Publications by authors named "Yang Zhou"

2,612 Publications

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Chitinase 3-like-1 contributes to the development of pulmonary vascular remodeling in pulmonary hypertension.

JCI Insight 2022 Aug 11. Epub 2022 Aug 11.

Department of Molecular Microbiology and Immunology, Brown University, Providence, United States of America.

Chitinase 3-like 1 (CHI3L1) is the prototypic chitinase-like protein mediating inflammation, cell proliferation, and tissue remodeling. Limited data suggests CHI3L1 is elevated in human pulmonary arterial hypertension (PAH) and is associated with disease severity. Despite its importance as a regulator of injury/repair responses, the relationship between CHI3L1 and pulmonary vascular remodeling is not well understood. We hypothesize that CHI3L1 and its signaling pathways contribute to the vascular remodeling responses that occur in pulmonary hypertension (PH). We examined the relationship of plasma CHI3L1 levels and severity of PH in patients with various forms of PH, including Group 1 PAH and Group 3 PH, and found that circulating levels of serum CHI3L1 were associated with worse hemodynamics and correlated directly with mean pulmonary artery pressure and pulmonary vascular resistance. We also used transgenic mice with constitutive knockout and inducible overexpression of CHI3L1 to examine its role in hypoxia-, monocrotaline-, and bleomycin-induced models of pulmonary vascular disease. In all 3 mouse models of pulmonary vascular disease, pulmonary hypertensive responses were mitigated in CHI3L1 null mice and accentuated in transgenic mice that overexpress CHI3L1. Finally, CHI3L1 alone was sufficient to induce pulmonary arterial smooth muscle cell proliferation, inhibit pulmonary vascular endothelial cell apoptosis, induce the loss of endothelial barrier function, and induce endothelial-to-mesenchymal transition. These findings demonstrate that CHI3L1 and its receptors play an integral role in pulmonary vascular disease pathobiology and may offer a novel target for the treatment PAH and PH associated with fibrotic lung disease.
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http://dx.doi.org/10.1172/jci.insight.159578DOI Listing
August 2022

First report of leaf spot caused by on in China.

Plant Dis 2022 Aug 10. Epub 2022 Aug 10.

Jiangxi Agricultural University, forest of college, No. 1101, Zhiminda Road, Nanchang, Jiangxi, China, 330045;

Nageia nagi (Thunb.) Kuntze is widely cultivated in China for its ornamental and economic value. In August 2019, a leaf spot was observed on N. nagi plants at the campus of Jiangxi Agricultural University (28°45'56″N, 115°50'21″E). Disease incidence was about 35%, and the diseased leaf rate was above 40%. The early symptoms were small spots on the edge or tip of the leaves. The spots gradually expanded and became reddish-brown, eventually developing large irregular lesions. Leaf pieces (5 × 5 mm) from the lesion borders were surfaced sterilized in 70% ethanol for 30 s, followed by 2% NaOCl for 1 min, and then rinsed three times with sterile water. Tissues were placed on potato dextrose agar (PDA) and incubated at 25°C (Zhang et al. 2021). Pure cultures were obtained by transferring hyphal tips to new PDA plates. Twenty-six isolates of Colletotrichum ssp. were obtained (isolation frequency about 82%). Three representative single-spore isolates (ZB-1, ZB-3, and ZB-7) were used for morphological studies and phylogenetic analyses. Colonies on PDA medium of the three isolates were white to gray in color with cottony mycelia. Conidia were single-celled, straight, hyaline, cylindrical, clavate, and measured 14.1-17.9 ×4.4-6.8 µm (15.6 ± 1.2 × 5.4 ± 0.3 µm, n = 100). Appressoria were brown to dark brown, ovoid to clavate, slightly irregular to irregular, and ranged from 5.7-9.3 × 4.6-6.9 µm (7.8 ± 0.2 × 5.6 ± 0.3 µm, n=100). Morphological features were similar to Colletotrichum siamense complex (Weir et al. 2012). The internal transcribed spacer (ITS) regions, actin (ACT), calmodulin (CAL), β-tubulin 2 (TUB2), chitin synthase (CHS-1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were amplified from genomic DNA for the three isolates using primers ITS1/ITS4, ACT-512F/ACT-783R, CL1/CL2, T1/Bt2b, CHS-79F/CHS-354R and GDF/GDR (Weir et al. 2012), respectively. Sequences of them deposited in GenBank under nos. OL826760 - OL826762 (ITS), OL830205 - OL830207 (ACT), OL830196 - OL830198 (GAPDH), OL830193 - OL830195 (TUB2), OL830199 - OL830201 (CHS-1), and OL830202 - OL830204 (CAL). A Blast search of GenBank showed that ITS, ACT, GAPDH, TUB2, CHS-1, and CAL sequences of the three isolates were identical to Colletotrichum siamense at a high level (Table 1). A maximum likelihood and Bayesian posterior probability analyses using IQtree v. 1.6.8 and Mr. Bayes v. 3.2.6 with the concatenated sequences placed ZB-1, ZB-3, and ZB-7 in the clade of C. siamense. Based on the multi-locus phylogeny and morphology, three isolates were identified as C. siamense. The pathogenicity of three isolates was tested on six N. nagi plants (three for inoculation, three for controls), which were grown in the field. Six healthy leaves were wounded with a sterile needle and inoculated with 10 µL of conidial suspension (1 × 106 conidia/mL) per plant. Healthy leaves were inoculated with ddH2O as a control by the same method. All the inoculated leaves were covered with plastic bags to keep a high-humidity environment for 2 days. The experiment was repeated three times. All the inoculated leaves showed similar symptoms to those observed in the field, whereas control leaves were asymptomatic for 8 days. C. siamense was reisolated from the lesions, whereas no fungus was isolated from control leaves. Up to now, Cephleuros virescens, Pestalotiopsis longisetula, Alternaria tenuissima, A. alternate, and Phoma glomerata could infect N. nagi (Zhou et al. 2015; Zhang et al. 2016), and cause leaf spots in China. To our knowledge, this is the first report of C. siamense causing leaf spots on N. nagi worldwide. This work provided crucial information for epidemiologic studies and appropriate control strategies for this newly emerging disease.
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http://dx.doi.org/10.1094/PDIS-06-22-1417-PDNDOI Listing
August 2022

Which combination of different ultrasonography modalities is more appropriate to diagnose breast cancer?: A network meta-analysis (a PRISMA-compliant article).

