Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy.

Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of Mic60 reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age-dependent manner. Moreover, haploinsufficiency of Mic60 compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N-acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo-insufficient Mic60 mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies.

Effects of different depth of anesthesia on perioperative inflammatory reaction and hospital outcomes in elderly patients undergoing laparoscopic radical gastrectomy.

BACKGROUND: To investigate the effect of different depth of anesthesia on inflammatory factors and hospital outcomes in elderly patients undergoing laparoscopic radical gastrectomy for gastric cancer, in order to select an appropriate depth of anesthesia to improve the prognosis of patients undergoing surgery and improve the quality of life of patients. METHODS: A total of 80 elderly patients aged 65 and above who underwent laparoscopic radical gastrectomy in our hospital were by convenience sampling and randomly divided into two groups : 55 groups ( group H ) and 45 groups ( group L ), 40 cases in each group. The depth of anesthesia was maintained using a closed-loop target-controlled infusion system: the EEG bispectral index was set to 55 in the H group and 45 in the L group. Venous blood samples were collected 2 h (T2), 24 h (T3) and 72 h (T4) after the start of surgery. The intraoperative dosage of propofol and remifentanil, operation duration, postoperative PACU stay time, intraoperative consciousness occurrence, postoperative hospital stay and postoperative pulmonary inflammatory events were recorded. RESULTS: The patient characteristic of the two groups had no statistical difference and were comparable (P > 0.05). The intraoperative dosage of propofol in group H was lower than that in group L (P < 0.05). Compared with the L group, the plasma IL-6 and IL-10 concentrations in the H group were significantly increased at T2 (P < 0.05), and the plasma IL-10 concentration was significantly increased at T4 (P < 0.05). The plasma concentrations of IL-6 and IL-10 were higher in both groups at T2, T3 and T4 than at T1, while at T4, the concentration of TNF-α in group H was higher than at T1 (P < 0.05). CONCLUSION: When the BIS value of the depth of anesthesia is 45, the perioperative release of inflammatory factors in elderly patients with laparoscopic radical gastrectomy for gastric cancer is less than BIS 55, and does not affect the prognosis.

Two new species and a new record of eriophyoid mites (Acari: Eriophyodea) from Guangxi, China.

Two new species of eriophyoid mites are described and illustrated from Guangxi, China: Acaphylla quercus sp. nov. collected on Quercus glauca Thunb. (Fagaceae), Rhyncaphytoptus miliusius sp. nov. collected on Miliusa sinensis Finet Gagnep. (Annonaceae). We further report Cecidodectes euzonus Nalepa, 1917, collected on Trema tomentosa (Roxb.) H.Hara (Cannabaceae), for the first time from China. All the species are vagrants on lower leaf surface causing no apparent damage to their host plants.

Two new Diptacus and one new Trimeroptes species (Acari: Diptilomiopidae) from China.

Two new Diptacus species and one new Trimeroptes species (Acari: Eriophyoidea: Diptilomiopidae) are described and illustrated from China: Diptacus suichangensis sp. nov. on Aralia chinensis L. (Araliaceae) and Diptacus pyracanthae sp. nov. on Pyracanthafortuneana (Maxim.) Li (Rosaceae), and Trimeroptes longlinensis sp. nov. on Carpinus sp. (Betulaceae). These new species were found to be vagrant on the lower surface of their associated plants leaves, albeit with no apparent damage observed.

8-Methoxypsoralen protects bovine mammary epithelial cells against lipopolysaccharide-induced inflammatory injury via suppressing JAK/STAT and NF-κB pathway.

