Light-Activated Nanodiamond-Based Drug Delivery Systems for Spatiotemporal Release of Antisense Oligonucleotides.

Nanodiamonds (NDs) are considered promising delivery platforms, but inaccurate and uncontrolled release of drugs at target sites is the biggest challenge of NDs in precision medicine. This study presents the development of phototriggerable ND-based drug delivery systems, utilizing ortho-nitrobenzyl (o-NB) molecules as photocleavable linkers between drugs and nanocarriers. UV irradiation specifically cleaved o-NB molecules and then was followed by releasing antisense oligonucleotides from ND-based carriers in both buffer and cellular environments. This ND system carried cell nonpermeable therapeutic agents for bypassing lysosomal trapping and degradation. The presence of fluorescent nitrogen-vacancy centers also allowed NDs to serve as biological probes for tracing in cells. We successfully demonstrated phototriggered release of antisense oligonucleotides from ND-based nanocarriers, reactivating their antisense functions. This highlights the potential of NDs, photocleavable linkers, and light stimuli to create advanced drug delivery systems for controlled drug release in disease therapy, opening possibilities for targeted and personalized treatments.

Physiological and comprehensive transcriptome analysis reveals distinct regulatory mechanisms for aluminum tolerance of Trifolium repens.

It is estimated that up to 50 % of arable lands worldwide are acidic, and most crops are severely inhibited due to the high active aluminum (Al). Trifolium repens is an excellent legume forage with a certain acid tolerance, although it is affected by Al toxicity in acidic soil. In this study, physiological and transcriptomic responses of different white clover varieties were analyzed when exposed to a high-level of Al stress. The results revealed that Trifolium repens had a high level of Al toxicity tolerance, and accumulated nearly 70 % of Al3+ in its roots. Al toxicity significantly inhibited the root length and root activity, decreased the chlorophyll (Chl) content and photosynthetic pigments, while significantly increased the intercellular CO2 concentration (Ci). The content of malondialdehyde (MDA), electrolyte leakage (EL), proline and reactive oxygen species (ROS) were significantly accumulated under Al stress. Furthermore, a total of 27,480 differentially expressed genes (DEGs) were identified after the treatment. Gene ontology (GO) and Kyoto encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that most Al-responsive genes enriched to chloroplast thylakoid membrane, chloroplast stroma and photosynthesis in Haifa leaf while in MAG leaf highly enriched in response to regulation of defense response, which could induce the different tolerance of the two cultivars to Al stress. Besides, pectin methylesterase (PME), glycosyl transferases (GT1) and chalcone synthase genes associated with cell wall biosynthesis may improve the Al accumulation and enhance tolerance of Al toxicity. The results established here would help to understand the morphological structure, physiological and biochemical response, and molecular mechanism of white clover under Al tolerance.

Experimental Mode-Pairing Measurement-Device-Independent Quantum Key Distribution without Global Phase Locking.

In the past two decades, quantum key distribution networks based on telecom fibers have been implemented on metropolitan and intercity scales. One of the bottlenecks lies in the exponential decay of the key rate with respect to the transmission distance. Recently proposed schemes mainly focus on achieving longer distances by creating a long-arm single-photon interferometer over two communication parties. Despite their advantageous performance over long communication distances, the requirement of phase locking between two remote lasers is technically challenging. By adopting the recently proposed mode-pairing idea, we realize high-performance quantum key distribution without global phase locking. Using two independent off-the-shelf lasers, we show a quadratic key-rate improvement over the conventional measurement-device-independent schemes in the regime of metropolitan and intercity distances. For longer distances, we also boost the key rate performance by 3 orders of magnitude via 304 km commercial fiber and 407 km ultralow-loss fiber. We expect this ready-to-implement high-performance scheme to be widely used in future intercity quantum communication networks.

Ba4GeSb2Se11: An Infrared Nonlinear Optical Crystal with a V-Shaped Se32- Group Possessing a Large Contribution to the SHG Response.