Medicine (Baltimore) 2022 Aug;101(31):e29955

Ultrasound department of the First Affiliated Hospital of Dalian Medical University.

Background: Abundant amount of literature that analyze the various detection of different ultrasound methods, no comprehensive literature that investigates the diagnostic values of breast cancer (BC) by different ultrasonography modalities through a network meta-analysis (NMA) has been made available. Each imaging diagnostic examination has its own advantages and disadvantages, and any imaging examination is not enough to make an accurate diagnosis of the disease. Thus, this study aimed to compare diagnostic values among different ultrasonography modalities, including the information of 2-dimension, stiffness and blood flow, by a network meta-analysis in the hopes of understanding which imaging methods are better and which combination of different ultrasonography modalities is more appropriate to diagnose BC.

Methods: We made use of Cochrane Library, PubMed, and Embase in order to obtain literature and papers. The combination analysis of both direct and indirect evidence in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value(NPV) and accuracy was conducted so as to assess the odds ratios (ORs) and surface under the cumulative ranking curve (SUCRA) values of the 8 different ultrasound methods.

Results: A total of 36 eligible diagnostic tests regarding 8 ultrasound methods were included in the study. According to this network meta-analysis, Breast Imaging Reporting and Data System (BI-RADS) 4b exhibited higher specificity, PPV, and accuracy and lower sensitivity and NPV than BI-RADS 4a. Contrast-enhanced ultrasound (CEUS) had the highest sensitivity, PPV, NPV and accuracy and superb microvascular imaging (SMI) had the highest specificity among color Doppler flow imaging (CDFI), power Doppler imaging(PDI), SMI and CEUS. There was no significant difference in diagnostic indexes between SMI and CEUS. Shear wave elastrography (SWE) had higher PPV and accuracy and lower sensitivity, specificity NPV than strain elastography (SE).

Conclusion: The results of this network meta-analysis suggested more appropriate combination of different ultrasound modalities is BI-RADS 4b, SMI, and SWE for the diagnosis of breast cancer.
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http://dx.doi.org/10.1097/MD.0000000000029955DOI Listing
August 2022

Adverse role of colonial morphology and favorable function of microcystins for Microcystis to compete with Scenedesmus.

Harmful Algae 2022 Aug 30;117:102293. Epub 2022 Jul 30.

Jiangsu Key Laboratory for Biodiversity and Biotechnology, School of Biological Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing, 210023, China. Electronic address:

In eutrophic freshwaters, Microcystis usually becomes dominant in phytoplankton communities due to the synergistic effects of its special eco-physiological traits and environmental factors. Colonial morphology can protect Microcystis from zooplankton grazing, which indirectly favors Microcystis to outcompete other phytoplankton, although the colonial form is not conducive to the absorption of nutrients. Moreover, unicellular Microcystis usually has competitive advantages over other phytoplankton due to its efficient absorption capacity for nutrients and releasing microcystins. However, the consequence of direct competition between toxic colonial Microcystis and green algae without external grazing pressure still remained unknown. In this study, the competition between toxic colonial Microcystis aeruginosa and a common green alga Scenedesmus obliquus was explored. Results showed that: (1) colonial M. aeruginosa had a higher requirement for key macro-nutrient phosphorus than S. obliquus, and thus its population declined and was replaced by S. obliquus eventually; (2) microcystins released by colonial M. aeruginosa inhibited the photosynthetic activity and growth of S. obliquus at early stage of the competition; (3) the photosynthetic potential of colonial M. aeruginosa was stimulated in response to the competitive stress from S. obliquus, although the population of colonial M. aeruginosa declined eventually; (4) microcystin production of colonial M. aeruginosa was enhanced by phosphorus limitation due to S. obliquus competition and was positively related to photosynthetic potential of colonial M. aeruginosa. These results indicated that, in the absence of complex natural environment, colonial Microcystis cannot outcompete Scenedesmus in a pure competition, although microcystins can play a favorable role in the competition, which clarified the opposite role of colonies and microcystins in the competition of colonial Microcystis against other phytoplankton.
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http://dx.doi.org/10.1016/j.hal.2022.102293DOI Listing
August 2022

Human adipose-derived mesenchymal stem cells-derived exosomes encapsulated in pluronic F127 hydrogel promote wound healing and regeneration.

Stem Cell Res Ther 2022 Aug 8;13(1):407. Epub 2022 Aug 8.

Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

Background: Large area skin trauma has always been a great challenge for both patients and clinicians. Exosomes originating from human adipose-derived mesenchymal stem cells (hADSCs) have been a novel promising cell-free treatment in cutaneous damage repair. Nevertheless, the low retention rate of exosomes post-transplantation in vivo remains a significant challenge in clinical applications. Herein, we purposed to explore the potential clinical application roles of hADSCs-Exos encapsulated in functional PF-127 hydrogel in wound healing.

Methods: hADSCs-Exos were isolated from human hADSCs by ultracentrifugation. An injectable, biocompatible, and thermo-sensitive hydrogel Pluronic F-127 hydrogel was employed to encapsulate allogeneic hADSCs-Exos, and this complex was topically applied to a full-thickness cutaneous wound in mice. On different days post-transplantation, the mice were sacrificed, and the skin tissue was excised for histological and immunohistochemical analysis.

Results: Compared with hADSCs-Exos or PF-127 only, PF-127/hADSCs-Exos complexes enhanced skin wound healing, promoted re-epithelialization, increased expression of Ki67, α-SMA, and CD31, facilitated collagen synthesis (Collagen I, Collagen III), up-regulated expression of skin barrier proteins (KRT1, AQP3), and reduced inflammation (IL-6, TNF-α, CD68, CD206). By using PF-127/hADSCs-Exos complexes, hADSCs-Exos can be administrated at lower doses frequency while maintaining the same therapeutic effects.

Conclusion: Administration of hADSCs-Exos in PF-127 improves the efficiency of exosome delivery, maintains the bioactivity of hADSCs-Exos, and optimizes the performance of hADSCs-Exos. Thus, this biomaterial-based exosome will be a promising treatment approach for the cutaneous rejuvenation of skin wounds.
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http://dx.doi.org/10.1186/s13287-022-02980-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9358082PMC
August 2022

ZnO nanoparticles interfere with top-down effect of the protozoan paramecium on removing microcystis.

