Tree shrews have a close relationship to primates and have many advantages over rodents in biomedical research. However, the laek of gene manipulation methods has hindered the wider use of this ...animal. Spermatogonial stem cells （SSCs） have been successfully expanded in culture to permit sophisticated gene editing in the mouse and rat. Here, we describe a culture system for the long-term expansion of tree shrew SSCs without the loss of stem cell properties. In our study, thymus cell antigen 1 was used to enrich tree shrew SSCs. RNA-sequencing analysis revealed that the Wnt/β-catenin signaling pathway was active in undifferentiated SSCs, but was downregulated upon the initiation of SSC differentiation. Exposure of tree shrew primary SSCs to recombinant Wnt3a protein during the initial passages of culture enhanced the survival of SSCs. Use of tree shrew Sertoli cells, but not mouse embryonic fibroblasts, as feeder was found to be necessary for tree shrew SSC proliferation, leading to a robust cell expansion and long-term culture. The expanded tree shrew SSCs were transfected with enhanced green fluorescent protein （EGFP）-expressing lentiviral vectors. After transplantation into sterilized adult male tree shrew＇s testes, the EGFP-tagged SSCs were able to restore spermatogenesis and successfully generate transgenic offspring. Moreover, these SSCs were suitable for the CRISPR/Cas9-mediated gene modification. The development of a culture system to expand tree shrew SSCs in combination with a gene editing approach paves the way for precise genome manipulation using the tree shrew.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of ...demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model.
Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis.
Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post-bilateral carotid artery stenosis-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720's effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling.
Our study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.
Chemodivergent tandem radical cyclization offers exciting possibilities for the synthesis of structurally diverse cyclic compounds. Herein, we revealed a chemodivergent tandem cyclization of ...alkene‐substituted quinazolinones under metal‐ and base‐free conditions, this transformation is initiated by alkyl radicals produced from oxidant‐induced α‐C(sp3)−H functionalization of alkyl nitriles or esters. The reaction resulted in the selective synthesis of a series of mono‐ and di‐alkylated ring‐fused quinazolinones by modulating the loading of oxidant, reaction temperature, and reaction time. Mechanistic investigations show that the mono‐alkylated ring‐fused quinazolinones is constructed by the key process of 1,2‐hydrogen shift, whereas the di‐alkylated ring‐fused quinazolinones is mainly achieved through crucial steps of resonance and proton transfer. This protocol is the first example of remote second alkylation on the aromatic ring via α‐C(sp3)−H functionalization and difunctionalization achieved by association of two unsaturated bonds in radical cyclization.
A novel method for preparing mono‐ and di‐alkylated ring‐fused quinazolinones from alkene‐substituted quinazolinones via chemodivergent tandem radical cyclization under metal‐ and base‐free conditions has been established.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Here, we report a redox-mediated indirect fluorescence immunoassay (RMFIA) for the detection of the disease biomarker α-fetoprotein (AFP) using dopamine (DA)-functionalized CdSe/ZnS quantum dots ...(QDs). In this immunoassay, tyrosinase was conjugated with the detection antibody and acted as a bridge connecting the fluorescence signals of the QDs with the concentration of the disease biomarkers. The tyrosinase label used for RMFIA catalyzed the enzymatic oxidation of DAs on the surface of functionalized QDs and caused fluorescence quenching in the presence of the analyte. Using this technique, we obtained a limit of detection as low as 10 pM for AFP. This assay’s potential for clinical analysis was demonstrated by detecting the real sera of patients with hepatocellular carcinoma (HCC). This study makes the first use of RMFIA for the rapid detection of AFP, opening up a new pathway for the detection of disease biomarkers.
