When silk fibroin particles are used for controlled drug delivery, particle size plays a key role in the location of the carrier on the cells as well as the transport pathway, utilization efficiency, and therapeutic effect of the drugs. In this study, the interactions of different-sized silk fibroin particles and cell lines were investigated. Silk fibroin microparticles with dry size of 1.9 ± 0.4 μm (2.7 ± 0.3 μm in wet state) and silk fibroin nanoparticles with dry size of 51.5 ± 11.0 nm (174.8 ± 12.5 nm in wet state) were prepared by salting-out method and high-voltage electrospray method, respectively. CdSe/ZnS quantum dots were coupled to the surface of the micro/nanoparticles. Photostability observations indicated that the fluorescence stability of the quantum dots was much higher than that of fluorescein isothiocyanate. In vitro, microparticles and nanoparticles were co-cultured with human umbilical vein endothelial cells EA.hy 926 and cervical cancer cells HeLa, respectively. The fluorescence test and cell viability showed that the EA.hy926 cells tended to be adhered to the microparticle surfaces and the cell proliferation was significantly promoted, while the nanoparticles were more likely to be internalized in HeLa cells and the cell proliferation was notably inhibited. Our findings might provide useful information concerning effective drug delivery that microparticles may be preferred if the drugs need to be delivered to normal cell surface, while nanoparticles may be preferred if the drugs need to be transmitted in tumor cells.

The antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) has been extensively studied; growing evidence suggests that changes in lipid composition may be involved in the pathogenesis of depression and may be a targeted mechanism for treatment. However, the influence of rTMS on lipid composition and the differences between these effects compared to antidepressants like fluoxetine (Flx) have never been investigated. Using a chronic unpredictable stress (CUS) model in rats, we assessed the antidepressive effects of rTMS and Flx treatments and evaluated changes in lipid composition in the hippocampus and prefrontal cortex (PFC) using a mass spectrometry-based lipidomic approach. Both rTMS and Flx treatments ameliorated depressive-like behaviors induced by CUS. Moreover, changes in lipid composition, especially glycerophospholipids, sphingolipids, and glycerolipids induced by CUS in the hippocampus were more robust than those observed in the PFC. CUS led to decreased levels of 20 carbon-containing fatty acyls and polyunsaturated fatty acyls in the PFC, and decreased levels of acyl carnitines (AcCa) in both the hippocampus and PFC. Notably, rTMS treatment had higher impact than Flx on composition of glycerophospholipids and sphingolipids in the hippocampus that were altered by CUS, while Flx attenuated CUS-induced changes in the PFC to a greater extent than rTMS. However, neither was able to restore fatty acyls and AcCa to baseline levels. Altogether, modulation of the brain lipidome may be involved in the antidepressant action of rTMS and Flx, and the degree to which these treatments induce changes in lipid composition within the hippocampus and PFC might explain their differential antidepressant effects.

N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells. NMT1 sustains proliferation and/or survival of cancer cells through mechanisms that are not completely understood. We used genetic and pharmacological inhibition of NMT1 to further dissect the role of this enzyme in cancer, and found an unexpected essential role for NMT1 at promoting lysosomal metabolic functions. Lysosomes mediate enzymatic degradation of vesicle cargo, and also serve as functional platforms for mTORC1 activation. We show that NMT1 is required for both lysosomal functions in cancer cells. Inhibition of NMT1 impaired lysosomal degradation leading to autophagy flux blockade, and simultaneously caused the dissociation of mTOR from the surface of lysosomes leading to decreased mTORC1 activation. The regulation of lysosomal metabolic functions by NMT1 was largely mediated through the lysosomal adaptor LAMTOR1. Accordingly, genetic targeting of LAMTOR1 recapitulated most of the lysosomal defects of targeting NMT1, including defective lysosomal degradation. Pharmacological inhibition of NMT1 reduced tumor growth, and tumors from treated animals had increased apoptosis and displayed markers of lysosomal dysfunction. Our findings suggest that compounds targeting NMT1 may have therapeutic benefit in cancer by preventing mTORC1 activation and simultaneously blocking lysosomal degradation, leading to cancer cell death.