Environ Pollut 2022 Aug 5:119900. Epub 2022 Aug 5.

Jiangsu Key Laboratory for Biodiversity and Biotechnology, School of Biological Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing, 210023, China. Electronic address:

Under intensive human activity, sewage discharge causes eutrophication-driven cyanobacteria blooms as well as nanomaterial pollution. In biological control of harmful cyanobacteria, top-down effect of protozoan has great potentials for removing cyanobacterial populations, degrading cyanotoxins, and improving phytoplankton community. ZnO nanoparticles as a kind of emerging contaminants have attracted increasing attention because of wide application and their high bio-toxicity effects on reducing the ingestion of aquatic animals including Paramecium, thereby possibly disturbing top-down control of cyanobacteria. Therefore, this study investigated the effects of ZnO nanoparticles at environmental-relevant concentrations on the protozoan Paramecium removing toxic Microcystis. Results showed Paramecium effectively eliminated all the Microcystis, despite exposure to ZnO nanoparticles. However, their ingestion rate was significantly reduced at more than 0.1 mg L ZnO nanoparticles, thereby delaying Microcystis removal. Nevertheless, at 0.1 mg L ZnO nanoparticles, the time to Microcystis extinction decreased compared to the group without ZnO nanoparticles, because Microcystis populations were reduced under this circumstance, while ingestion rate of Paramecium was unaffected. Furthermore, ZnO nanoparticles obviously accumulated in food vacuoles of Paramecium, and the size of nanoparticles aggregates and zinc concentrations in Paramecium were increased with ZnO nanoparticles concentrations. At the end of experiment, these food vacuoles were not dissipated. Overall, these findings suggest that ZnO nanoparticles impair protozoan top-down effects through reducing Microcystis and ingestion rate as well as disturbing functions of their digestive organelles, and highlight the need to consider the interfering effects of environmental pollutants on cyanobacterial removal efficiency by protozoans in natural waters.
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http://dx.doi.org/10.1016/j.envpol.2022.119900DOI Listing
August 2022

Manganese and cobalt bimetallic-doped Prussian blue analogs as a bifunctional electrocatalyst for zinc-air batteries.

J Colloid Interface Sci 2022 Jul 28;628(Pt A):588-596. Epub 2022 Jul 28.

School of Chemical Engineering and Materials, Changzhou Institute of Technology, Changzhou 213032, China. Electronic address:

Zinc-air battery is a novel safe and environment-friendly energy storage device, but the noble-metal electrocatalysts at the air electrode urge people to search for new substitutes. Herein, different ratios of manganese (Mn) and cobalt (Co) are doped into the iron Prussian blue analogs (PBAs) and used as bifunctional electrocatalysts. The MnCo-PBA shows the outstanding electrocatalytic properties that the half-wave potential is 0.79 V, the E of OER is 1.54 V, and the ΔE is as low as 0.75 V, which is superior to that of Pt/C + RuO system (0.78 V). Benefiting from the bimetallic-doping advantage, the MnCo-PBA has good stability in alkaline solutions. Besides, the MnCo-PBA was assembled into ZAB, possessing a high maximum power density of 161 mW cm and a large specific capacity of 617 mAh g, as well as excellent cycle stability. The as-prepared bimetallic-doped PBA has the potential for applications in the energy storage and conversion field.
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http://dx.doi.org/10.1016/j.jcis.2022.07.148DOI Listing
July 2022

Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13.

J Med Chem 2022 Aug 8. Epub 2022 Aug 8.

International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, People's Republic of China.

Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound effectively degraded CDK12 and CDK13 with DC values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of . , suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC value of 47 nM. Importantly, displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor , suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy.
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http://dx.doi.org/10.1021/acs.jmedchem.2c00384DOI Listing
August 2022

A Self-Powered Optogenetic System for Implantable Blood Glucose Control.

Research (Wash D C) 2022 16;2022:9864734. Epub 2022 Jun 16.

Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.

Diabetes treatment and rehabilitation are usually a lifetime process. Optogenetic engineered designer cell-therapy holds great promise in regulating blood glucose homeostasis. However, portable, sustainable, and long-term energy supplementation has previously presented a challenge for the use of optogenetic stimulation . Herein, we purpose a self-powered optogenetic system (SOS) for implantable blood glucose control. The SOS consists of a biocompatible far-red light (FRL) source, FRL-triggered transgene-expressing cells, a power management unit, and a flexible implantable piezoelectric nanogenerator (i-PENG) to supply long-term energy by converting biomechanical energy into electricity. Our results show that this system can harvest energy from body movement and power the FRL source, which then significantly enhanced production of a short variant of human glucagon-like peptide 1 (shGLP-1) and . Indeed, diabetic mice equipped with the SOS showed rapid restoration of blood glucose homeostasis, improved glucose, and insulin tolerance. Our results suggest that the SOS is sufficiently effective in self-powering the modulation of therapeutic outputs to control glucose homeostasis and, furthermore, present a new strategy for providing energy in optogenetic-based cell therapy.
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http://dx.doi.org/10.34133/2022/9864734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9275083PMC
June 2022

Summer ozone pollution in China affected by the intensity of Asian monsoon systems.

Sci Total Environ 2022 Aug 2:157785. Epub 2022 Aug 2.

Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Jiangsu Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Nanjing University of Information Science and Technology, Nanjing, Jiangsu, China.