Bovine mastitis is the most common disease in dairy cattle. Bacterial infections are the main cause of mastitis. Lipopolysaccharide (LPS), a major structural component of the cell wall of Escherichia coli, is a good inducer used to replicate inflammation models. 8-Methoxypsoralen (8-MOP), a formerly considered photosensitizing agent, has been used in immunotherapy. This study investigated the protective effects of 8-MOP on LPS-induced inflammatory injury in bovine mammary epithelial cells (BMECs). LPS treatment (50 µg/mL for 12 hr) caused a decrease in cell viability, morphological damage, and cell apoptosis. Pretreatment with 8-MOP at concentrations of 25 and 50 µg/ml significantly attenuated LPS-induced inflammation in BMECs. qRT-PCR analysis revealed that the messenger RNA expression of inflammatory cytokines and chemokine (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, and IL-8) was suppressed by 8-MOP in LPS-stimulated BMECs. Western blot analysis showed that 8-MOP could also reduce the protein levels of cyclooxygenase-2 and promote the translocation of high-mobility group box 1 from the nucleus to cytoplasm. Furthermore, the anti-inflammatory property of 8-MOP was mediated by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells activation and STAT1 phosphorylation. Taken together, 8-MOP could protect cells from inflammatory injury induced by LPS, and may be a potential agent against bovine mastitis.

Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance.

Diabetes mellitus (DM) can increase the risk of Alzheimer's disease (AD) in patients. However, no effective approaches are available to prevent its progression and development. Recently, autophagy dysfunction was identified to be involved in the pathogenesis of neurodegenerative diseases. This study was designed to investigate the effect of metformin on hyperphosphorylated tau proteins in diabetic encephalopathy (DE) by regulating autophagy clearance. db/db mice were randomly divided into four groups, db/+ mice were used as control group. Twelve-week old male db/db mice received consecutive intraperitoneal injection of 200 mg/kg/d metformin or (and) 10 mg/kg/d chloroquine for eight weeks. Morris water maze (MWM) tests were performed to test cognitive functions before the mice were euthanized. Metformin attenuated cognitive impairment in db/db mice, reduced hyperphosphorylated tau proteins, restored the impaired autophagy in diabetic mice, all of which were reversed by inhibiting of autophagy activity. In high glucose-cultured HT22 cells, metformin increased autophagy in a dose-dependent manner. Besides, metformin enhanced autophagy activity in an AMPK dependent manner. These data show that metformin may reduce tauopathy and improve cognitive impairment in db/db mice by modulating autophagy through the AMPK dependent pathway. These findings highlight metformin as a new therapeutic strategy for the treatment of DE.

DNA nanotriangle-scaffolded activatable aptamer probe with ultralow background and robust stability for cancer theranostics.

Activatable aptamers have emerged as promising molecular tools for cancer theranostics, but reported monovalent activatable aptamer probes remain problematic due to their unsatisfactory affinity and poor stability. To address this problem, we designed a novel theranostic strategy of DNA nanotriangle-scaffolded multivalent split activatable aptamer probe (NTri-SAAP), which combines advantages of programmable self-assembly, multivalent effect and target-activatable architecture. Methods: NTri-SAAP was assembled by conjugating multiple split activatable aptamer probes (SAAPs) on a planar DNA nanotriangle scaffold (NTri). Leukemia CCRF-CEM cell line was used as the model to investigate its detection, imaging and therapeutic effect both in vitro and in vivo. Binding affinity and stability were evaluated using flow cytometry and nuclease resistance assays. Results: In the free state, NTri-SAAP was stable with quenched signals and loaded doxorubicin, while upon binding to target cells, it underwent a conformation change with fluorescence activation and drug release after internalization. Compared to monovalent SAAP, NTri-SAAP displayed greatly-improved target binding affinity, ultralow nonspecific background and robust stability in harsh conditions, thus affording contrast-enhanced tumor imaging within an extended time window of 8 h. Additionally, NTri-SAAP increased doxorubicin loading capacity by ~5 times, which further realized a high anti-tumor efficacy in vivo with 81.95% inhibition but no obvious body weight loss. Conclusion: These results strongly suggest that the biocompatible NTri-SAAP strategy would provide a promising platform for precise and high-quality theranostics.

Ultra-pH-responsive split i-motif based aptamer anchoring strategy for specific activatable imaging of acidic tumor microenvironment.

A non-blocking split i-motif based aptamer anchoring strategy was developed as a general platform for sensing weakly acidic tumor microenvironment. By rationally tuning the response range to pH 7.0-6.4 and adjusting aptamer types, the strategy achieved specific, pHe-activated imaging of different cancers in vitro and in vivo.

