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Abstract Background The 9th edition of the TNM Classification for lung cancer delineates M1c into two subcategories: M1c1 (Multiple extrathoracic lesions within a single organ system) and M1c2 (Multiple extrathoracic lesions involving multiple organ systems). Existing research indicates that patients with lung cancer in stage M1c1 exhibit superior overall survival compared to those in stage M1c2. The primary frontline therapy for patients with advanced non‐small cell lung cancer (NSCLC), lacking driver gene mutations, involves the use of immune checkpoint inhibitors (ICIs) combined with chemotherapy. Nevertheless, a dearth of evidence exists regarding potential survival disparities between NSCLC patients with M1c1 and M1c2 undergoing first‐line immune‐chemotherapy, and reliable biomarkers for predicting treatment outcomes are elusive. Serum metabolic profiles may elucidate distinct prognostic mechanisms, necessitating the identification of divergent metabolites in M1c1 and M1c2 undergoing combination therapy. This study seeks to scrutinize survival discrepancies between various metastatic patterns (M1c1 and M1c2) and pinpoint metabolites associated with treatment outcomes in NSCLC patients undergoing first‐line ICIs combined with chemotherapy. Method In this study, 33 NSCLC patients lacking driver gene mutations diagnosed with M1c1, and 22 similarly diagnosed with M1c2 according to the 9th edition of TNM Classification, were enrolled. These patients received first‐line PD‐1 inhibitor plus chemotherapy. The relationship between metastatic patterns and progression‐free survival (PFS) in patients undergoing combination therapy was analyzed using univariate and multivariate Cox regression models. Serum samples were obtained from all patients before treatment initiation for untargeted metabolomics analysis, aiming to identify differential metabolites. Results In the univariate analysis of PFS, NSCLC patients in M1c1 receiving first‐line PD‐1 inhibitor plus chemotherapy exhibited an extended PFS (HR = 0.49, 95% CI, 0.27–0.88, p = 0.017). In multivariate PFS analyses, these M1c1 patients receiving first‐line PD‐1 inhibitor plus chemotherapy also demonstrated prolonged PFS (HR = 0.45, 95% CI, 0.22–0.92, p = 0.028). The serum metabolic profiles of M1c1 and M1c2 undergoing first‐line PD‐1 inhibitors plus chemotherapy displayed notable distinctions. In comparison to M1c1 patients, M1c2 patients exhibited alterations in various pathways pretreatment, including platelet activation, linoleic acid metabolism, and the VEGF signaling pathway. Diminished levels of lipid‐associated metabolites (diacylglycerol, sphingomyelin) were correlated with adverse outcomes. Conclusion NSCLC patients in M1c1, devoid of driver gene mutations, receiving first‐line PD‐1 inhibitors combined with chemotherapy, experienced superior outcomes compared to M1c2 patients. Moreover, metabolomic profiles strongly correlated with the prognosis of these patients, and M1c2 patients with unfavorable outcomes manifested distinct changes in metabolic pathways before treatment. These changes predominantly involved alterations in lipid metabolism, such as decreased diacylglycerol and sphingomyelin, which may impact tumor migration and invasion.

Abstract The growth of newly formed particles through new particle formation (NPF) contributes a significant fraction to the cloud condensation nuclei, yet the driving mechanisms remain unclear, especially for polluted environments. To investigate the potential species contributing for nanoparticle growth in environments with significant anthropogenic influences, we measured the hygroscopicity of newly formed particles at 20–40 nm at a rural observational site in the North China Plain during winter 2018. Our results demonstrate that these particles were not very hygroscopic, with the mean hygroscopicity parameter κ of 0.13 ± 0.09. Clear differences in the inferred κ of the growing material responsible for the growth were observed among different events, indicating that even at the same region, the compounds driving particle growth may not be identical. This may be synergistically influenced by the NPF precursors, oxidants and meteorological conditions, suggesting complex mechanisms might co‐exist behind nanoparticle growth in polluted environments.

Abstract Atmospheric aerosols not only cause severe haze pollution, but also affect climate through changes in cloud properties. However, during the haze pollution, aerosol‐cloud interactions are not well understood due to a lack of in situ observations. In this study, we conducted simultaneous observations of cloud droplet and particle number size distribution, together with supporting atmospheric parameters, from ground to cloud base in East China using a high‐payload tethered airship. We found that high concentrations of aerosols and cloud condensation nuclei were constrained below cloud, leading to the pronounced “Twomey effect” near the cloud base. The cloud inhibited the pollutants dispersion by reducing surface heat flux and thus deteriorated the near‐surface haze pollution. Satellite retrievals matched well with the in situ observations for low stratus clouds, while were insufficient to quantify aerosol‐cloud interactions for other cases. Our results highlight the importance to combine in situ vertical and satellite observations to quantify the aerosol‐cloud interactions.

Abstract How brain functions in the distorted ischemic state before and after reperfusion is unclear. It is also uncertain whether there are any indicators within ischemic brain that could predict surgical outcomes. To alleviate these issues, we applied individual brain connectome in chronic steno‐occlusive vasculopathy (CSOV) to map both ischemic symptoms and their postbypass changes. A total of 499 bypasses in 455 CSOV patients were collected and followed up for 47.8 ± 20.5 months. Using multimodal parcellation with connectivity‐based and pathological distortion‐independent approach, areal MR features of brain connectome were generated with three measurements of functional connectivity (FC), structural connectivity, and PageRank centrality at the single‐subject level. Thirty‐three machine‐learning models were then trained with clinical and areal MR features to obtain acceptable classifiers for both ischemic symptoms and their postbypass changes, among which, 11 were deemed acceptable (AUC > 0.7). Notably, the FC feature‐based model for long‐term neurological outcomes performed very well (AUC > 0.8). Finally, a Shapley additive explanations plot was adopted to extract important individual features in acceptable models to generate “fingerprints” of brain connectome. This study not only establishes brain connectomic fingerprint databases for brain ischemia with distortion, but also provides informative insights for how brain functions before and after reperfusion.