Ozone in the troposphere is harmful to human health and ecosystems. It has become the most severe air pollutant in China. Here, based on global atmospheric chemistry model simulations during 1981-2019 and nation-wide surface observations, the impacts of interannual variations in Asian summer monsoon (ASM), including East Asian summer monsoon (EASM) and South Asian summer monsoon (SASM), on surface O concentrations during June-July-August (JJA) in China are investigated. EASM intensity has a significant positive correlation with the surface O concentration in south-central China (97.5°-117.5°E, 20°-35°N) with a correlation coefficient of 0.6. Relative to the weak EASM years, O concentrations in strong EASM years increased by up to 5 ppb (10 % relative to the average) due to the weakened transboundary transport of O resulting from the decrease in prevailing southwesterlies. SASM can be divided into two components. The one near East Asia has a similar relation with O in southern China (100°-117.5°E, 22°-32°N) as that of EASM. The other component of SASM is negatively correlated with surface O concentration in eastern China (110°-117.5°E, 22°-34°N) and the maximum difference in O concentrations exceeded 5 ppb (10 %) between the strong and weak monsoon years, which can be explained by the O divergence caused by the anomalous southerlies blowing pollutants away from the northern boundary of eastern China. This study shows that the ASM has an important impact on the O concentrations in China, primarily through changing transboundary transport related to the variability of large-scale circulations, which has great implications for air pollution prevention and mitigation in China. Future projections of ASM suggests that the sustainable and medium development scenarios are the perfect pathways that can help to mitigate O pollution, while high social vulnerability and radiative forcing scenarios could enhance future O pollution in China.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157785DOI Listing
August 2022

Hepatocellular carcinoma: Novel understandings and therapeutic strategies based on bile acids (Review).

Int J Oncol 2022 Oct 5;61(4). Epub 2022 Aug 5.

Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110122, P.R. China.

Bile acids (BAs) are the major components of bile and products of cholesterol metabolism. Cholesterol is catalyzed by a variety of enzymes in the liver to form primary BAs, which are excreted into the intestine with bile, and secondary BAs are formed under the modification of the gut microbiota. Most of the BAs return to the liver via the portal vein, completing the process of enterohepatic circulation. BAs have an important role in the development of hepatocellular carcinoma (HCC), which may participate in the progression of HCC by recognizing receptors such as farnesoid X receptor (FXR) and mediating multiple downstream pathways. Certain BAs, such as ursodeoxycholic acid and obeticholic acid, were indicated to be able to delay liver injury and HCC progression. In the present review, the structure and function of BAs were introduced and the metabolism of BAs and the process of enterohepatic circulation were outlined. Furthermore, the mechanisms by which BAs participate in the development of HCC were summarized and possible strategies for targeting BAs and key sites of their metabolic processes to treat HCC were suggested.
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http://dx.doi.org/10.3892/ijo.2022.5407DOI Listing
October 2022

Complete Genome Sequence of the Cluster P Mycobacteriophage Phegasus.

Microbiol Resour Announc 2022 Aug 4:e0054022. Epub 2022 Aug 4.

School of Life Sciences, Arizona State University, Tempe, Arizona, USA.

We characterized the complete genome of the cluster P mycobacteriophage Phegasus. Its 47.5-kb genome contains 81 protein-coding genes, 36 of which could be assigned a putative function. Phegasus is most closely related to two subcluster P1 bacteriophages, Mangethe and Majeke, with an average nucleotide identity of 99.63% each.
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http://dx.doi.org/10.1128/mra.00540-22DOI Listing
August 2022

Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Psoriasis: A Systematic Review and Meta-Analysis of Observational Studies.

Front Oncol 2022 15;12:934093. Epub 2022 Jul 15.

Oncology Department of Integrative Medicine, China-Japan Friendship Hospital, Beijing, China.

Background: Immunotherapies represented by immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. A large part of the population has both cancer and psoriasis but is usually excluded from ICI clinical trials because of the dysregulated activation of the immune system. This is the first study to evaluate the safety and efficacy of ICI therapy in patients with cancer and preexisting psoriasis.

Methods: PubMed, EMBASE, Cochrane, and MEDLINE databases were searched from inception through February 2022. Observational studies on patients with cancer and confirmed psoriasis before ICI initiation were included. Outcomes included the incidence of psoriasis flares, immune-related adverse events (irAEs), discontinuation rate due to flare/ irAEs, and efficacy of ICI therapy. Clinical manifestations, management, and outcomes for adverse events (AEs) were systematically reviewed. All pooled analyses were based on a random-effects model using Stata software. Meta-regression and subgroup analyses were performed to identify sources of heterogeneity.

Results: Twelve studies involving 191 patients were included. The pooled incidence of psoriasis flares was 45.0% (95% CI: 31.1%-58.9%, I = 71.7%) and 44.9% (95% CI: 29.0%-60.7%, I = 71.8%) for irAEs. The tumor type, psoriasis subtype, ICI class, and country were the main sources of heterogeneity. Grade 3-4 flares occurred in 10.8% (95% CI: 5.3%-16.3%) of patients, and about 16.6% (95% CI: 10.7%-22.5%) of patients experienced grade 3-4 irAEs. The estimated incidence of ICI discontinuation due to AE was 18.5% (95% CI: 6.1%-30.8%, I = 68.7%). The median times to develop flare and irAEs were 44 and 63 days, respectively. Endocrinopathies and colitis were the most common irAEs. Conventional therapy is effective for most AEs. The estimated objective response rate (ORR) of ICIs was 38.1% (95% CI: 11.8%-64.3%, I = 81.7%), and the disease control rate (DCR) was 64.5% (95% CI: 55.3%-73.8%, I = 0).

Conclusions: The flare of patients with cancer and preexisting psoriasis treated with ICI therapy is frequent, but the incidence of irAEs and the efficacy of ICI therapy are comparable to those of the general population. Most AEs are mild and manageable with conventional therapy, which required discontinuation of ICI therapy in 18.5%.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022320646.
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http://dx.doi.org/10.3389/fonc.2022.934093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334704PMC
July 2022

Design, Synthesis and Antibacterial Activities of Novel Amide Derivatives Bearing Dioxygenated Rings as Potential β-Ketoacyl-acyl Carrier Protein Synthase III (FabH) Inhibitors.

Chem Pharm Bull (Tokyo) 2022 ;70(8):544-549

School of Biological & Chemical Engineering, Zhejiang University of Science & Technology.

Fatty acid biosynthesis is essential for bacterial survival. Of these promising targets, β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target. FabH would trigger the initiation of fatty acid biosynthesis and it is highly conserved among Gram-positive and -negative bacteria. A series of novel amide derivatives bearing dioxygenated rings were synthesized and developed as potent inhibitors of FabH. These compounds were determined by H-NMR, C-NMR, MS and further confirmed by crystallographic diffraction study for compound 19. Furthermore, these compounds were evaluated strong broad-spectrum antibacterial activity. Some compounds with potent antibacterial activities were tested for their Escherichia coli (E. coli) FabH inhibitory activity. Especially, compound 19 showed the most potent antibacterial activity with minimum inhibitory concentration (MIC) values of 1.56-3.13 mg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC of 2.4 µM. Docking simulation was performed to position compound 19 into the E. coli FabH active site to determine the probable binding conformation.
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http://dx.doi.org/10.1248/cpb.c22-00090DOI Listing
August 2022

An Optically Anisotropic Crystal with Large Birefringence Arising from Cooperative π Orbitals.