Hairpin-Contained i-Motif Based Fluorescent Ratiometric Probe for High-Resolution and Sensitive Response of Small pH Variations.

Intracellular pH (pHi) is an important parameter associated with cellular behaviors and pathological conditions. Sensing pHi and monitoring its changes are essential but challenging due to the lack of high-sensitive probes. Herein, a ratiometric fluorescent probe with ultra pH-sensitivity is developed based on hairpin-contained i-motif strand (I-strand, labeled with Rhodamine Green and BHQ2 at two termini) and complementary strand (C-strand, labeled with Rhodamine Red at its 5'-end). At neutral pH, both I-strand and C-strand hybridize into a rigid duplex (I-C), which holds the Rhodamine Red and the BHQ2 in close proximity. As a result, the fluorescence emission (F597 nm) of the Rhodamine Red is strongly suppressed, while the Rhodamine Green (F542 nm) is in a "signal on" state. However, the slightly acidic pH enforced the I-strand to form an intramolecular i-motif and initiated the dehybridization of I-C duplex, leading to Rhodamine Red in a "signal on" state and a decreased fluorescence of Rhodamine Green. The ratio (F542 nm/F597 nm) can be used as a signal for pH sensing. Due to the rational internal hairpin design of I-C duplex probe, almost 70-fold change in the ratio was observed in the physiological pH range (6.50-7.40). This probe possesses efficient stability, fast response, and reversible pH measurement capabilities. Furthermore, intracellular application of the ratiometric probe was demonstrated on the example of SMMC-7721 cells. With different recognition elements in engineering of i-motif based platforms, the design might hold great potential to become a versatile strategy for intracellular pH sensing.

Temperature-responsive split aptamers coupled with polymerase chain reaction for label-free and sensitive detection of cancer cells.

A label-free and general thermo-controlled split apta-PCR strategy was first developed for the sensitive and specific detection of cancer cells. By integrating the temperature-responsive function of split aptamers with PCR amplification, a facile fluorescence assay of liver cancer SMMC-7721 cells was successfully realized with the detection of as low as 100 cells.

The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK/Sirt1 pathway.

Sarcopenia is an age-related syndrome characterized by progressive loss of muscle mass and function. Exercise is an important strategy to prolong life and increase muscle mass, and resveratrol has been shown a variety beneficial effects on skeletal muscle. In the present study, we investigated the potential efficacy of using short-term exercise (six weeks), resveratrol (150mg/kg/day), or combined exercise+resveratrol (150mg/kg/day) on gastrocnemius muscle mass, grip strength, cross-sectional area and microscopic morphology in aged rats, and explored the potential mechanism at the apoptosis level. Six months old SD rats were used as young control group and 24months old SD rats were adopted as aged group. After six weeks intervention, the data provide evidence that exercise, resveratrol or their combination significantly increase the relative grip strength and muscle mass in aged rats (P<0.05). Electron microscopy discovered a significant increase in sarcomere length, I-band and H-zone in aged rats (P<0.05), and exercise, resveratrol or their combination significantly reduced the increasement (P<0.05). Moreover, light microscopy revealed a significant increase on Feret's diameter and cross-sectional area (CSA) in aged rats (P<0.05), but exercise and resveratrol did not show significant effects on them (P>0.05). Furthermore, exercise, resveratrol or their combination significantly increased the expression of p-AMPK and SIRT1, decreased the expression of acetyl P53 and Bax/Bcl-2 ratio in aged rats (P<0.05). These findings show that aged rats show significant changes in gastrocnemius muscle morphology and ultrastructure, and the protective effects of exercise, resveratrol and their combination are probably associated with anti-apoptotic signaling pathways through activation of AMPK/Sirt1.

Relationship of miRNA-146a to primary Sjögren's syndrome and to systemic lupus erythematosus: a meta-analysis.

Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE) are common systemic autoimmune diseases, which impact not only patient health but also their quality of life. miRNA-146a is a microRNA that participates in the pathophysiology of SjS and SLE. In this investigation, we conducted a meta-analysis to determine the relationship of miR-146a to primary SjS (PSS) and to SLE. The following databases were interrogated; Pubmed, Cochrane Central Register of Controlled Trials, WANFANG, Chinese National Knowledge Infrastructure, and WEIPU. Standard mean difference with 95% confidence intervals (CI) were used to study the relationship between miRNA-146a expression and thee diseases by random-effects model. A total of six studies, with 158 cases and 124 controls were included for the meta-analysis. The meta-analysis shows that miRNA-146a expression is associated with the risk of PSS (MD = 6.32, p = 0.005). No relationship between miR-146a expression and SLE was identified (MD = -0.86, p = 0.26). SLE subgroup analysis (peripheral blood mononuclear cells and serum) confirmed this result. The risk for PSS is related to miR-146a expression, while miRNA-146a expression is not related to SLE. As such, miRNA-146a may serve as a novel biomarker for the diagnosis of PSS, but not SLE.

Nature-Inspired Smart DNA Nanodoctor for Activatable In Vivo Cancer Imaging and In Situ Drug Release Based on Recognition-Triggered Assembly of Split Aptamer.

DNA-based activatable theranostic nanoprobes are still unmet for in vivo applications. Here, by utilizing the "induced-fit effect", a smart split aptamer-based activatable theranostic probe (SATP) was first designed as "nanodoctor" for cancer-activated in vivo imaging and in situ drug release. The SATP assembled with quenched fluorescence and stable drug loading in its free state. Once binding to target proteins on cell surface, the SATP disassembled due to recognition-triggered reassembly of split aptamers with activated signals and freed drugs. As proof of concept, split Sgc8c against CEM cancer was used for theranostic studies. Benefiting from the design without blocking aptamer sequence, the SATP maintained an excellent recognition ability similar to intact Sgc8c. An "incubate-and-detect" assay showed that the SATP could significantly lower background and improve signal-to-background ratio (∼4.8 times of "always on" probes), thus affording high sensitivity for CEM cell analysis with 46 cells detected. Also, its high selectivity to target cells was demonstrated in analyzing mixed cell samples and serum samples. Then, using doxorubicin as a model, highly specific drug delivery and cell killing was realized with minimized toxicity to nontarget cells. Moreover, in vivo and ex vivo investigations also revealed that the SATP was specifically activated by CEM tumors inside mice. Especially, contrast-enhanced imaging was achieved in as short as 5 min, thus, laying a foundation for rapid diagnosis and timely therapy. As a biocompatible and target-activatable strategy, the SATP may be widely applied in cancer theranostics.

Tumor cell-specific split aptamers: target-driven and temperature-controlled self-assembly on the living cell surface.

An activatable split aptamer probe with target-induced shape change and thermosensitivity was developed. Triggered by proteins on the cell surface, the probe could assemble into a desired binding shape, thus affording a FRET-based tumor cell assay. Moreover, a reversible cell catch/release strategy was realized through mild temperature switching (4°C/37°C).

Placement of Teflon Sponges in Microvascular Decompression Procedure for Treatment of Hemifacial Spasm.

Background Hemifacial spasm (HFS) is generally treated by microvascular decompression (MVD). Inadequate separation of vessel and nerve or adhesive inflammation surrounding the nerve root may cause recurrence. Objective To explore a method to reduce the incidence of adhesions and to ensure sufficient separation of the offending vessel and nerve during MVD. Methods Fifty-one patients diagnosed with HFS were studied. During the MVD procedure, Teflon sponges were placed between the offending vessels and medulla oblongata to push compressing vessels away from the facial nerve without contacting the nerve. Results Our method of placement of the Teflon sponge effectively shifts the compressing artery and ensures that both the Teflon sponge and offending vessels do not contact the root exit zone. This method also ensures that the Teflon sponge is fixed in place. Conclusion The technique described for the treatment of HFS provides an effective, safe, and durable resolution to patient symptoms that minimizes surgical complications and may be useful in treating HFS.