Abstract Exchange bias is extensively studied and widely utilized in spintronic devices, such as spin valves and magnetic tunnel junctions. 2D van der Waals (vdW) magnets, with high‐quality interfaces in heterostructures, provide an excellent platform for investigating the exchange bias effect. To date, intrinsic modulation of exchange bias, for instance, via precise manipulation of the magnetic phases of the antiferromagnetic layer, is yet to be fully reached, owing partly to the large exchange fields of traditional bulk antiferromagnets. Herein, motivated by the low‐field spin‐flop transition of a 2D antiferromagnet, CrPS4, exchange bias is explored by modulating the antiferromagnetic spin‐flop phase transition in all‐vdW magnetic heterostructures. The results demonstrate that undergoing the spin‐flop transition during the field cooling process, the A‐type antiferromagnetic ground state of CrPS4 turns into a canted antiferromagnetic one, therefore, it reduces the interfacial magnetic coupling and suppresses the exchange bias. Via conducting different cooling fields, one can select the exchange bias effect switching among the “ON”, “depressed”, and “OFF” states determined by the spin flop of CrPS4. This work provides an approach to intrinsically modulate the exchange bias in all‐vdW heterostructures and paves new avenues to design and manipulate 2D spintronic devices.

Abstract Previous studies revealed a controversial role of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC1‐regulated macroautophagy in isoproterenol (ISO)‐induced cardiac injury. Here we investigated the role of mTORC1 and potential underlying mechanisms in ISO‐induced cardiomyocyte necrosis. Two consecutive daily injections of ISO (85 mg/kg, s.c.) or vehicle control (CTL) were administered to C57BL/6J mice with or without rapamycin (RAP, 5 mg/kg, i.p.) pretreatment. Western blot analyses showed that myocardial mTORC1 signaling and the RIPK1–RIPK3–MLKL necroptotic pathway were activated, mRNA expression analyses revealed downregulation of representative TFEB target genes, and Evan's blue dye uptake assays detected increased cardiomyocyte necrosis in ISO‐treated mice. However, RAP pretreatment prevented or significantly attenuated the ISO‐induced cardiomyocyte necrosis, myocardial inflammation, downregulation of TFEB target genes, and activation of the RIPK1–RIPK3–MLKL pathway. LC3‐II flux assays confirmed the impairment of myocardial autophagic flux in the ISO‐treated mice. In cultured neonatal rat cardiomyocytes, mTORC1 signaling was also activated by ISO, and inhibition of mTORC1 by RAP attenuated ISO‐induced cytotoxicity. These findings suggest that mTORC1 hyperactivation and resultant suppression of macroautophagy play a major role in the induction of cardiomyocyte necroptosis by catecholamine surges, identifying mTORC1 inhibition as a potential strategy to treat heart diseases with catecholamine surges.

Abstract Introduction This study examines the associations between asthma and nitric oxide (NO) synthase (NOS) gene polymorphisms. Methods After a systematic literature search in electronic databases, studies were selected based on eligibility criteria. Data were extracted from research articles and were synthesized and tabulated. Where a particular polymorphism data were reported by multiple studies, meta‐analyses of odds ratios were performed, or odds ratios reported by individual studies were pooled. Results Twenty studies (4450 asthma patients and 5306 non‐asthmatic individuals) were identified. Many studies did not find any association between CCTTT repeat polymorphism in NOS2 gene and asthma. However, a study reported that pretreatment mean exhaled NO levels in asthmatics were found to be significantly higher in genotypes with higher number of CCTTT repeats. Also, alleles with

Abstract The intelligent sensing system is the digital basis for zero‐carbon park operation. Due to the immaturity of its cost‐benefit accounting method and the lack of a special construction mode evaluation system, there is blindness in its investment and construction process. In order to select the suitable construction mode for the intelligent sensing system scientifically and effectively, this paper first establishes the architecture of the intelligent sensing system, and determines a cost‐benefit accounting method of the intelligent sensing system. Then, this paper establishes a construction mode evaluation index system including techno‐economic indicators, and proposes a fuzzy comprehensive evaluation method combing analytic hierarchy process and the decision‐making trial and evaluation laboratory to select the optimal construction mode. The numerical analyses show that the public‐private‐partnership mode of the intelligent sensing system has achieved ideal implementation results.

Abstract Background F‐box and WD repeat domain containing 7 (FBXW7) is a critical tumor suppressor. The expression of FBXW7 is decreased in oral squamous cell carcinoma (OSCC) tissues and shows diagnosis value. We aimed to investigate the influence of FBXW7 overexpression on OSCC cell proliferation and autophagy. Methods In Balb/c nude mice, CAL27 xenograft tumor model was established. Western blot was employed to evaluate protein level. Messenger RNA level was analyzed by quantitative reverse transcription‐polymerase chain reaction. Colony formation assay and MTT assay were employed to evaluate cell proliferation. Results FBXW7 expression was decreased in OSCC cell lines. FBXW7 inhibited cell proliferation of SCC9 and CAL27. FBXW7 increased Autophagy related 7 (Atg7), Beclin1 (BECN1), B‐cell lymphoma 2 (BCL2) ‐associated X (BAX), BCL2 antagonist killer (BAK), and microtubule‐associated protein 1 light chain 3 (LC3) levels and decreased MCL1 and BCL2 levels in CAL27 cells. FBXW7 decreased tumor volume and weight in CAL27 xenograft tumor model. FBXW7 increased BECN1, Atg7, and LC3 levels in CAL27 xenograft tumor model. Conclusion In conclusion, decreased expression of FBXW7 is confirmed in diverse OSCC cell lines. The enhanced FBXW7 expression inhibits cancer cell proliferation and promotes autophagy in both OSCC cells and xenograft tumor model.