The quaternary selenide Ba4GeSb2Se11 was prepared by a high-temperature solid state reaction method. Ba4GeSb2Se11 crystallizes in an acentric orthorhombic space group Cmc21 with the lattice constants a = 9.370(11) Å, b = 25.850(0) Å, and c = 8.798(10) Å. The compound is composed of a [SbSe3]3- trigonal pyramid, [GeSbSe5]3- dimers, V-shaped Se32-, and the adjacent Ba2+ ions. It has indirect band gap of 1.35 eV and exhibits a second harmonic generation intensity of about 0.2 times that of the benchmark compound AgGaS2 at the same particle size. Interestingly, theoretical analyses show that the central Se atom of Se32- has the largest contribution (8.1%) to d31 compared to that of other Se atoms, which may be due to its easy swing in the a-axis direction.

Theoretical Evaluation of Terahertz Sources Generated From SnGa4 Q7 (Q=S, Se) as Infrared Nonlinear Optical Materials.

We theoretically evaluated the integrated knowledge that contributes to conversion efficiency, including the phonon, photon, and electron properties of infrared nonlinear optical materials such as SnGa4 Q7 (Q=S, Se), which are terahertz (THz) sources. Specifically, we developed a new formula to calculate the susceptibility of the difference frequency generation (DFG) optical process. By evaluating the characteristics of the materials themselves in the THz region, we found that a larger nonlinear susceptibility or a large figure of merit resulted in a large efficiency of the THz source by comparing the findings of SnGa4 Se7 and SnGa4 S7 under the same experimental conditions; furthermore, THz absorption was found to reduce the efficiency of the THz source for the two SnGa4 Q7 (Q=S, Se) materials. The efficiency of the THz source also depended on the experimental conditions. A large crystal size, strong pump intensity, and small THz wavelength resulted in better efficiency of the THz source based on the DFG process. The efficiency was found to be a comprehensive index to evaluate the THz source based on the DFG process.

MARK2 Rescues Nogo-66-Induced Inhibition of Neurite Outgrowth via Regulating Microtubule-Associated Proteins in Neurons In Vitro.

The ability of neurons in the adult mammalian central nervous system (CNS) to regenerate after injury is limited by inhibitors in CNS myelin. Nogo-66 is the most important myelin inhibitor but the mechanisms of Nogo-66 inhibition of neurite outgrowth remain poorly understood. Particularly, the relationship between Nogo-66 and microtubule-affinity regulating kinase 2 (MARK2) has not been examined. This study investigated the role of MARK2 in Nogo-66 inhibition and the function of MARK2 in neurite elongation in neurons in vitro. MARK2 and phosphorylated MARK2 at Ser212 (p-Ser212) alterations in Neuro 2a cells were assessed at different Nogo-66 exposure times; the relationships between MARK2 and microtubule-associated proteins (MAPs) were determined via the overexpression or interference of MARK2. Our study reports that Nogo-66 inhibited the expression of total MARK2 but also reduced Ser212 phosphorylation of MARK2, whereas levels of MAP1-b and tau varied depending on MARK2 overexpression or reduced expression. Furthermore, MARK2 increased the proportion of tyrosinated α-tubulin, thereby disrupting the stability of tubulin, most likely affecting axonal growth. In line with these results, overexpression of MARK2 promoted neurite elongation and therefore is able to rescue the inhibitory effect of Nogo-66 on neurite growth. In conclusion, the intracellular PKB/MARK2/MAPs/α-tubulin pathway appears to be essential for neurite elongation in neurons in vitro. These results suggest a critical role for MARK2 in overcoming Nogo-66-induced inhibition of axon outgrowth in neurons. Pharmacological activators of MARK2 may be applicable to promote successful axonal outgrowth following many types of CNS injuries.

Aggregatibacter Actinomycetemcomitans With Periodontitis and Rheumatoid Arthritis.

