heteroatom in target products to ...the maximum extent by traditional methods. In this work, we take corn cob core as instance to fabricate N‐doped hard carbon with high N content by a newly developed pyrolysis‐deposition‐self‐doping (PDSD) in confined graphite canister. Compared with the traditional method of pyrolysis by placing the sample in an open corundum crucible, the N doping amount of hard carbon obtained by PDSD method in a sealed graphite canister significantly increases from 0.93 to 5.63 at%. It demonstrates the crucial function of confined graphite canister in tuning the doped heteroatom's weight of carbon matrix. The influence of two kinds of pyrolysis methods on the microstructure of the materials was systematically analyzed by X‐ray diffractometer, Raman, X‐ray photoelectron spectrometer, and high resolution transmission electron microscopy (HRTEM). Furthermore, corresponding electrochemical tests are measured as anode materials for sodium‐ion batteries and the results suggest that the product prepared by PDSD method exhibits better cycling and rate performance. This fully proves the advantages of PDSD method for improving the amount of heteroatom doping, and lays the experimental and theoretical foundation for the future research and development of heteroatom doped carbon materials.
In this work, we fabricate a high content of N doped hard carbon by unique pyrolysis‐deposition‐self‐doping (PDSD) in confined graphite canister. Compared with conventional pyrolysis at 1400 oC in a open corundum crucible, an unexpected increase of N doping amount from 0.93 at. % to 5.63 at. % is obtained by PDSD method. Meanwhile, owing to the escaped N atom from precursor react with the pyrolysis carbon, the ordering degree also improved.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
An efficient and safe delivery system for small interfering RNA (siRNA) is required for clinical application of RNA interfering therapeutics. Polyethyleneimine (PEI)‐capped gold nanoparticles (AuNPs) ...are successfully manufactured using PEI as the reductant and stabilizer, which bind siRNA at an appropriate weight ratio by electrostatic interaction and result in well‐dispersed nanoparticles with uniform structure and narrow size distribution. With siRNA binding, PEI‐capped AuNPs induce more significant and enhanced reduction in targeted green fluorescent protein expression in MDA‐MB‐435s cells, though more internalized PEI/siRNA complexes in cells are evidenced by confocal laser scanning microscopy observation and fluorescence‐activated cell sorting analyses. PEI‐capped AuNPs/siRNA targeting endogenous cell‐cycle kinase, an oncogene polo‐like kinase 1 (PLK1), display significant gene expression knockdown and induce enhanced cell apoptosis, whereas it is not obvious when the cells are treated with PLK1 siRNA using PEI as the carrier. Without exhibiting cellular toxicity, PEI‐capped AuNPs appear to be suitable as a potential carrier for intracellular siRNA delivery.
Delivery to cancer cells of small interfering RNA (siRNA) is mediated by polyethyleneimine (PEI)‐capped gold nanoparticles (AuNPs), which results in efficient gene expression silencing to both exogenous green fluorescent protein and endogenous PLK1 genes. PEI‐capped AuNPs and AuNPssiRNA show good cytocompatibility and are suitable for intracellular delivery of siRNA for potential cancer therapy (see picture).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A visible-light-mediated late-stage sulfonylation of anilines with sulfonamides under simple reaction conditions is presented. Various primary or secondary sulfonamides including several ...pharmaceuticals were incorporated successfully via N-S bond activation and C-H bond sulfonylation. The synthetic utility of this strategy is highlighted by the construction of complex anilines bearing diverse bioactive groups.
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IJS, KILJ, NUK, PNG, UL, UM
A novel arylation of sulfonamides with boronic acids to afford numerous diaryl sulfones via a visible light-mediated N–S bond cleavage other than the typical transition-metal-catalyzed C(O)–N bond ...activation is described. This methodology, which represents the first catalyst-free protocol for the sulfonylation of boronic acids, is characterized by its simple reaction conditions, good functional group tolerance and high efficiency. Several successful examples for the late-stage functionalization of diverse sulfonamides indicate the high potential utility of this method in pharmaceutical science and organic synthesis.
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