With the advent of globalization, computing speed has increased tremendously, greatly advancing algorithm research in multiple fields. This paper studies the parameter optimization problem of the improved multipopulation genetic algorithm in the tuned mass damper (TMD) structure considering the soil-structure interaction (SSI) effect. The Newmark time-domain analysis method was used to analyze the dynamic response of a 40-story building under the excitation of EL Centro waves and Tangshan waves in China, respectively. The mass, damping coefficient, and spring stiffness of TMD system are used as the design variables of the controller. To reduce structural damage and obtain better comfort, the displacement response and acceleration response are optimized simultaneously in this paper, achieving multiobjective optimization. The results show that the improved multipopulation genetic algorithm method has faster convergence speed and greater accuracy than the traditional genetic algorithm; thus it can be applied to the TMDs parameter optimization of high-rise buildings. Besides, the soil types have a great influence on TMD parameter optimization and structural time history response. If ignoring SSI effect will lead to underestimation of parameter design, the reason is that the soft soil foundations can absorb a lot of seismic energy compared with rigid foundations and then reduce the effect of seismic excitation on the structure. The intention of the research helps researchers to better understand vibration control and provides suggestions for the application of TMD in high-rise buildings.

Abstract The sulfur redox kinetics critically matters to superior lithium–sulfur (Li–S) batteries, for which single atom catalysts (SACs) take effect on promoting Li2S redox process and mitigating the shuttle behavior of lithium polysulfide (LiPs). However, conventional trial‐and‐error strategy significantly slows down the development of SACs in Li–S batteries. Here, the Li2S oxidation processes over MN4@G catalysts are fully explored and energy barrier of Li2S decomposition (Eb) is identified to correlate strongly with three parameters of energy difference between initial and final states of Li2S decomposition, reaction energy of Li2S oxidation and LiS bond strength. These three parameters can serve as efficient descriptors by which two excellent SACs of MoN4@G and WN4@G are screened which give rise to Eb values of 0.58 and 0.55 eV, respectively, outperforming other analogues in adsorbing LiPs and accelerating the redox kinetics of Li2S. This method can be extended to a wider range of SACs by coupling MN4 moiety with heterostructures and heteroatoms beyond N where WN4@G/TiS2 heterointerface is predicted to exhibit enhanced catalytic performance for Li2S decomposition with Eb of 0.40 eV. This work will help accelerate the process of designing a wider range of efficient catalysts in Li–S batteries and even beyond, e.g. alkali‐ion‐Chalcogen batteries.

Hyperspectral dorsal hand vein image analysis for biometrics is a relatively new technology with great potential. Compared to traditional dorsal hand biometrics that use only one spectral band to capture and analyse the veins, hyperspectral imaging allows additional information to be included. Given the difficulties of processing hyperspectral dorsal hand images, including uneven illuminations, a noisy background, translation, and deformation, this study proposes a robust and adaptive region of interest (ROI) extraction algorithm. First, a novel knuckle pinky invariant point is located. Next, based on this invariant point a key line on the dorsal hand representing one side of the squared ROI is found. The remaining three sides of the ROI can then be formed. To evaluate the proposed method, both identification and verification experiments were conducted on a large hyperspectral dorsal hand vein database. The experimental results showed that the proposed method outperformed other dorsal hand ROI extraction algorithms for each hyperspectral band. Having performed well in both experiments, the groundwork has been laid to further analyse the extracted ROI in terms of feature extraction.

Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) is currently considered a novel therapeutic strategy for diabetic nephropathy (DN). However, the mechanisms by which UC-MSCs ameliorate renal fibrosis in DN are not well understood. Herein, we firstly investigated the therapeutic effects of mouse UC-MSC infusion on kidney structural and functional impairment in streptozotocin- (STZ-) induced diabetic mice. We found that the repeated injection with mUC-MSCs alleviates albuminuria, glomerulus injury, and fibrosis in DN mouse models. Next, mesangial cells were exposed to 5.6 mM glucose, 30 mM glucose, or mUC-MSC-conditioned medium, and then we performed western blotting, immunofluorescence, wound healing assay, and cell proliferation assay to measure extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), myofibroblast transdifferentiation (MFT), and cell proliferation. We demonstrated that mUC-MSC paracrine decreased the deposition of fibronectin and collagen I by inhibiting TGF-β1-triggered MFT and cell proliferation mediated by PI3K/Akt and MAPK signaling pathways, and elevating the levels of MMP2 and MMP9. Importantly, we provided evidence that the antifibrosis role of mUC-MSC paracrine in DN might be determined by exosomes shed by MSCs. Together, these findings reveal the mechanisms underlying the therapeutic effects of UC-MSCs on renal fibrosis in DN and provide the evidence for DN cell-free therapy based on UC-MSCs in the future.