OBJECTIVE: The aim of this work was to explore the association between Aggregatibacter actinomycetemcomitans (A actinomycetemcomitans) infection and disease activity amongst those with rheumatoid arthritis (RA) with or without periodontitis (PD) in a Chinese population. METHODS: A case-control study was conducted from November 2017 to March 2019. The correlation coefficients between A actinomycetemcomitans positivity and RA-related examination indicators as well as periodontal examination parameters were calculated by using the Spearman correlation analysis. RESULTS: A total of 115 patients with RA were recruited: 67 patients with RA only and 48 with RA + PD. The percentage of A actinomycetemcomitans positivity was significantly higher in the RA + PD group compared with the RA-only group (P = .007 for positive percentage; P = .020 for percentage of A actinomycetemcomitans positivity in the total oral microbiome). Furthermore, RA-related measures such as Disease Activity Score 28, rheumatoid factor, anticyclic citrullinated peptide, and anticitrullinated protein antibodies were all positively correlated with the percentage of A actinomycetemcomitans positivity (P range: .002∼.041). In addition, significant correlations were observed amongst A actinomycetemcomitans positivity and probing pocket depth (P = .027) and gingival index (P = .043), whereas null correlations were found amongst the percentage of A actinomycetemcomitans positivity and plaque index (P = .344), clinical attachment loss (P = .217), and bleeding on probing (P = .710). CONCLUSIONS: A actinomycetemcomitans infection may be related to the development of PD amongst patients with RA.

Identification of two flavonoids antiviral inhibitors targeting 3C-like protease of porcine epidemic diarrhea virus.

Porcine epidemic diarrhea virus (PEDV) has caused severe damage to the global pig industry in the past 20 years, creating an urgent demand for the development of associated medications. Flavonoids have emerged as promising candidates for combating coronaviruses. It is believed that certain flavonoids can directly inhibit the 3C-like protease (3CLpro), thus displaying antiviral activity against coronaviruses. In this investigation, we applied a flavonoid library to screen for natural compounds against PEDV 3CLpro. Baicalein and baicalin were found to efficiently inhibit PEDV 3CLproin vitro, with the IC50 value of 9.50 ± 1.02 µM and 65.80 ± 6.57 µM, respectively. A docking analysis supported that baicalein and baicalin might bind to the active site and binding pocket of PEDV 3CLpro. Moreover, both baicalein and baicalin successfully suppressed PEDV replication in Vero and LLC-PK1 cells, as indicated by reductions in viral RNA, protein, and titer. Further investigation revealed that baicalein and baicalin mainly inhibited the early viral replication of the post-entry stage. Furthermore, baicalein showed potential effects on the attachment or invasion step of PEDV. Collectively, our findings provide experimental proof for the inhibitory effects of baicalein and baicalin on PEDV 3CLpro activity and PEDV infection. These discoveries may introduce novel therapeutic strategies for controlling porcine epidemic diarrhea (PED).

NSUN2 promotes colorectal cancer progression by enhancing SKIL mRNA stabilization.

BACKGROUND: NOP2/Sun domain 2 (NSUN2) is one of the important RNA methyltransferases catalyzing 5-methylcytosine (m5C) formation and participates in many critical bioprocesses. However, the roles and underlying molecular mechanisms of NSUN2-mediated m5C modification in colorectal cancer (CRC) remain unclear. METHODS: To explore the NSUN2 expression in CRC, fresh tissue samples were collected and Nsun2 knockout mouse was constructed. In vitro and in vivo functional assays were conducted to assess the role of NSUN2. RNA array and bisulfite sequencing were used to investigate the potential targets. The mechanisms of NSUN2 function on SKIL were identified by m5C-methylated-RNA immunoprecipitation and RNA stability assays. Additionally, tissue microarray analysis was conducted and patient-derived tumour xenograft mouse (PDX) models were used to define the potential therapeutic targets. RESULTS: NSUN2 was highly expressed in CRC and correlated with poor CRC patient survival. Moreover, silencing NSUN2 suppressed CRC tumourigenesis and progression in Nsun2 knockout mouse models. In vitro and in vivo studies suggested that NSUN2 promoted colorectal cancer cell growth. Mechanistically, SKI-like proto-oncogene (SKIL) is positively regulated by NSUN2, and the NSUN2-SKIL axis is clinically relevant to CRC. NSUN2 induced m5C modification of SKIL and stabilized its mRNA, which was mediated by Y-box binding protein 1 (YBX1). Elevated SKIL levels increased transcriptional coactivator with PDZ-binding motif (TAZ) activation. CONCLUSIONS: Our findings highlight the importance of NSUN2 in the initiation and progression of CRC via m5C-YBX1-dependent stabilization of the SKIL transcript, providing a promising targeted therapeutic strategy for CRC.