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IJS, KILJ, NUK, PNG, UL, UM
Exosomes are key mediators of intercellular communication and play a role in the pathogenesis and progression of cancer. Exosomes in circulating body fluids serve as molecular markers for cancer ...diagnosis. This study aimed to investigate the role of exosomal microRNA (miR)-1910-3p in breast cancer and determine its clinical diagnostic value. MiR-1910-3p promoted proliferation and migration of breast cancer cells in vitro and in vivo. In vitro, exosomes enriched in miR-1910-3p transferred miR-1910-3p to mammary epithelial cells and breast cancer cells, promoting proliferation and migration, inhibiting apoptosis, and inducing autophagy. In vivo, exosomes enriched in miR-1910-3p promoted the proliferation and migration of breast cancer cells. MiR-1910-3p downregulated myotubularin-related protein 3, activated the NF-κB and wnt/β-catenin signaling pathway, and promoted breast cancer progression. Serum miR-1910-3p in exosomes was an effective diagnostic marker that improved the sensitivity of breast cancer diagnosis when used in combination with the traditional tumor marker CA153. In conclusion, breast cancer cell-derived exosomes promoted the growth, metastasis, and autophagy of breast cancer cells by transferring miR-1910-3p. MiR-1910-3p in serum exosomes may serve as a novel molecular marker for breast cancer diagnosis.
•Exosome miR-1910-3p promoted proliferation and migration of breast cancer cells in vitro and in vivo.•Exosomes transferred miR-1910-3p, promoting proliferation and migration, and inducing autophagy in breast cancer.•MiR-1910-3p downregulated MTMR3, activated the NF-κB signaling pathway, and promoted breast cancer progression.•Serum miR-1910-3p in exosomes was an effective diagnostic marker that improved the sensitivity of breast cancer diagnosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Naphthols and 3‐trifluoroethylidene oxindoles were found to undergo an asymmetric Friedel–Crafts alkylation/lactonization reaction, catalyzed by only 2.5 mol % of a quinine‐derived squaramide ...catalyst, to afford the corresponding α‐aryl‐β‐trifluoromethyl dihydrocoumarin derivatives in high yields (up to 99 %) with excellent enantio‐ and diastereoselectivities (up to 98 % ee, >20:1 d.r.). Importantly, the lactonization proceeded by nucleophilic attack of the naphthol hydroxy group at the amide motif of the oxindoles under mild reaction conditions. This protocol represents a new strategy for the formation of dihydrocoumarins by an efficient intramolecular amide C−N bond‐cleavage and esterification process.
Crafty: A new 3+3 strategy has been developed for the organocatalytic enantioselective synthesis of α‐aryl‐β‐trifluoromethyl dihydrocoumarins. The Friedel–Crafts addition of naphthols to 3‐trifluoroethylidene oxindoles and subsequent esterification, through cleavage of the amide C−N bond by the hydroxy group of the naphthol, furnished the corresponding dihydrocoumarin products in high yields and excellent enantio‐ and diastereoselectivities.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Nuclear structure models built from phenomenological mean fields, the effective nucleon–nucleon interactions (or Lagrangians), and the realistic bare nucleon–nucleon interactions are reviewed. The ...success of covariant density functional theory (CDFT) to describe nuclear properties and its influence on Brueckner theory within the relativistic framework are focused upon. The challenges and ambiguities of predictions for unstable nuclei without data or for high-density nuclear matter, arising from relativistic density functionals, are discussed. The basic ideas in building an ab initio relativistic density functional for nuclear structure from ab initio calculations with realistic nucleon–nucleon interactions for both nuclear matter and finite nuclei are presented. The current status of fully self-consistent relativistic Brueckner–Hartree–Fock (RBHF) calculations for finite nuclei or neutron drops (ideal systems composed of a finite number of neutrons and confined within an external field) is reviewed. The guidance and perspectives towards an ab initio covariant density functional theory for nuclear structure derived from the RBHF results are provided.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Quantitative evidence on the impact of meteorological factors on influenza transmissibility across different virus types/subtypes is scarce, and no previous studies have reported the effect of hourly ...temperature variability (HTV) on influenza transmissibility. Herein, we explored the associations between meteorological factors and influenza transmissibility according to the influenza type and subtype in Guangzhou, a subtropical city in China.
We collected influenza surveillance and meteorological data of Guangzhou between October 2010 and December 2019. Influenza transmissibility was measured using the instantaneous effective reproductive number (R
). A gamma regression with a log link combined with a distributed lag non-linear model was used to assess the associations of daily meteorological factors with R
by influenza types/subtypes.