Objective. There is a limited diagnosis of nonalcoholic fatty liver disease (NAFLD). Thus, the noninvasive assessments are worth exploring. We determined the associations of phase angles (PhAs) obtained from bioelectric impedance analysis (BIA) with the risk of NAFLD in an overweight population. Methods. A study involving 953 overweight participants was conducted in Wuhan city, China. The associations between PhAs (right arm, left arm, body trunk, right leg, left leg, and whole body) and the risk of NAFLD were conducted using multivariate logistic regression analyses. The associations of PhAs with the controlled attenuation parameter (CAP), a noninvasive assessment of liver steatosis and fibrosis, were also evaluated by both linear and logistic regression analyses. Results. The PhA values of the whole body, trunk, and legs were significantly lower (P

This study analyses a gas insulated switchgear explosion accident caused by a failure of the circuit breaker (CB) in a thermal power plant, which resulted in the explosion of the CB and the burning of the potential transformer (PT). Through X-ray detection and disassemble examination of the damaged CB, it is found that the A-phase moveable contact was not opened completely. After analysing the voltage waveform obtained from the phasor measurement unit recorder system, it is speculated that this failure is caused by the process of repeated arc strike. For verification and further analysis, the fault process is simulated in the EMTP; the arc is properly modelled by an extended KEMA's equation-based model which is proposed in this study. The simulation results match well with the actual situation; the contact gap would be repeated breakdown because its breakdown voltage is reduced, and the very fast transient overvoltage (VFTO) would be generated in these repeated strike processes. Due to the steep front and high amplitude of VFTO, the insulation of the PT would be damaged and led to the occurrence of PT short-circuit fault. The current would increase rapidly and causes the CB to explode subsequently.

Premise: Whole-genome duplication (neopolyploidy) can instantly differentiate the phenotype of neopolyploids from their diploid progenitors. These phenotypic shifts in organs such as roots and leaves could also differentiate the way neopolyploids interact with microbial species. While some studies have addressed how specific microbial interactions are affected by neopolyploidy, we lack an understanding of how genome duplication affects the diversity and composition of microbial communities., Methods: We performed a common garden experiment with multiple clones of artificially synthesized autotetraploids and their ancestral diploids, derived from 13 genotypes of wild strawberry, Fragaria vesca. We sequenced epiphytic bacteria and fungi from roots and leaves and characterized microbial communities and leaf functional traits., Results: Autotetraploidy had no effect on bacterial alpha diversity of either organ, but it did have a genotype-dependent effect on the diversity of fungi on leaves. In contrast, autotetraploidy restructured the community composition of leaf bacteria and had a genotype-dependent effect on fungal community composition in both organs. The most differentially abundant bacterial taxon on leaves belonged to the Sphingomonas, while a member of the Trichoderma was the most differentially abundant fungal taxon on roots. Ploidy-induced change in leaf size was strongly correlated with a change in bacterial but not fungal leaf communities., Conclusions: Genome duplication can immediately alter aspects of the plant microbiome, but this effect varies by host genotype and bacterial and fungal community. Expanding these studies to wild settings where plants are exposed continuously to microbes are needed to confirm the patterns observed here., (© 2024 The Authors. American Journal of Botany published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

Acute myeloid leukaemia (AML) continues to have a poor prognosis, warranting new therapeutic strategies. The bone marrow (BM) microenvironment consists of niches that interact with not only normal haematopoietic stem cells (HSC) but also leukaemia cells like AML. There are many adhesion molecules in the BM microenvironment; therein, integrins have been of central interest. AML cells express integrins that bind to ligands in the microenvironment, enabling adhesion of leukaemia cells in the microenvironment, thereby initiating intracellular signalling pathways that are associated with cell migration, cell proliferation, survival, and drug resistance that has been described to mediate cell adhesion-mediated drug resistance (CAM-DR). Identifying and targeting integrins in AML to interrupt interactions with the microenvironment have been pursued as a strategy to overcome CAM-DR. Here, we focus on the BM microenvironment and review the role of integrins in CAM-DR of AML and discuss integrin-targeting strategies. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Evidence of a clear causal relationship between telomere length and aortic aneurysms is limited by the potential for confounding or reverse causation effects. In this study, we used a Mendelian randomisation (MR) approach to investigate this putative causal association., Methods: In total, 118 telomere length-associated single-nucleotide polymorphisms, identified in 472,174 individuals of European ancestry, were used as the instrumental variables. Summary statistics for genome-wide association studies of aortic aneurysms were obtained from the FinnGen consortium. For the primary MR analyses, the inverse-variance weighted random-effects method was used and was supplemented with multivariable MR, weighted median and MR-Egger approaches. The MR-Egger intercept test, Cochran's Q test and 'leave-one-out' sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneity and stability of the genetic variants. Forward and reverse MR analyses were performed., Results: All forward univariable MR analyses showed that longer telomere lengths decreased aortic aneurysm risks (total aortic aneurysms: OR = 0.80, 95% CI 0.67-0.96, p = .015; thoracic aortic aneurysms: OR = 0.82, 95% CI 0.68-0.98, p = .026; abdominal aortic aneurysms: OR = 0.525, 95% CI 0.398-0.69, p < .001), whereas all reverse MR analyses suggested the absence of aortic aneurysm liability on telomere length. The sensitivity analysis results were robust, and no evidence of horizontal pleiotropy was observed., Conclusions: Our results support a possible causal association between telomere length and aortic aneurysms, providing new insights into the involvement of telomere biology in this condition and offering a potential avenue for targeted therapeutic interventions., (© 2023 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Objective: To assess clinical and psychosocial outcomes of nurse-led follow-up in survivorship care of gynaecological malignancies., Methods: Women with endometrial or ovarian cancer who were attending regular post-treatment follow-up at a tertiary referral centre were randomised into two groups-group-1: telephone follow-up by nurses and group-2: gynaecologists-led clinic follow-up. Women in group-1 were asked about their symptoms and quality of life (QoL) by nurses. Women in group-2 were followed up by gynaecologists and underwent symptom reviews and physical examinations. All ovarian cancer patients in both groups also had CA125 measured. All recruited women completed a QoL questionnaire (EORTC QLQ-C30), HADS-anxiety questionnaire and symptom checklist., Results: 385 women (215 with endometrial and 170 with ovarian cancer) were randomised. There was no significant difference in the detection of recurrence according to the two follow-up protocols. However, women in the nurse-led arm scored higher on emotional (p = 0.023) and cognitive functioning (p = 0.012). Those in the gynaecologist-led arm scored higher on the HADS-anxiety scale (p = 0.001) and were more likely to report symptoms., Conclusions: Our results demonstrate a preliminary non-inferiority of nurse-led follow-up, with improved psychological morbidity and QoL. Thus, nurse-led follow-up can be considered an effective substitute for hospital-based care., (© 2020 John Wiley & Sons Ltd.)