New facile method for the preparation of M3B7O13I boracites (M = Mn, Fe, Co, Ni, Cd).

Five iodine boracites, M(3)B(7)O(13)I (M = Mn, Fe, Co, Ni, Cd), have been synthesized by reactions of metal oxide, B(2)O(3), element B, and I(2) at intermediate temperature above 350 °C. Powder X-ray diffraction analyses verify the identities and purity of the products, which are also confirmed by magnetic property measurement. Except safe, cheap, and convenient, this novel method is significantly flexible in the selection of the starting metal oxide. The influence of the reaction temperature and time has also been studied.

Reactive Oxygen Species Scavenging Hydrogel Regulates Stem Cell Behavior and Promotes Bone Healing in Osteoporosis.

BACKGROUND: Implantation of bone marrow mesenchymal stem cells (BMSCs) is a potential alternative for promoting bone defects healing or osseointegration in osteoporosis. However, the reactive oxygen species (ROS) accumulated and excessive inflammation in the osteoporotic microenvironment could weaken the self-replication and multi-directional differentiation of transplanted BMSCs. METHODS: In this study, to improve the hostile microenvironment in osteoporosis, Poloxamer 407 and hyaluronic acid (HA) was crosslinked to synthetize a thermos-responsive and injectable hydrogel to load MnO2 nanoparticles as a protective carrier (MnO2@Pol/HA hydrogel) for delivering BMSCs. RESULTS: The resulting MnO2@Pol/HA hydrogel processed excellent biocompatibility and durable retention time, and can eliminate accumulated ROS effectively, thereby protecting BMSCs from ROS-mediated inhibition of cell viability, including survival, proliferation, and osteogenic differentiation. In osteoporotic bone defects, implanting of this BMSCs incorporated MnO2@Pol/HA hydrogel significantly eliminated ROS level in bone marrow and bone tissue, induced macrophages polarization from M1 to M2 phenotype, decreased the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1ß, and IL-6) and osteogenic related factors (e.g., TGF-ß and PDGF). CONCLUSION: This hydrogel-based BMSCs protected delivery strategy indicated better bone repair effect than BMSCs delivering or MnO2@Pol/HA hydrogel implantation singly, which providing a potential alternative strategy for enhancing osteoporotic bone defects healing.

An open label, safety study of Asian patients with advanced non-small-cell lung cancer receiving second-line nivolumab monotherapy (CheckMate 870).