Angew Chem Int Ed Engl 2022 Jul 29. Epub 2022 Jul 29.

Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, State Key Laboratory of Structrual Chemistry, 155 Yangqiao Road West, 350002, 350002, Fuzhou, CHINA.

Birefringent materials are highly demanded for high-performance polarized optics. As compared with artificial anisotropic metamaterials, anisotropic crystals have advantages of low optical losses and easy processing, but their birefringence is still limited. Herein, based on first-principles studies, we identified a new type of functional anion units, (HxC6N9)(3-x)- (x = 0, 1, 2), and then successfully synthesized a new anisotropic crystal, namely, CsH2C6N9·H2O (I), whose crystal structure consists of (H2C6N9)- anions. Remarkably, I is ultraviolet transparent and exhibits very large birefringence of about [email protected] nm, which is much larger than those of commercial birefringent crystals. These results make I a candidate for highly efficient manipulation of optics and light in optical modulation devices. Theoretical calculations reveal that large birefringence mainly arises from the cooperative π orbitals in (H2C6N9)- anions. This work provides a new insight on the underlying structure-property relationships of anisotropic crystals.
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http://dx.doi.org/10.1002/anie.202208811DOI Listing
July 2022

Obesity Increases In-Hospital Mortality of Acute Type A Aortic Dissection Patients Undergoing Open Surgical Repair: A Retrospective Study in the Chinese Population.

Front Cardiovasc Med 2022 12;9:899050. Epub 2022 Jul 12.

Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, China.

Objective: The prevalence of obesity is increasing worldwide, and the role of the obesity paradox in cardiovascular surgery remains controversial. In this study, we redefined obesity according to the Chinese criteria and examined the relationship between obesity and in-hospital mortality in patients with acute type A aortic dissection (AAD) undergoing open surgical repair.

Materials And Methods: A total of 289 patients with AAD (between 2014 and 2016) were divided into the non-obese group and obese group for correlation analysis, general information, demographic factors, blood biochemistry, surgical details, and complications, which were used as covariates. Survival was estimated by the Kaplan-Meier method, and any differences in survival were evaluated with a stratified log-rank test. Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression were used to evaluate the effect and interaction of obesity on surgical mortality.

Results: All the 289 patients had a mean age of 48.64 (IQR 44.00-55.00) and 74.39% were men. Of the 289 patients, 228 were non-obese (78.89%) and 61 were obese (21.11%). Patients with obesity were younger and more prone to unstable blood pressure [systolic blood pressure (SBP) and diastolic blood pressure (DBP)], preoperative hypoxemia and delirium, prolonged operative time, and surgical wound deep infection ( < 0.05). In the fully adjusted model, we observed an increased risk of in-hospital mortality in patients with obesity after fine-tuning other covariates including age and sex (HR = 2.65; 95% CI = 1.03 to 6.80; = 0.042). The interaction suggested that obesity was more likely to cause death in elderly patients (age ≥ 60), although it was more common in younger patients (test for interaction, = 0.012).

Conclusion: Obesity, interacting with age, increases the risk of in-hospital mortality in patients with AAD undergoing open surgical repair. Although more verification is needed, we believe these findings provide further evidence for the treatment of AAD.
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http://dx.doi.org/10.3389/fcvm.2022.899050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315262PMC
July 2022

Lipid-related FABP5 activation of tumor-associated monocytes fosters immune privilege via PD-L1 expression on Treg cells in hepatocellular carcinoma.

Cancer Gene Ther 2022 Jul 28. Epub 2022 Jul 28.

Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, Liaoning, 116027, China.

Monocytes/macrophages, a plastic and heterogeneous cell population of the tumor microenvironment (TME), can constitute a major component of most solid tumors. Under the pressure of rapid proliferation of the tumor, monocytes/macrophages can be educated and foster immune tolerance via metabolic reprogramming. Our studies have shown that the activation of FABP5, a lipid-binding protein, decreases the rate of β-oxidation causing the accumulation of lipid droplets in monocytes. We found that hepatocellular carcinoma cells (HCC) increased IL-10 secretion by monocytes, which depended on the expression of FABP5 and suppressing of the PPARα pathway. Moreover, the elevated level of IL-10 promotes PD-L1 expression on Treg cells via the JNK-STAT3 pathway activation. We also observed that elevation of FABP5 in monocytes was negatively related to HCC patients' overall survival time. Thus, FABP5 promotes monocyte/macrophage lipid accumulation, fosters immune tolerance formation, and might represent itself as a therapeutic target in both tumor-associated monocytes (TAMs) and cancer cells.
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http://dx.doi.org/10.1038/s41417-022-00510-0DOI Listing
July 2022

Stable and flexible photodetector based on liquid-phase exfoliated titanium disulfide nanosheets.

Nanotechnology 2022 Jul 27. Epub 2022 Jul 27.

School of Physics and Optoelectronics, Xiangtan University, School of Physics and Optoelectronics, Xiangtan University, Hunan 411105, PR China, Xiangtan, 411105, CHINA.

Herein, the TiS2 nanosheets (NSs) are prepared from the TiS2 bulk by the liquid-phase exfoliation to fabricate photoelectrochemical-type (PEC) photodetector. SEM images and Raman spectra show the successful acquisition of the TiS2 NSs. The as-prepared TiS2 photodetector shows self-powered ability with an applicable photoresponsivity that is about 0.37 μA W-1 under zero bias potential, which the response time of rise is 0.67s and the decay time is 2.81s. In this case, the photodetector is made of ITO-coated polyethylene terephthalate (PET), so it can maintain stable performance under the bending conditions. These results display that the as-prepared photodetector has excellent photoelectric properties, which facilitates the development of TiS2 NSs in optoelectronic devices.
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http://dx.doi.org/10.1088/1361-6528/ac8488DOI Listing
July 2022

Research Progress of Cholesteric Liquid Crystals with Broadband Reflection.