Background: Few studies have assessed the sensitization of mycotic allergens and Aspergillus fumigatus molecular allergens. This study aimed to investigate the relationships of A fumigatus components and mycotic allergens in allergic bronchopulmonary aspergillosis (ABPA) patients and A fumigatus (Af)-sensitized asthma patients., Methods: Serum sIgE levels of Penicillium chrysogenum, Cladosporium herbarum, Mucor racemosus, Candida albicans, Alternaria alternata, Helminthosporium halodes, and A fumigatus allergen components (Asp f 1, Asp f 2, Asp f 3, Asp f 4, and Asp f 6) were measured via the ImmunoCAP assay in 18 ABPA and 54 Af-sensitized asthma patients in Guangzhou city, China., Results: 94.44% of ABPA patients and 87.04% of Af-sensitized asthma patients were co-sensitized to at least one other fungal allergen. The positive rates of Asp f 1 (88.89% vs 59.26%, P < .05), Asp f 2 (66.67% vs 33.33%, P < .05), Asp f 4 (61.11% vs 33.33%, P < .05), and Asp f 6 (66.67% vs 14.81%, P < .001) in ABPA patients were higher than those in Af-sensitized asthma patients. IgE levels of Asp f 1 (P < .05), Asp f 4 (P < .05), and Asp f 6 (P < .001) were higher in ABPA patients than in Af-sensitized asthma patients. Optimal scale analysis showed that ABPA was more relevant to Af components (Cronbach's alpha = 90.7%)., Conclusion: The A fumigatus components and their relationships with various mycotic allergens were different in ABPA and Af-sensitized asthma patients. This finding may help local doctors in the diagnosis and immunotherapy of fungal allergies., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

During the last decade, the problem of suicide has become more serious in individuals with depression. Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD). This study aims to investigate the efficacy of magnetic resonance imaging (MRI)-based neuronavigation-guided daily high-dose rTMS for rapidly improving suicidal ideation in treatment-naive patients with MDD. In the present 1-week double-blind study, 42 treatment-naive patients with MDD with suicidal ideation were randomly assigned to the treatment of escitalopram oxalate tablets (10 mg/d) in combination with either active (n = 21) or sham (n = 21) rTMS. The TMS coil was positioned over a specified target location (-44, 40, and 29) in left dorsolateral prefrontal cortex based on MRI data. The severity of suicidal ideation was measured by the Beck Scale for Suicide Ideation (BSI). The 24-item Hamilton Depression Rating Scale (HAMD-24) and Montgomery-Åsberg Depression Rating Scale (MADRS) were utilized to assess the severity of depression. The Wisconsin Card Sorting Test, Continuous Performance Test, and Stroop Color-Word Test were adopted to assess executive function. In contrast to the sham group, the active rTMS group showed a significantly greater BSI score reduction at the third day and the seventh day (P < 0.001). Moreover, the active rTMS group showed a significantly greater HAMD (P < 0.001) and MADRS (P < 0.001) score reduction at the seventh day in comparison to the sham group. The present findings suggested that the neuronavigation-guided high-dose rTMS may be a novel method to rapidly reduce suicidal ideation and mitigate depressive symptoms., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Premise: Divergence in functional traits and adaptive responses to environmental change underlies the ecological advantage of polyploid plants in the wild. While established polyploids may benefit from combined outcomes of genome doubling, hybridization, and polyploidy-enabled adaptive evolution, whether genome doubling alone can drive ecological divergence or whether the outcome is genetically variable remains less clear., Methods: Using synthetic, colchicine-induced, autotetraploid (4x) plants derived from self-pollinated diploid (2x) seeds, and their colchicine-treated but unconverted diploid (2x.nc) full sibs from two diploid wild strawberry taxa (Fragaria vesca subsp. vesca and F. vesca subsp. bracteata), we examined the effects of genome doubling on functional traits, heat stress tolerance, and fitness components across taxa and maternal families (i.e., genetic families) within taxa., Results: Comparisons between 2x and 2x.nc plants indicated a negligible effect of colchicine treatment on functional traits. Genome doubling increased stomatal length and decreased stomatal density, specific leaf area, and leaf vein density, recapitulating patterns observed in wild polyploid Fragaria. Trichome density, heat stress tolerance, and relative growth rate were not significantly affected by genome doubling. Although clonal reproduction was reduced in response to genome doubling, this effect was strongly genetic-family dependent., Conclusions: The results suggest that genome doubling during incipient speciation alone can generate ecological divergence and variation among genetic lineages. This response potentially allows for rapid short-term evolutionary adaptation and fuels genomic diversity and independent origins of polyploidy., (© 2019 Botanical Society of America.)