Iodide-Responsive Cu-Au Nanoparticle-Based Colorimetric Platform for Ultrasensitive Detection of Target Cancer Cells.

Colorimetric analysis is promising in developing facile, fast, and point-of-care cancer diagnosis techniques, but the existing colorimetric cancer cell assays remain problematic because of dissatisfactory sensitivity as well as complex probe design or synthesis. To solve the problem, we here present a novel colorimetric analytical strategy based on iodide-responsive Cu-Au nanoparticles (Cu-Au NPs) combined with the iodide-catalyzed H2O2-TMB (3,3,5,5-tetramethylbenzidine) reaction system. In this strategy, bimetallic Cu-Au NPs prepared with an irregular shape and a diameter of ∼15 nm could chemically absorb iodide, thus indirectly inducing colorimetric signal variation of the H2O2-TMB system. By further utilizing its property of easy biomolecule modification, a versatile colorimetric platform was constructed for detection of any target that could cause the change of Cu-Au NPs concentration via molecular recognition. As proof of concept, an analysis of human leukemia CCRF-CEM cells was performed using aptamer Sgc8c-modified Cu-Au NPs as the colorimetric probe. Results showed that Sgc8c-modified Cu-Au NPs successfully achieved a simple, label-free, cost-effective, visualized, selective, and ultrasensitive detection of cancer cells with a linear range from 50 to 500 cells/mL and a detection limit of 5 cells in 100 µL of binding buffer. Moreover, feasibility was demonstrated for cancer cell analysis in diluted serum samples. The iodide-responsive Cu-Au NP-based colorimetric strategy might not only afford a new design pattern for developing cancer cell assays but also greatly extend the application of the iodide-catalyzed colorimetric system.

Masking agent-free and channel-switch-mode simultaneous sensing of Fe(3+) and Hg(2+) using dual-excitation graphene quantum dots.

A novel channel-switch-mode strategy for simultaneous sensing of Fe(3+) and Hg(2+) is developed with dual-excitation single-emission graphene quantum dots (GQDs). By utilizing the dual-channel fluorescence response performance of GQDs, this strategy achieved a facile, low-cost, masking agent-free, quantitative and selective dual-ion assay even in mixed ion samples and practical water samples.

A versatile activatable fluorescence probing platform for cancer cells in vitro and in vivo based on self-assembled aptamer/carbon nanotube ensembles.

Activatable aptamer probes (AAPs) have emerged as a promising strategy in cancer diagnostics, but existing AAPs remain problematic due to complex design and synthesis, instability in biofluids, or lack of versatility for both in vitro and in vivo applications. Herein, we proposed a novel AAP strategy for cancer cell probing based on fluorophore-labeled aptamer/single-walled carbon nanotube (F-apt/SWNT) ensembles. Through π-stacking interactions and proximity-induced energy transfer, F-apt/SWNT with quenched fluorescence spontaneously formed in its free state and realized signal activation upon targeting surface receptors of living cells. As a demonstration, Sgc8c aptamer was used for in vitro analysis and in vivo imaging of CCRF-CEM cancer cells. It was found that self-assembled Cy5-Sgc8c/SWNT held robust stability for biological applications, including good dispersity in different media and ultralow fluorescence background persistent for 2 h in serum. Flow cytometry assays revealed that Cy5-Sgc8c/SWNT was specifically activated by target cells with dramatic fluorescence elevation and showed improved sensitivity with as low as 12 CCRF-CEM cells detected in mixed samples containing ~100,000 nontarget cells. In vivo studies confirmed that specifically activated fluorescence was imaged in CCRF-CEM tumors, and compared to "always on" probes, Cy5-Sgc8c/SWNT greatly reduced background signals, thus resulting in contrast-enhanced imaging. The general applicability of the strategy was also testified by detecting Ramos cells with aptamer TD05. It was implied that F-apt/SWNT ensembles hold great potential as a simple, stable, sensitive, specific, and versatile activatable platform for both in vitro cancer cell detection and in vivo cancer imaging.