Molecules 2022 Jul 11;27(14). Epub 2022 Jul 11.

School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China.

Cholesteric liquid crystal (ChLC) materials with broadband reflection are witnessing a significant surge in interest due to their unique ability to self-organize into a helical supra-molecular architecture and their excellent selective reflection of light based on the Bragg relationship. Nowadays, by the virtue of building self-organized nanostructures with pitch gradient or non-uniform pitch distribution, extensive work has already been performed to obtain ChLC films with a broad reflection band. This critical review systematically summarizes the optical background of the ChLCs with broadband reflection characteristics, methods to obtain broadband reflection of ChLCs, as well as the application in this area. Combined with the research status and the advantages in the field, the challenges and opportunities of applied scientific problems in the research direction are also introduced.
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http://dx.doi.org/10.3390/molecules27144427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317135PMC
July 2022

Tumor-Localized Administration of α-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity against Solid Tumors.

Int J Mol Sci 2022 Jul 7;23(14). Epub 2022 Jul 7.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

Invariant natural killer T (iNKT) cells have the capacity to mount potent anti-tumor reactivity and have therefore become a focus in the development of cell-based immunotherapy. iNKT cells attack tumor cells using multiple mechanisms with a high efficacy; however, their clinical application has been limited because of their low numbers in cancer patients and difficulties in infiltrating solid tumors. In this study, we aimed to overcome these critical limitations by using α-GalCer, a synthetic glycolipid ligand specifically activating iNKT cells, to recruit iNKT to solid tumors. By adoptively transferring human iNKT cells into tumor-bearing humanized NSG mice and administering a single dose of tumor-localized α-GalCer, we demonstrated the rapid recruitment of human iNKT cells into solid tumors in as little as one day and a significantly enhanced tumor killing ability. Using firefly luciferase-labeled iNKT cells, we monitored the tissue biodistribution and pharmacokinetics/pharmacodynamics (PK/PD) of human iNKT cells in tumor-bearing NSG mice. Collectively, these preclinical studies demonstrate the promise of an αGC-driven iNKT cell-based immunotherapy to target solid tumors with higher efficacy and precision.
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http://dx.doi.org/10.3390/ijms23147547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317565PMC
July 2022

Energy Metabolic Disorder of Astrocytes May Be an Inducer of Migraine Attack.

Brain Sci 2022 Jun 28;12(7). Epub 2022 Jun 28.

Neurology Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 201306, China.

Migraine is a chronic headache disease, which ranks second in years lost due to disability. However, the mechanism of migraines is still not clear. In migraine patients, fasting can trigger headache attacks. We explored the probable mechanism of why fasting can induce headaches. Nitroglycerin (NTG) was used to induce acute migraine attacks in mice. Primary astrocytes were used to study the pathophysiological mechanism and a Seahorse analyzer was used to detect mitochondrial function. NTG induced more serious headaches in the fasting group. Both the head-scratching times and climbing-cage times in the fasting group were higher than those in normal-diet group. More ROS and inflammatory factors, such as IL-6 and IL-1β, were induced in low-glucose conditions. Seahorse showed that the basal oxygen consumption rate (OCR) and OCR for ATP production were lower in mice who had received NTG with low glucose levels than in other groups. The activity of AMPK was inhibited in this group, which may explain the Seahorse results. We concluded that in the low-glucose state, astrocytes produce more inflammatory factors, ROS, which may be a result of mitochondrial metabolism dysfunction. Improving mitochondrial function and supplying enough substrates may be an option for relieving migraine attacks.
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http://dx.doi.org/10.3390/brainsci12070844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312932PMC
June 2022

Mechanistic Studies on the Stereoselectivity of FFAR1 Modulators.

J Chem Inf Model 2022 Aug 25;62(15):3664-3675. Epub 2022 Jul 25.

Department of Theoretical Chemistry and Biology, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), KTH Royal Institute of Technology, Stockholm SE-106 91, Sweden.

Free fatty acid receptor 1 (FFAR1) is a potential therapeutic target for the treatment of type 2 diabetes (T2D). It has been validated that agonists targeting FFAR1 can achieve the initial therapeutic endpoints of T2D, and the epimer agonists (,) AM-8596 can activate FFAR1 differently, with one acting as a partial agonist and the other as a full agonist. Up to now, the origin of the stereoselectivity of FFAR1 agonists remains elusive. In this work, we used molecular simulation methods to elucidate the mechanism of the stereoselectivity of the FFAR1 agonists ()-AM-8596 and ()-AM-8596. We found that the full agonist ()-AM-8596 disrupts the residue interaction network around the receptor binding pocket and promotes the opening of the binding site for the G-protein, thereby resulting in the full activation of FFAR1. In contrast, the partial agonist ()-AM-8596 forms stable electrostatic interactions with FFAR1, which stabilizes the residue network and hinders the conformational transition of the receptor. Our work thus clarifies the selectivity and underlying molecular activation mechanism of FFAR1 agonists.
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http://dx.doi.org/10.1021/acs.jcim.2c00417DOI Listing
August 2022

Metabolomics-Driven Exploration of the Antibacterial Activity and Mechanism of 2-Methoxycinnamaldehyde.

Front Microbiol 2022 7;13:864246. Epub 2022 Jul 7.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.

Methicillin-resistant (MRSE) is one of the most commonly found pathogens that may cause uncontrollable infections in immunocompromised and hospitalized patients. Compounds isolated from cinnamon such as cinnamaldehyde and cinnamic acid showed promising anti-oxidant, anti-tumor, and immunoregulatory effects; more importantly, these compounds also possess promising broad-spectrum antibacterial activity. In this study, the potential antibacterial activity of 2-methoxycinnamaldehyde (MCA), another compound in cinnamon, against MRSE was investigated. Combining the broth microdilution test, live/dead assay, and biofilm formation assay, we found MCA was able to inhibit the proliferation, as well as the biofilm formation of MRSE, indicating MCA could not only affect the growth of MRSE but also inhibit the pathogenic potential of this bacterium. Additionally, the results of scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that MCA caused morphological changes and the leakage of DNA, RNA, and cellular contents of MRSE. Due to the close relationship between cell wall synthesis, ROS formation, and cell metabolism, the ROS level and metabolic profile of MRSE were explored. Our study showed MCA significantly increased the ROS production in MRSE, and the following metabolomics analysis showed that the increased ROS production may partially be due to the increased metabolic flux through the TCA cycle. In addition, we noticed the metabolic flux through the pentose phosphate pathway (PPP) was upregulated accompanied by elevated ROS production. Therefore, the alterations in cell metabolism and increased ROS production could lead to the damage of the cell wall, which in turn decreased the proliferation of MRSE. In conclusion, MCA seemed to be a promising alternative antimicrobial agent to control MRSE infections.
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http://dx.doi.org/10.3389/fmicb.2022.864246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301309PMC
July 2022

Omicron Booster in Ancestral Strain Vaccinated Mice Augments Protective Immunities Against Both Delta and Omicron Variants.