A deterministic source of coherent single photons is an enabling device for quantum information processing. Quantum dots in nanophotonic structures have been employed as excellent sources of single photons with the promise of scaling up towards multiple photons and emitters. It remains a challenge to implement deterministic resonant optical excitation of the quantum dot required for generating coherent single photons, since residual light from the excitation laser should be suppressed without compromising source efficiency and scalability. Here, we present a planar nanophotonic circuit that enables deterministic pulsed resonant excitation of quantum dots using two orthogonal waveguide modes for separating the laser and the emitted photons. We report a coherent and stable single-photon source that simultaneously achieves high-purity (g(2)(0) = 0.020 ± 0.005), high-indistinguishability (V = 96 ± 2%), and >80% coupling efficiency into the waveguide. Such 'plug-and-play' single-photon source can be integrated with on-chip optical networks implementing photonic quantum processors.

Prostate cancer (PCa) remains a leading cause of mortality among men in the United States and Western Europe. The molecular mechanism of PCa pathogenesis has not been fully elucidated. In the present study, the expression profile of E2F transcription factor 7 (E2F7) in PCa was examined using immunohistochemistry and reverse transcription‑quantitative PCR, whilst cell cycle progression and apoptosis were determined using fluorescent cell activated sorting techniques. Cell viability was measured using Cell Counting Kit‑8 in loss‑ and gain‑of‑function studies. Dual‑luciferase reporter assay was used to verify if E2F7 was one of the potential targets of miR‑30c. The staining score of E2F7 of PCa tissues was found to be notably higher compared with that of adjacent normal tissues. Suppression of E2F7 expression in PCa cell lines led to significantly reduced proliferation rates, increased proportion of cells in the G1 phase of the cell cycle and higher apoptotic rates compared with those in negative control groups. Dual‑luciferase reporter assay revealed E2F7 to be one of the binding targets of microRNA (miR)‑30c. In addition, transfection of miR‑30c mimics into PCa cells resulted in reduced cell viability, increased proportion of cells in the G1 phase and higher apoptotic rates. By contrast, transfection with the miR‑30c inhibitor led to lower apoptosis rates of PCa cells compared with negative control groups, whilst E2F7 siRNA co‑transfection reversed stimulatory effects of miR‑30c inhibitors on cell viability. In addition, the expression of cyclin‑dependent kinase inhibitor p21 were found to be upregulated by transfection with either E2F7 siRNA or miR‑30c mimics into PCa cells. In conclusion, the present study suggested that E2F7 may be positively associated with PCa cell proliferation by inhibiting p21, whereas E2F7 is in turn under regulation by miR‑30c. These observations suggest the miR‑30c/E2F7/p21 axis to be a viable therapeutic target for PCa.

Adjuvants that contain pathogen-associated molecular patterns (PAMPs) can enhance vaccination efficacy by binding to pattern recognition receptors (PRRs), thereby stimulating immune responses. Particularly effective may be the combination of multiple PAMPs that activate different PRRs, which occurs with natural pathogens. Here we hypothesized the enhanced effects would occur in two adjuvants that stimulate different PRRs: CpG oligodeoxynucleotide (CpG-ODN), which is Toll-like receptor 9 agonist; and 5'-triphosphate, short, double-stranded RNA (3pRNA), which activates retinoic acid-inducible gene I (RIG-I). The model antigen ovalbumin (OVA) was loaded and adjuvants were surface-adsorbed to aluminum hydroxide nanoparticles (hereafter NP-3pRNA-CpG) by electrostatic interaction with an average size of 120 nm and a negative surface charge for targeting lymph nodes. These nanoparticles were efficiently internalized by antigen-presenting cells (APCs) in the lymph nodes, and the resulting APC activation and antigen cross-presentation generated strong humoral immunity and cytotoxic T lymphocyte responses and IFN-γ secretion. NP-3pRNA-CpG significantly suppressed B16-OVA tumor growth and prolonged survival of tumor-bearing mice in therapeutic and prophylactic models, illustrating the enhanced effects of CpG-ODN and 3pRNA. Our study highlights the potential of combining multiple adjuvants for effective vaccine design.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

The polyandrous mating system of honeybees (Apis mellifera L.) has garnered widespread attention. Long-lived honeybee queens only mate early in maturation, and the sperm obtained from the aerial mating is stored in the spermatheca. The maintenance of sperm viability in the spermatheca is an intriguing and complex process. However, the key physiological and biochemical adaptations underlying the long-term storage of sperm remain unclear. Analysis of the metabolite profile could help better understand the biology of the spermatheca and offer insights into the breeding and conservation of honeybees and even pest control strategies. Here, the changes in metabolites in the spermatheca were quantified between virgin queens and new-laying queens (with stored sperm) via liquid chromatography-mass spectrometry. Compared with virgin queens, changes occurred in lipids and lipid-like molecules, including fatty acyls and glycerophospholipids (GPL), prenol lipids, and sterol lipids, during storage of sperm in new-laying honeybee queens. Furthermore, the metabolic pathways that were enriched with the differentially expressed metabolites were identified and included GPL metabolism, biosynthesis of amino acids, and the mTOR signaling pathway. The likely roles of the pathways in the maintenance and protection of sperm are discussed. The study identifies key metabolites and pathways in the complex interplay of substances that contribute to the long-term storage of sperm and ultimately reproductive success of honeybee queens.