The exposure-response relationship between ambient temperature and R
was non-linear, with elevated transmissibility at low and high temperatures. Influenza transmissibility increased as HTV increased when HTV < around 4.5 °C. A non-linear association was observed between absolute humidity and R
, with increased transmissibility at low absolute humidity and at around 19 g/m
. Relative humidity had a U-shaped association with influenza transmissibility. The associations between meteorological factors and influenza transmissibility varied according to the influenza type and subtype: elevated transmissibility was observed at high ambient temperatures for influenza A(H3N2), but not for influenza A(H1N1)pdm09; transmissibility of influenza A(H1N1)pdm09 increased as HTV increased when HTV < around 4.5 °C, but the transmissibility decreased with HTV when HTV < 2.5 °C and 3.0 °C for influenza A(H3N2) and B, respectively; positive association of R
with absolute humidity was witnessed for influenza A(H3N2) even when absolute humidity was larger than 19 g/m
, which was different from that for influenza A(H1N1)pdm09 and influenza B.
Temperature variability has an impact on influenza transmissibility. Ambient temperature, temperature variability, and humidity influence the transmissibility of different influenza types/subtypes discrepantly. Our findings have important implications for improving preparedness for influenza epidemics, especially under climate change conditions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prostate-specific membrane antigen (PSMA) has been found in tumor neovasculature endothelial cells (NECs) of non-prostate cancers and may become the most promising target for anti-tumor therapy. To ...study the value of PSMA as a potential new target for lung cancer treatment, PSMA expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) tissues and its relationship with clinicopathology were investigated in the current study.
Immunohistochemistry was used to detect PSMA expression in a total of 150 lung specimens of patients with lung cancer. The data were analyzed using univariate and multivariate statistical analyses.
The percentages of NSCLC patients who had PSMA (+) tumor cells and PSMA (+) NECs were 54.02% and 85.06%, respectively. The percentage of patients younger than 60 years old who had PSMA (+) tumor cells was 69.05%, which was significantly greater than the percentage of patients aged 60 years or older (40.00%, p<0.05). A significant difference was observed in the percentage of NSCLC patients with PMSA (+) NECs and stage I or II cancer (92.98%) and those patients with stage III or IV cancer (76.77%). In the SCLC tissues, NEC PSMA expression (70.00%) did not differ significantly from NSCLC. SCLC tumor cells and normal lung tissues cells were all negative. There was no significant correlation between the presence of PSMA (+) NECs in SCLC patients and the observed clinicopathological parameters.
PSMA is expressed not only in NECs of NSCLC and SCLC but also in tumor cells of most NSCLC patients. The presence of PSMA (+) tumor cells and PSMA (+) NECs in NSCLC was negatively correlated with age and the clinicopathological stage of the patients, respectively.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
According to the literature and our experience, the most common sites of non-small cell lung cancer (NSCLC) metastases include the brain, bone, liver, adrenal glands, contralateral lung and distant ...lymph nodes. Metastases to other organs are relatively rare. There have been numerous case reports and a few small case series of uncommon metastases derived from NSCLC.
We defined all organs except the common metastatic sites mentioned above as uncommon sites of metastasis. Patients with uncommon metastases among 2,872 consecutive NSCLC patients with stage IV disease at the Guangdong Lung Cancer Institute (GLCI) from 2006 to 2012 were included in this study. The diagnosis of uncommon metastases was based on pathology or imaging studies.
Uncommon metastases were diagnosed in 193 cases at anatomical sites such as the soft tissue, kidney, pancreas, spleen, peritoneum, intestine, bone marrow, eye, ovary, thyroid, heart, breast, tonsil and nasal cavity. Uncommon metastases were identified as independent poor prognostic factors through a multivariate analysis with a HR (hazard ratio) of 1.29 95% confidence interval (CI) 1.09-1.52, P < 0.01. Those patients who received systemic therapy plus local treatment had a better survival rate than did those who received systemic therapy only (P < 0.01); all patients received best supportive care.
Metastases to the above mentioned sites are infrequent. The presentation of uncommon metastases tends to indicate a poor outcome, and selected patients may benefit from local treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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