Front Immunol 2022 6;13:897879. Epub 2022 Jul 6.

Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

A booster vaccination is called for constraining the evolving epidemic of SARS-CoV-2. However, the necessity of a new COVID-19 vaccine is currently unclear. To compare the effect of an Omicron-matched S DNA vaccine and an ancestral S DNA vaccine in boosting cross-reactive immunities, we firstly immunized mice with two-dose of a DNA vaccine encoding the spike protein of the ancestral Wuhan strain. Then the mice were boosted with DNA vaccines encoding spike proteins of either the Wuhan strain or the Omicron variant. Specific antibody and T cell responses were measured at 4 weeks post boost. Our data showed that the Omicron-matched vaccine efficiently boosted RBD binding antibody and neutralizing antibody responses against both the Delta and the Omicron variants. Of note, antibody responses against the Omicron variant elicited by the Omicron-matched vaccine were much stronger than those induced by the ancestral S DNA vaccine. Meanwhile, CD8 T cell responses against both the ancestral Wuhan strain and the Omicron strain also tended to be higher in mice boosted by the Omicron-matched vaccine than those in mice boosted with the ancestral S DNA vaccine, albeit no significant difference was observed. Our findings suggest that an Omicron-matched vaccine is preferred for boosting cross-protective immunities.
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http://dx.doi.org/10.3389/fimmu.2022.897879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298979PMC
July 2022

Cervical Sagittal Alignment in Patients with Basilar Invagination.

Spine (Phila Pa 1976) 2022 Jul 15. Epub 2022 Jul 15.

Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Study Design: Retrospective study.

Objective: To present a morphological map of cervical sagittal alignment in basilar invagination (BI), a congenital anomaly of the craniovertebral junction (CVJ), and contribute to a comprehensive understanding of cervical sagittal alignment in congenital cervical deformities.

Summary Of Background Data: Ideal cervical sagittal alignment and surgical targets are debated by scholars. However, most of the literature focuses on the description of cervical sagittal alignment in acquired cervical diseases and normal subjects and few on congenital cervical spine deformities.

Methods: This study analyzed cervical spine lateral radiographs of 87 BI patients and 98 asymptomatic subjects. They were analyzed for cranial, cervical spine, and thoracic inlet parameters.

Results: Patients with BI manifested significantly larger values for the following parameters than asymptomatic subjects: cranial tilt, cranial incidence angle, SVA CGH-C7, C2-C7 angle, cervical tilt, and significantly smaller values for the following parameters: cranial slope, C0-C2 angle, C0-C7 angle, SVA C2-C7, spine tilt, TIA, and neck tilt. In the BI group, SVA C2-C7 was the cervical parameter most strongly correlated with the cranial, cervical spine, and thoracic inlet parameters, and was smaller in BI patients with fusion (atlanto-occipital assimilation) than in those without.

Conclusion: A significant difference was observed between BI patients and asymptomatic subjects. BI patients have craniums tilted forward and downward, smaller upper cervical lordosis, larger lower cervical lordosis, and smaller thoracic inlet angle. In BI patients, the SVA C2-C7 is an important parameter in cervical sagittal alignment. In both individuals with congenital anomalies of the CVJ and the asymptomatic population, cervical spine alignment is significantly associated with cranial alignment, particularly thoracic inlet alignment.
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http://dx.doi.org/10.1097/BRS.0000000000004423DOI Listing
July 2022

Clinical Metagenomic Next-Generation Sequencing for Diagnosis of Secondary Glaucoma in Patients With Cytomegalovirus-Induced Corneal Endotheliitis.

Front Microbiol 2022 5;13:940818. Epub 2022 Jul 5.

The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China.

Glaucoma is the second leading cause of blindness globally. Growing scientific evidence indicated that inflammation of the trabecular meshwork induced by corneal endotheliitis could lead to secondary glaucoma. Cytomegalovirus (CMV) has been identified as the most common herpes virus in corneal endotheliitis patients. Early detection is critical in preventing endothelial cell loss, and patient management should vary based on different pathological factors. However, routine culture and real-time polymerase chain reaction (qPCR) have difficult in distinguishing whether CMV, Varicella Zoster Virus (VZV) or Herpes Simplex Virus (HSV) causes endothiliitis. This may result in inappropriate treatment, which may prolong or aggravate the status of disease. We compared the sensitivity and specificity of qPCR and Metagenomic Next-Generation Sequencing (mNGS) in the aqueous humor of patients with suspected CMV endotheliitis in this study. Our results showed that four out of 11 (36.4%) of our patients were positive for CMV by qPCR, whereas mNGS had a 100% detection rate of CMV. Our findings implied that mNGS could be a useful diagnostic tool for CMV-induced endotheliitis.
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http://dx.doi.org/10.3389/fmicb.2022.940818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295740PMC
July 2022

Highly Fluorescent Collagen-Based Quantum Dots as an Efficient Interlinkage in the 2D Perovskite Bulk for Improved Solar Cells.

ACS Appl Mater Interfaces 2022 Aug 21;14(30):34706-34713. Epub 2022 Jul 21.

State Key Laboratory of Petroleum Resources and Prospecting, Beijing Key Laboratory of Biogas Upgrading Utilization, China University of Petroleum (Beijing), Beijing 102249, China.