The aim of the present study was to investigate the therapeutic effect of magnesium sulfate combined with labetalol on the early-onset severe pre-eclampsia (ES-PE) and explore the role of soluble fms-like tyrosine kinase-1 (sFlT-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in the treatment. A total of 164 ES-PE patients admitted to the Maternity and Child Health Care Hospital of Hubei (Wuhan, China) were assigned to this observational study. Among them, 83 patients were enrolled in group A and treated with magnesium sulfate combined with labetalol hydrochloride, and 81 patients were enrolled in group B and treated with magnesium sulfate. The therapeutic effect, adverse reactions and pregnancy outcomes in the two groups were analyzed. Serum sFlt-1 and PlGF concentrations, before and after treatment, were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of pre-treatment serum sFlt-1/PlGF ratio for the clinical outcome. The effective rate was significantly higher in group A than that in group B. Group A presented superior pregnancy outcomes over group B. The serum sFlt-1 concentration and sFlt-1/PlGF ratio after treatment were significantly lower than those before treatment in groups A and B, whereas PlGF concentration was significantly higher after treatment in both groups. After treatment, group A had markedly lower serum sFlt-1 concentration and sFlt-1/PlGF ratio than group B, and markedly higher PlGF concentration than group B. The area under curve (AUC) of serum sFlt-1/PlGF ratio before treatment for the prediction of the clinical efficacy was 0.737. In conclusion, magnesium sulfate combined with labetalol could be effectively used for the treatment of ES-PE. The results of ELISA revealed that the balance of sFlT-1 and PlGF was improved after treatment and the sFlT-1/PlGF ratio was decreased. The assessment of sFlt-1/PlGF ratio before treatment was shown to have a certain predictive value for the efficacy of ES-PE treatment.

Due to the multi-potential differentiation and immunomodulatory function, mesenchymal stem cells (MSCs) have been widely used in the therapy of chronic and autoimmune diseases. Recently, the novel coronavirus disease 2019 (COVID-19) has grown to be a global public health emergency but no effective drug is available to date. Several studies investigated MSCs therapy for COVID-19 patients. However, it remains unclear whether MSCs could be the host cells of SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) and whether they might affect the SARS-CoV-2 entry into other cells. Here, we report that human MSCs barely express ACE2 and TMPRSS2, two receptors required for the virus endocytosis, indicating that MSCs are free from SARS-CoV-2 infection. Furthermore, we observed that MSCs were unable to induce the expression of ACE2 and TMPRSS2 in epithelial cells and macrophages. Importantly, under different inflammatory challenge conditions, implanted human MSCs failed to up-regulate the expression of ACE2 and TMPRSS2 in the lung tissues of mice. Intriguingly, we showed that a SARS-CoV-2 pseudovirus failed to infect MSCs and co-cultured MSCs did not increase the risk of SARS-CoV-2 pseudovirus infection in epithelial cells. All these results suggest that human MSCs have no risk of assisting SARS-CoV-2 infection and the use of MSCs as the therapy for COVID-19 patients is feasible and safe.

CD47 is a widely expressed transmembrane protein located on the surface of somatic cells. It mediates a variety of cellular processes including apoptosis, proliferation, adhesion, and migration. An important role for CD47 is the transmission of a "Don't eat me" signal by interacting with SIRPα on the macrophage surface membrane, thereby preventing the phagocytosis of normal cells. However, cancer cells can take advantage of this autogenous signal to protect themselves from phagocytosis, thus enabling immune escape. Blocking the interaction between CD47 and SIRPα has proven to be effective in removing cancer cells. The treatment of various cancers with CD47 monoclonal antibodies has also been validated.

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.

Escherichia coli K1 (E. coli K1) caused neonatal meningitis remains a problem, which rises the urgent need for an effective vaccine. Previously, we rationally designed and produced the recombinant protein OmpAVac (Vo), which elicited protective immunity against E. coli K1 infection. However, Vo has limited stability, which hinders its future industrial application.

Cumulating evidence indicates that the systemic inflammatory response (SIR) plays a crucial role in the prognosis of various cancers. We aimed to generate a preoperative risk grade (PRG) by integrating SIR markers to preoperatively predict the long-term prognosis of intrahepatic cholangiocarcinoma (ICC).