Background: Nivolumab has been approved in China as second-line treatment for advanced non-small-cell lung cancer (NSCLC) via weight-based infusion, based on the CheckMate 078 study. We investigated the safety and efficacy of 240 mg flat-dose nivolumab in patients with advanced NSCLC, including those with hepatitis B virus (HBV) and epidermal growth factor receptor (EGFR) mutation/ALK receptor tyrosine kinase (ALK) translocation due to high prevalence in China. Methods: CheckMate 870 was a single-arm, open-label, phase IIIb trial in Asian (primarily Chinese) patients with previously treated advanced NSCLC. Patients received flat-dose nivolumab 240 mg every 2 weeks (Q2W) for up to 2 years. The primary endpoint was the incidence and severity of treatment-related select adverse events (TRsAEs) in non-HBV patients; secondary and exploratory endpoints included severity of high-grade TRsAEs in HBV-infected patients, and safety, efficacy and patient-reported outcomes (PROs) in the whole population. Results: Out of 404 patients enrolled, 400 received treatment. Median (standard deviation) age was 60.5 (8.68) years and the majority were male (78.5%). At a median follow-up of 37.6 months, no Grade 5 TRsAEs were reported, and the frequency of Grade 3-4 TRsAEs was low (0.0-5.9%) in non-HBV and HBV NSCLC patients. Median overall survival (OS) and progression-free survival (PFS) in all treated patients were 14.7 (12.3-18.1) and 3.6 (2.3-3.8) months, respectively. Median OS was 14.2 (12.3-18.1) and 22.3 (10.0-NA) months for non-HBV and HBV-infected patients, 19.3 (11.2-31.7) and 13.7 (11.5-18.1) months for EGFR-positive and wild-type subgroups, and 19.3 (12.9-23.5) and 13.3 (10.9-17.7) months for those with programmed death-ligand 1 (PD-L1) expression ⩾1% and <1%, respectively. No notable changes from baseline were observed in PROs throughout the study. Conclusion: Nivolumab 240 mg infusion Q2W was well tolerated, efficacious, and maintained health status and quality of life in Asian patients with previously treated advanced NSCLC regardless of HBV, EGFR, or PD-L1 status.

A retrospective study of orthodontic treatment on anterior tooth displacement caused by periodontal disease.

ABSTRACT: This retrospective study aimed to explore the effect of orthodontic treatment (ODT) on anterior tooth displacement (ATD) caused by periodontal disease (PD).A total of 72 patients were selected and were divided into a control group (n = 36) and an experimental group (n = 36). Patients in both groups received conventional periodontal treatment. In addition, patients in the experimental group also received ODT. Outcomes include probing depth, percentage of bleeding sites, clinical attachment loss, clinical crown length, tooth root length, and periodontal tissue of the affected tooth (alveolar bone height, periodontal pocket depth, bleeding index).After treatment, the patients in the experimental group achieved more improvements in probing depth (P < .01), percentage of bleeding sites (P < .01), clinical attachment loss (P < .01), clinical crown length (P = .04), and periodontal tissue of the affected tooth (periodontal pocket depth (P < .01), and bleeding index (P < .01)), than those of patients in the control group.This study suggests that ODT is beneficial for ATD caused by PD. Future studies are still needed to verify the findings of this study.

Exogenous Methyl Jasmonate Improves Heat Tolerance of Perennial Ryegrass Through Alteration of Osmotic Adjustment, Antioxidant Defense, and Expression of Jasmonic Acid-Responsive Genes.

Perennial ryegrass (Lolium perenne L.) is an important cool-season grass species that is widely cultivated in temperate regions worldwide but usually sensitive to heat stress. Jasmonates (JAs) may have a positive effect on plant tolerance under heat stress. In this study, results showed that exogenous methyl jasmonic acid (MeJA) could significantly improve heat tolerance of perennial ryegrass through alteration of osmotic adjustment, antioxidant defense, and the expression of JA-responsive genes. MeJA-induced heat tolerance was involved in the maintenance of better relative water content (RWC), the decline of chlorophyll (Chl) loss for photosynthetic maintenance, as well as maintained lower electrolyte leakage (EL) and malondialdehyde (MDA) content under heat condition, so as to avoid further damage to plants. Besides, results also indicated that exogenous MeJA treatment could increase the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX), thus enhancing the scavenging ability of reactive oxygen species, alleviating the oxidative damage caused by heat stress. Heat stress and exogenous MeJA upregulated transcript levels of related genes (LpLOX2, LpAOC, LpOPR3, and LpJMT) in JA biosynthetic pathway, which also could enhance the accumulation of JA and MeJA content. Furthermore, some NAC transcription factors and heat shock proteins may play a positive role in enhancing resistance of perennial ryegrass with heat stress.