A design-inexpensive, effective, and easy-to-prepare additive in the large-scale preparation of perovskite solar cells (PSCs) is urgently desired to alleviate the future energy crisis. Carbon-based quantum dots have demonstrated novel nanomaterials with excellent chemical stability and high electrical conductivity, which exhibit great potential as additives for perovskite optoelectronics. Herein, we designed novel highly fluorescent collagen-based quantum dots (Col-QDs) and thoroughly studied the micromorphological characteristics, photoluminescence properties, and the states of surface-functionalized groups on the Col-QDs. It is found that the introduction of Col-QDs in the two-dimensional (2D) perovskite precursor can be further confirmed as an efficient interlinkage via Col-Pb bands in the pure 2D perovskite heterojunction, which significantly improves the crystallinity, orientation, and interlayer coupling of perovskite crystal plates, as observed by grazing incidence X-ray diffraction (GIWAXS) and X-ray photoelectron spectroscopy (XPS). Finally, the champion Col-QD additive can efficiently modulate the photovoltaic performance of pure 2D PSCs with a significant increase of photoelectric conversion efficiency (PCE) from 8.18% up to 10.45%, which ranks among the best efficiencies of highly pure 2D PSCs. These results provide a facile and feasible approach to modulate the interlayer interaction of pure 2D perovskites and further improve their output of PSCs, which would further facilitate the burgeoning applications of the Col-QDs in various perovskite-based optical-related fields.
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http://dx.doi.org/10.1021/acsami.2c07097DOI Listing
August 2022

Discovery of Hexahydrofuro[3,2-]furans as New Kinase-Selective and Orally Bioavailable JAK3 Inhibitors for the Treatment of Leukemia Harboring a JAK3 Activating Mutant.

J Med Chem 2022 Aug 20;65(15):10674-10690. Epub 2022 Jul 20.

International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.

Janus kinase 3 (JAK3) is a potential target for the treatment of hematological malignancies. Herein, we report the discovery of a series of new orally bioavailable irreversible JAK3 kinase inhibitors. The representative compound potently inhibited JAK3 kinase activity with an IC value of 1.2 nM and was more than 900-fold selective over JAK1, JAK2, and Tyk2. Cell-based assays revealed that significantly suppressed phosphorylation of JAK3 and the downstream effectors STAT3/5 and also robustly restrained proliferation of BaF3 cells transfected with JAK3 activating mutation and human leukemia U937 cells harboring JAK3 with IC values of 22.9 and 20.2 nM, respectively. More importantly, showed reasonable pharmacokinetic (PK) properties, and oral administration of at a dose of 50 mg/kg twice daily led to tumor regression in a U937 cell inoculated xenograft mouse model. Thus, represents a promising lead compound for further optimization to discover new therapeutic agents for hematological malignancies.
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http://dx.doi.org/10.1021/acs.jmedchem.2c00922DOI Listing
August 2022

Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis an Artificial-Intelligence-Based Pipeline.

Front Bioeng Biotechnol 2022 4;10:914450. Epub 2022 Jul 4.

Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, United States.

Adult mammalian cardiomyocytes have very limited capacity to proliferate and repair the myocardial infarction. However, when apical resection (AR) was performed in pig hearts on postnatal day (P) 1 (AR) and acute myocardial infarction (MI) was induced on P28 (MI), the animals recovered with no evidence of myocardial scarring or decline in contractile performance. Furthermore, the repair process appeared to be driven by cardiomyocyte proliferation, but the regulatory molecules that govern the AR-induced enhancement of myocardial recovery remain unclear. Single-nucleus RNA sequencing (snRNA-seq) data collected from fetal pig hearts and the hearts of pigs that underwent AR, MI, both AR and MI, or neither myocardial injury were evaluated autoencoder, cluster analysis, sparse learning, and semisupervised learning. Ten clusters of cardiomyocytes (CM1-CM10) were identified across all experimental groups and time points. CM1 was only observed in AR hearts on P28 and was enriched for the expression of T-box transcription factors 5 and 20 (TBX5 and TBX20, respectively), Erb-B2 receptor tyrosine kinase 4 (ERBB4), and G Protein-Coupled Receptor Kinase 5 (GRK5), as well as genes associated with the proliferation and growth of cardiac muscle. CM1 cardiomyocytes also highly expressed genes for glycolysis while lowly expressed genes for adrenergic signaling, which suggested that CM1 were immature cardiomyocytes. Thus, we have identified a cluster of cardiomyocytes, CM1, in neonatal pig hearts that appeared to be generated in response to AR injury on P1 and may have been primed for activation of CM cell-cycle activation and proliferation by the upregulation of TBX5, TBX20, ERBB4, and GRK5.
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http://dx.doi.org/10.3389/fbioe.2022.914450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9289371PMC
July 2022

Early identification and severity prediction of acute respiratory infection (ESAR): a study protocol for a randomized controlled trial.

BMC Infect Dis 2022 Jul 20;22(1):632. Epub 2022 Jul 20.

Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Jing'an, Shanghai, 200040, China.

Background: The outbreak of SARS-CoV-2 at the end of 2019 sounded the alarm for early inspection on acute respiratory infection (ARI). However, diagnosis pathway of ARI has still not reached a consensus and its impact on prognosis needs to be further explored.

Methods: ESAR is a multicenter, open-label, randomized controlled, non-inferiority clinical trial on evaluating the diagnosis performance and its impact on prognosis of ARI between mNGS and multiplex PCR. Enrolled patients will be divided into two groups with a ratio of 1:1. Group I will be directly tested by mNGS. Group II will firstly receive multiplex PCR, then mNGS in patients with severe infection if multiplex PCR is negative or inconsistent with clinical manifestations. All patients will be followed up every 7 days for 28 days. The primary endpoint is time to initiate targeted treatment. Secondary endpoints include incidence of significant events (oxygen inhalation, mechanical ventilation, etc.), clinical remission rate, and hospitalization length. A total of 440 participants will be enrolled in both groups.

Discussion: ESAR compares the efficacy of different diagnostic strategies and their impact on treatment outcomes in ARI, which is of great significance to make precise diagnosis, balance clinical resources and demands, and ultimately optimize clinical diagnosis pathways and treatment strategies. Trial registration Clinicaltrial.gov, NCT04955756, Registered on July 9th 2021.
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http://dx.doi.org/10.1186/s12879-022-07552-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296892PMC
July 2022
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