The surface display laccase (SDL) biocatalyst, where the enzyme laccase is displayed on the surface of biological cells through synthetic biology, provides a new opportunity to develop sustainable technologies for removal of emerging contaminants from wastewater. This study vigorously characterized biocatalytic properties of the SDL in comparison to free laccase in removing emerging contaminant acetaminophen (APAP), with the aim to understand the effect of surface display on enzyme functionality and identify the strategy to overcome the potential limitation. The SDL could effectively remove APAP. Adding redox mediators substantially improved the removal efficiency. The Michaelis-Menten kinetic analysis showed that the redox mediator 2,2-azinobis-3-ethylbenzothiazoline-6-sulfonate could overcome the limitation of APAP accessing the active site of laccase in the SDL biocatalyst. The APAP removal rate catalyzed by the SDL in real secondary wastewater effluent was higher than that in acetate buffer; comprehensive enzyme kinetic analysis provided clear evidence that there were redox mediating compounds in the wastewater. Analysis of transformation products revealed that surface display did not change laccase functionality in terms of APAP transformation mechanism. In addition, the SDL retained 88% of the initial activity after six repeated APAP biotransformation reactions. Results from this study provide a scientific basis for developing and implementing SDL as an innovative biocatalytic material for contaminant treatment applications., (© 2019 Wiley Periodicals, Inc.)

Treating systemic metastases at the micrometastatic stage is a potential strategy to inhibit cancer metastasis. This study aims to establish an apoptosis sensor-based platform for rapid, effective, and noninvasive identification of drugs that can inhibit the proliferation of micrometastatic cancer cells. We stably transfected the plasmid DNA encoding the fluorescence resonance energy transfer-based caspase-3 sensor into highly metastatic melanoma B16F10 cells. The resulting B16F10-C3 cells were applied for screening of antiproliferative and proapoptotic drugs in two-dimensional (2D) monolayer, three-dimensional (3D) spheroids, and zebrafish xenotransplantation tumors. All studies were conducted in 96-well plates in a high throughput manner. Fourteen compounds including six chemotherapeutic drugs and eight kinase inhibitors were tested. Thirteen compounds failed the tests due to: Drug resistance, low efficacy, poor pharmacokinetic profile, and/or high side effects to zebrafish. The only compound that passed all tests was pan-phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, which inhibited the proliferation of B16F10-C3 cells in both 2D and 3D cultures. More important, it significantly reduced the xenograft tumor size in zebrafish by decreasing the viability of metastatic cancer cells. Our study suggests that the PI3K/AKT pathway is a potential therapeutic target for the reactivation of tumor dormancy and proliferation of micrometastases. Moreover, this integrated approach is effective for rapid identification of systemic antimetastases drugs., (© 2018 Wiley Periodicals, Inc.)

Premise of the Study: Recurrent formation of polyploid taxa is a common observation in many plant groups. Haploid, cytoplasmic genomes like the plastid genome can be used to overcome the problem of homeologous genes and recombination in polyploid taxa. Fragaria (Rosaceae) contains several octo- and decaploid species. We use plastome sequences to infer the plastid ancestry of these taxa with special focus on the decaploid Fragaria cascadensis., Methods: We used genome skimming of 96 polyploid Fragaria samples on a single Illumina HiSeq 3000 lane to obtain whole plastome sequences. These sequences were used for phylogenetic reconstructions and dating analyses. Ploidy of all samples was inferred with flow cytometry, and plastid inheritance was examined in a controlled cross of F. cascadensis., Key Results: The plastid genome phylogeny shows that only the octoploid F. chiloensis is monophyletic, all other polyploid taxa were supported to be para- or polyphyletic. The decaploid Fragaria cascadensis has biparental plastid inheritance and four different plastid donors. Diversification of the F. cascadensis clades occurred in the last 230,000 years. The southern part of its distribution range harbors considerably higher genetic diversity, suggestive of a potential refugium., Conclusions: Fragaria cascadensis had at least four independent origins from parents with different plastomes. In contrast, para- and polyphyletic taxa of the octoploid Fragaria species are best explained by incomplete lineage sorting and/or hybridization. Biogeographic patterns in F. cascadensis are probably a result of range shift during the last glacial maximum., (© 2018 The Authors. American Journal of Botany is published by Wiley Periodicals, Inc. on behalf of the Botanical Society of America.)