The oomycete genus Phytophthora includes devastating plant pathogens that are found in almost all ecosystems. We sequenced the genomes of two quarantined Phytophthora species-P. fragariae and P. rubi. Comparing these Phytophthora species and related genera allowed reconstruction of the phylogenetic relationships within the genus Phytophthora and revealed Phytophthora genomic features associated with infection and pathogenicity. We found that several hundred Phytophthora genes are putatively inherited from red algae, but Phytophthora does not have vestigial plastids originating from phototrophs. The horizontally-transferred Phytophthora genes are abundant transposons that "transmit" exogenous gene to Phytophthora species thus bring about the gene recombination possibility. Several expansion events of Phytophthora gene families associated with cell wall biogenesis can be used as mutational targets to elucidate gene function in pathogenic interactions with host plants. This work enhanced the understanding of Phytophthora evolution and will also be helpful for the design of phytopathological control strategies.

WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, it was considered as a promising epigenetic target involving in anti-cancer drug development. In view of the protein-protein interaction nature of WDR5, we initialized a campaign to discover new peptide-mimic inhibitors of WDR5. In current study, we utilized the phage display technique and screened with a disulfide-based cyclic peptide phage library. Five rounds of biopanning were performed and isolated clones were sequenced. By analyzing the sequences, total five peptides were synthesized for binding assay. The four peptides are shown to have the moderate binding affinity. Finally, the detailed binding interactions were revealed by solving a WDR5-peptide cocrystal structure.

Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to explore alternative treatment strategies. Upon investigation of public perturbation data, we identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells and its deletion leads to impaired proliferation in those cells. Consistently, high IRF8 expression is associated with poorer patients' prognoses. Combining gene expression changes upon IRF8 deletion and the genome-wide localization of IRF8 in the AML cell line MV4-11, we demonstrate that IRF8 directly regulates key signaling molecules, such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5, and the cell cycle regulator Cyclin D1. IRF8 loss impairs AML-driving signaling pathways, including the WNT, Chemokine, and VEGF signaling pathways. Additionally, many members of the focal adhesion pathway showed reduced expression, providing a putative link between high IRF8 expression and poor prognosis. Thus, this study suggests that IRF8 could serve as a biomarker and potential molecular target in a subset of human AMLs.

There is evidence that DNA methylation play major roles in lung cancer. In our previously study, C3 or f21 , also referred to as XXYLT1, rs2131877 polymorphism is associated with a reduced risk of lung adenocarcinoma. So, we explored the role of XXYLT1 methylation in lung adenocarcinoma.

Wet age-related macular degeneration (wAMD), characterized by choroidal neovascularization (CNV), is a leading cause of irreversible vision loss among elderly people in developed nations. Subretinal fibrosis, mediated by epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells, leads to unsuccessful anti-vascular endothelial growth factor (VEGF) agent treatments in CNV patients. Under hypoxic conditions, hypoxia-inducible factor-1α (HIF-1α) increases the stability and activation of p53, which activates microRNA-34a (miRNA-34a) transcription to promote fibrosis. Additionally, Klotho is a target gene of miRNA-34a that inhibits fibrosis. This study aimed to explore the role of the HIF-1α/p53/miRNA-34a/Klotho axis in subretinal fibrosis and CNV. Hypoxia-induced HIF-1α promoted p53 stability, phosphorylation and nuclear translocation in ARPE-19 cells (a human RPE cell line). HIF-1α-dependent p53 activation up-regulated miRNA-34a expression in ARPE-19 cells following hypoxia. Moreover, hypoxia-induced p53-dependent miRNA-34a inhibited the expression of Klotho in ARPE-19 cells. Additionally, the HIF-1α/p53/miRNA-34a/Klotho axis facilitated hypoxia-induced EMT in ARPE-19 cells. In vivo, blockade of the HIF-1α/p53/miRNA-34a/Klotho axis alleviated the formation of mouse laser-induced CNV and subretinal fibrosis. In short, the HIF-1α/p53/miRNA-34a/Klotho axis in RPE cells promoted subretinal fibrosis, thus aggravating the formation of CNV.

A translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 which is a rare cytogenetic abnormality in CLL patients, has a more aggressive clinical course with a shorter time to first treatment (TTT) and worse overall survival (OS). To date, there is no literature reporting the identification of the t(14;19) in Chinese CLL patients and the reviewing the characteristic of all patients with this abnormality reported previously in the literature.