Impact of diabetes on promoting the growth of breast cancer.

BACKGROUND: Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well-established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression. METHODS: We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+ ) mice with MMTV-ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism. RESULTS: Treatment with metformin/rosiglitazone in MMTV-ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13 C pyruvate-to-lactate reaction. The tumor cells from MMTV-ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles. CONCLUSIONS: MMTV-ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti-insulin resistance therapy.

Pb2B5O9I: an iodide borate with strong second harmonic generation.

The combination of lone-pair effects on Pb(2+) cations and the smaller electronegativity of I(-) anions into the pentaborate framework generates a phase-matchable material, Pb(2)B(5)O(9)I, with the largest powder SHG response among borates, about 13.5 times that of KDP (KH(2)PO(4)), and transparency over the near-UV to middle-IR region. DFT calculations on electronic structure and cutoff-energy-dependent SHG coefficients confirm these origins.

Continuous band-gap reduction on ZnO submicrorods via covering with ZnS(1-x)Se(x) or ZnSe(1-x)Te(x) alloy in core/sheath morphology.

Submicrosized alloy cables of ZnO/w-ZnS(1-x)Se(x) (0 < x < 1) and ZnO/s-ZnSe(1-x)Te(x) (0.8 < or = x < 1) have been prepared. The lattice parameters of the sheath show linear compositional dependence following Vegard's law. The composition-band gap dependence follows the trend of E(g)(ZnO/w-ZnS(1-x)Se(x))(x) = 3.60 - 1.77x + 0.87x(2) (0.22 < or = x < or = 1), E(g)(ZnO/w-ZnS(1-x)Se(x)) = 3.25 eV (0 < or = x < or = 0.22), and E(g)(ZnO/s-ZnSe(1-x)Te(x))(x) = 2.65 - 1.82x + 1.41x(2) (0 < or = x < or = 1), respectively. The continuous band-gap modulations on ZnO-based heterostructures are associated with the core/sheath morphology and the nature of the sheath alloys.

Preoperative MRI Evaluation of Relationship between Trigeminal Nerve and Superior Petrosal Vein: Its Role in Treating Trigeminal Neuralgia.

OBJECTIVE: To assess the value of high-resolution magnetic resonance imaging (MRI) and three-dimensional (3D) reconstruction of the trigeminal nerve and the superior petrosal vein (SPV) in visualizing their anatomical relationship in patients with trigeminal neuralgia (TN). PATIENTS AND METHODS: This study included 97 patients with primary TN who underwent preoperative 3D constructive interference in steady state (CISS) MRI. Image analysis was performed by an independent observer blinded to the operative findings and then compared with surgical data. The 3D reconstruction was assessed dynamically using MIMICS software (Materialise Inc., Leuven, Belgium). RESULTS: The 3D relationship between visible structures seen on MRI was consistent with the intraoperative findings in all patients. All cases were divided into three groups by the degree of trigeminal nerve encroachment by SPV. Statistical analysis revealed that the distance from the SPV to the trigeminal nerve was significantly different among the three groups. The diameter of the SPV also differed among the three groups. CONCLUSION: Preoperative 3D imaging provides reliable and detailed information about the intraoperative anatomical relationship between the trigeminal nerve and the SPV. This evaluation is useful for preoperative planning.

Submicrosized rods, cables, and tubes of ZnE (E = S, Se, Te): exterior-interior boron-chalcogen conversions and optical properties.

The submicrosized ZnE rods, ZnO/ZnE cables, and ZnE tubes (E = S, Se, Te) have been synthesized via exterior-to-interior boron-chalcogen corrosions on the initial ZnO rods. The products are well characterized by XRD, SEM, TEM, and elemental analyses. The morphologies of both ZnE rods and ZnO/ZnE cables are roughly comparable to that of ZnO. The measured optical gaps of the ZnE rods are in agreement with those of the corresponding bulk materials, and the ZnO/ZnE cables exhibit type-I excitonic localization that is restrained in the region of the narrower band gap component.