Angiogenesis marks the transformation of a benign local tumor into a life-threatening disease. Many in vitro assays are available on two-dimensional (2D) platforms, however, limited research has been conducted to investigate the behavior of tumors and endothelial cells (ECs) grown on three-dimensional (3D) platforms. This study provides a 3D co-culture spheroid of tumor cells with ECs to study the interplay between ECs and tumor cells. In a 3D co-culture with HepG2 hepatocellular carcinoma (HCC) cells, ECs differentiate to form tubule networks when in co-culture. Addition of angiogenic factors or angiogenesis inhibitors to the model system enhanced or inhibited endothelial differentiation in the 3D model, enabling investigations of the cellular signaling pathways utilized in HCC development. The 3D model demonstrated similar protein expression levels as a HCC xenograft, as well as exhibited upregulation of essential signaling proteins such as Akt/mTor in the 3D model, which is not reflected in the 2D model. The effects of several anti-angiogenic agents, such as sorafenib, sunitinib, and axitinib were analyzed in the 3D co-culture model by utilizing fluorescent proteins and a fluorescence resonance energy transfer (FRET)-based caspase-3 sensor in the ECs, which can detect apoptosis in real time. The apoptotic capability of a drug to inhibit angiogenesis in the 3D model can be easily distinguished via the FRET sensor, and dual screening of anti-angiogenesis and anti-tumor drugs can be achieved in a single step via the 3D co-culture model. In summary, a 3D co-culture model is constructed, where a HCC tumor microenvironment with a hypoxic core and true gradient penetration of drugs is achieved for drug screening purposes and in vitro studies utilizing a small HCC tumor. Biotechnol. Bioeng. 2017;114: 1865-1877. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Xylose fermentation by engineered Saccharomyces cerevisiae expressing NADPH-linked xylose reductase (XR) and NAD + -linked xylitol dehydrogenase (XDH) suffers from redox imbalance due to cofactor difference between XR and XDH, especially under anaerobic conditions. We have demonstrated that coupling of an NADH-dependent acetate reduction pathway with surplus NADH producing xylose metabolism enabled not only efficient xylose fermentation, but also in situ detoxification of acetate in cellulosic hydrolysate through simultaneous co-utilization of xylose and acetate. In this study, we report the highest ethanol yield from xylose (0.463 g ethanol/g xylose) by engineered yeast with XR and XDH through optimization of the acetate reduction pathway. Specifically, we constructed engineered yeast strains exhibiting various levels of the acetylating acetaldehyde dehydrogenase (AADH) and acetyl-CoA synthetase (ACS) activities. Engineered strains exhibiting higher activities of AADH and ACS consumed more acetate and produced more ethanol from a mixture of 20 g/L of glucose, 80 g/L of xylose, and 8 g/L of acetate. In addition, we performed environmental and genetic perturbations to further improve the acetate consumption. Glucose-pulse feeding to continuously provide ATPs under anaerobic conditions did not affect acetate consumption. Promoter truncation of GPD1 and gene deletion of GPD2 coding for glycerol-3-phosphate dehydrogenase to produce surplus NADH also did not lead to improved acetate consumption. When a cellulosic hydrolysate was used, the optimized yeast strain (SR8A6S3) produced 18.4% more ethanol and 41.3% less glycerol and xylitol with consumption of 4.1 g/L of acetate than a control strain without the acetate reduction pathway. These results suggest that the major limiting factor for enhanced acetate reduction during the xylose fermentation might be the low activities of AADH and ACS, and that the redox imbalance problem of XR/XDH pathway can be exploited for in situ detoxification of acetic acid in cellulosic hydrolysate and increasing ethanol productivity and yield. Biotechnol. Bioeng. 2016;113: 2587-2596. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Yarrowia lipolytica is a promising production host for a wide range of molecules, but limited sugar consumption abilities prevent utilization of an abundant source of renewable feedstocks. In this study we created a Y. lipolytica strain capable of utilizing cellobiose as a sole carbon source by using endogenous promoters to express the cellodextrin transporter cdt-1 and intracellular β-glucosidase gh1-1 from Neurospora crassa. The engineered strain was also capable of simultaneous co-consumption of glucose and cellobiose. Although cellobiose was consumed slower than glucose when engineered strains were cultured with excess nitrogen, culturing with limited nitrogen led to cellobiose consumption rates comparable to those of glucose. Under limited nitrogen conditions, the engineered strain produced citric acid as a major product and we observed greater citric acid yields from cellobiose (0.37 g/g) than glucose (0.28 g/g). Culturing with a sole carbon source of either glucose or cellobiose induced additional differences on cell physiology and metabolism and a link is suggested to evasion of glucose-sensing mechanisms through intracellular creation and consumption of glucose. We ultimately applied this cellobiose-utilization system to produce citric acid from bioconversion of crystalline cellulose through simultaneous saccharification and fermentation (SSF)., (© 2014 Wiley Periodicals, Inc.)

Objective: To our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA., Methods: We conducted a comprehensive analysis of cytokine and chemokine activation and genes representative of the inflammatory processes in PsA. Paired PsA synovial tissue and skin samples were obtained from 12 patients on the same day. Gene expression studies were performed using Affymetrix HGU133 Plus 2.0 arrays. Confirmatory quantitative real-time polymerase chain reaction (PCR) was performed on selected transcripts. Cell populations were assessed by immunohistochemistry and immunofluorescence., Results: Globally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger interleukin-17 (IL-17) gene signature in skin than in synovium and more equivalent tumor necrosis factor (TNF) and interferon-γ gene signatures in both tissues. These results were confirmed with real-time PCR., Conclusion: This is the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in PsA. Our results support clinical trial data showing that PsA skin and joint disease are similarly responsive to TNF antagonists, while IL-17 antagonists have better results in PsA skin than in PsA joints. Genes selectively expressed in PsA synovium might direct future therapies for PsA., (© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Pseudolaric acid B (PB) is a major bioactive component extracted from Pseudolarix kaempferi. Traditional medicine practitioners in China have been using the roots of this plant to treat inflammatory and microbial dermatoses for centuries. In this study, the experiments were conducted to investigate immunosuppressive activity of PB on T lymphocytes in vitro. The results show that PB has hypotoxicity on hepatocytes and renal cells assessed by Methyl thiazolyl tetrazoliym (MTT) Assay and selectively inhibits the proliferation of T lymphocytes and antigen-specific T lymphocytes stimulated by concanavalin A and dinitrophenyl-modified spleen cells, respectively. Then, PB also shows suppressive effect on T lymphocytes in mixed lymphocyte reaction. Moreover, PB can depress the production of interleukin-2 (IL-2) secreted by concanavalin A-activated T lymphocytes or dinitrophenyl-modified spleen cells-activated antigen-specific T lymphocytes. It is first found that PB exhibits the inhibitory action on antigen-specific T lymphocytes and on the production of IL-2 from antigen-specific T lymphocytes and selectively inhibits the proliferation of T lymphocytes and the production of IL-2 as well. PB is in need of further study because of its potent immunosuppressive function., (Copyright © 2012 John Wiley & Sons, Ltd.)

Glucocorticoids (GCs) potentially regulate the proliferation, differentiation, and premature senescence of bone marrow mesenchymal stem/stromal cells (MSCs). In the present study we investigated the effects mediated by endogenous GCs and the effects of an antagonist of the glucocorticoid receptor, RU486, on the proliferative and differentiation capabilities of MSCs using an ovariectomized (OVX) animal model. Following ovariectomy and a decrease in systemic estradiol levels, the serum concentration of corticosterone is significantly increased in OVX rats. Compared to sham-operated controls, the total superoxide dismutase (SOD) activity in serum of OVX rats and the proliferation of their MSCs are significantly reduced. Furthermore, the osteogenic differentiation capabilities of OVX rat MSCs are significantly decreased, while adipogenic capabilities tend to increase. Subcutaneous administration of RU486 effectively increases the population and proliferative capacity of the MSCs in OVX rats. RU486 treatment also improves osteogenic capabilities and down-regulates adipogenic capabilities of MSCs. These results strongly indicate that the elevated levels of endogenous GCs induced by estrogen depletion might accelerate the premature senescence of MSCs and reduce their proliferative and osteogenic differentiation capabilities, while the blockage of the effects of endogenous GCs may restore their capabilities. These responses could potentially be developed to protect the capabilities of MSCs from oxidative stress-induced premature senescence and extend their lifespan in patients with advancing age and estrogen depletion., (Copyright © 2012 Orthopaedic Research Society.)

The present study demonstrates that Icariside II (10, 20, and 40 µM) reduced Leydig cell testosterone production and cell viability in a concentration- and time-dependent manner. Hoechst 33342/propidium iodide staining indicated that no morphological changes in Leydig cell nuclear chromatin occurred, caspase-3 expression also showed no significant change, but cell death was caused by the 10-µM Icariside II treatment. Furthermore, a significant reduction in NAD(+) levels was observed following Icariside II exposure (10, 20, and 40 µM). Cell death was avoided when Icariside II treated cells were incubated with extracellular NAD(+) (5 and 10 mM). Moreover, the addition of NAD(+) (5 and 10 mM) could restore ATP production and prevent cell death. The results suggest that Icariside II can reduce testosterone production by inducing necrosis, but not apoptosis, in rat Leydig cells. This mechanism may also account for the Icariside II induced depletion of NAD(+) and ATP levels., (© 2013 Wiley Periodicals, Inc.)

Introduction: Xuebijing injection (XBJ) is a traditional Chinese herbal prescription widely used in the treatment of sepsis. This is the first report concerning the identification of XBJ constituents. In addition, to evaluate XBJ's quality, partial least square discrimination analysis (PLS-DA) was performed on chemical fingerprint data., Objective: Establish an LC-MS method to identify the components in XBJ for the purpose of quality control., Methodology: Compounds were separated by HPLC using a C(18) column and gradient elution of acetonitrile-methanol (60:40, v/v) and water-acetic acid (100 : 0.5, v/v) in 80 min. HPLC equipped with diode array detector (DAD) coupled with time-of-flight (TOF) tandem mass spectrometry and HPLC electrospray ionisation (ESI) multi-stage tandem ion-trap mass spectrometry (IT-MS(n) ) method was developed to analyse XBJ's major components. Both positive and negative ionisation modes were employed., Results: Twenty-one compounds including amino acids, phenolic acids, flavonoid glycoside, terpene glycoside and phthalide were identified or tentatively characterised. Their retention times, UV and MS spectra were compared with those of authentic compounds or literature data. The score plot of PLS-DA clearly revealed variations among samples produced in different commercial batches., Conclusions: The analytical method developed is highly effective for the discrimination and quality control of XBJ., (Copyright © 2011 John Wiley & Sons, Ltd.)

Many genes are known to function in a region-specific manner in the developing secondary palate. We have previously shown that Shox2-deficient embryos die at mid-gestation stage and develop an anterior clefting phenotype. Here, we show that mice carrying a conditional inactivation of Shox2 in the palatal mesenchyme survive the embryonic and neonatal lethality, but develop a wasting syndrome. Phenotypic analyses indicate a delayed closure of the secondary palate at the anterior end, leading to a failed fusion of the primary and secondary palates. Consistent with a role proposed for Shox2 in skeletogenesis, Shox2 inactivation causes a significantly reduced bone formation in the hard palate, probably due to a down-regulation of Runx2 and Osterix. We conclude that the secondary palatal shelves are capable of fusion with each other, but fail to fuse with the primary palate in a developmentally delayed manner. Mice carrying an anterior cleft can survive neonatal lethality.

Fermentation industries would benefit from on-line monitoring of important parameters describing cell growth such as cell density and viability during fermentation processes. For this purpose, an in situ probe has been developed, which utilizes a dark field illumination unit to obtain high contrast images with an integrated CCD camera. To test the probe, brewer's yeast Saccharomyces cerevisiae is chosen as the target microorganism. Images of the yeast cells in the bioreactors are captured, processed, and analyzed automatically by means of mechatronics, image processing, and machine learning. Two support vector machine based classifiers are used for separating cells from background, and for distinguishing live from dead cells afterwards. The evaluation of the in situ experiments showed strong correlation between results obtained by the probe and those by widely accepted standard methods. Thus, the in situ probe has been proved to be a feasible device for on-line monitoring of both cell density and viability with high accuracy and stability., ((c) 2007 Wiley Periodicals, Inc.)