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Objective. The objective of this study is to explore the utilization of next-generation sequencing (NGS) technology in evaluating the likelihood of identifying individuals with papillary thyroid microcarcinoma (PTMC ≤10 mm) who are at high or low risk. Design. NGS was used to analyze 393 formalin-fixed, paraffin-embedded tissues of PTC tumors, all of which were smaller than 15 mm. Results. The study found that bilateralism, multifocality, intrathyroidal spread, and extrathyroidal extension were present in 84 (21.4%), 153 (38.9%), 16 (4.1%), and 54 (13.7%) cases, respectively. Metastasis of cervical lymph nodes was identified in 226 (57.5%) cases and 96 (24.4%) cases with CLNM >5. Out of the total number of cases studied, 8 cases (2.3%) showed signs of tumor recurrence, all of which were localized and regional. Genetic alterations were detected in 342 cases (87.0%), with 336 cases revealing single mutations and 6 cases manifesting compound mutations. 332 cases (84.5%) had BRAFV600E mutation, 2 cases had KRASQ61K mutation, 2 cases had NRASQ61R mutation, 8 cases had RET/PTC1 rearrangement, 3 cases had RET/PTC3 rearrangement, and 1 case had TERT promoter mutation. Additionally, six individuals harbored concurrent mutations in two genes. These mutations were of various types and combinations: BRAFV600E and NRASQ61R (n = 2), BRAFV600E and RET/PTC3 (n = 2), BRAFV600E and RET/PTC1 (n = 1), and BRAFV600E and TERT promoter (n = 1). The subsequent analysis did not uncover a significant distinction in the incidence of gene mutation or fusion between the cN0 and cN1 patient cohorts. The presence of BRAFV600E mutation and CLNM incidence rates were found to be positively correlated with larger tumor size in PTMC. Our data showed that gene mutations did not appear to have much to do with high-risk papillary thyroid microcarcinoma (PTMC). However, when we looked at tumor size, we found that if the tumor was at least 5 millimeters in size, there was a higher chance of it being at high risk for PTM (P < 0.001 , odds ratio (OR) = 2.55, 95% confidence interval (CI): 1.57–4.14). Identification of BRAFV600E mutation was not demonstrated to be significantly correlated with advanced clinicopathological characteristics, although it was strongly associated with a bigger tumor diameter (OR = 4.92, 95% CI: 2.40–10.07, P < 0.001). Conclusion. In clinical practice, BRAFV600E mutation does not consistently serve as an effective biomarker to distinguish high-risk PTMC or predict tumor progression. The size of the tumor has a significant correlation with its aggressive characteristics. PTMC with a diameter of ≤5 mm should be distinguished and targeted as a unique subset for specialized treatment. [ABSTRACT FROM AUTHOR]

Prunella vulgaris has long been used in traditional medicine and is consumed as a tea in China. Here, the total phenolic and flavonoid concentrations of plants from different geographical regions were measured. It was found that the total phenolic acid concentration ranged from 4.15 to 8.82 g of gallic acid equivalent per 100 g of dry weight (DW), and the total flavonoid concentration was 4.67–7.33 g of rutin equivalent per 100 g DW. Antioxidant activities were measured using 2,2‐diphenyl‐1‐picrylhydrazyl and 2,2′‐azino‐bis‐(3‐ethylbenzothiazoline‐6‐sulfonic acid) diammonium salt, and the results ranged from 73.47% to 94.43% and 74.54% to 93.39%, respectively, whereas α‐glucosidase inhibition was between 75.31% and 95.49%. Correlation analysis showed that the total flavonoids in P. vulgaris had superior antioxidant and anti‐α‐glucosidase activities compared to the total phenolic compounds. The active components of P. vulgaris were analyzed using high‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry combined with both classical molecular networking and feature‐based molecular networking on the Global Natural Products Social platform, identifying 32 compounds, namely 14 flavonoids, 12 phenolic compounds, and 6 other chemical components. These results could provide useful information on the use of P. vulgaris as a functional tea. [ABSTRACT FROM AUTHOR]

Owing to their simple and convenient synthesis, the application of metal–organic gels (MOGs) in fluorescence detection has been increasingly studied. However, most relevant studies are based on the fluorescence changes of MOGs themselves caused by the direct interaction between the target and MOG, resulting in limited universality and insufficient sensitivity and other shortcomings. Thus, we combined a Cu-based metal–organic gel (Cu-MOG) with an entropy-driven circuit (EDC), as an isothermal enzyme-free amplification technique, to detect miR-155 as a proof-of-principle target. The substrate for the EDC was designed as a three-strand duplex (TD) containing an output strand (OS) which was modified with 6-carboxyfluorescein (FAM). In the presence of the target, namely miR-155, the EDC was triggered and OS was released, making the OS transition from the hybrid state to the free state. The fluorescence of the FAM modified free OS strand was then quenched owing to the intramolecular photo-induced electron transfer (PET) of the new ground state complex formed between the OS and MOG with a quenching constant of 1.48 mL μg−1, which is much higher than that (0.08 mL μg−1) of the hybrid state OS. This method provided a dynamic detection range of 1 nM to 5 nM with a detection limit of 0.23 nM for miR-155, demonstrating that the Cu-MOG coupled EDC has promising applications in bioassays, and opens up a new application field of MOGs in EDC development. [ABSTRACT FROM AUTHOR]

This study is the first to assess the safety and therapeutic efficacy of vagus nerve stimulation (VNS) as an adjunctive treatment for Chinese patients suffering from treatment-resistant depression (TRD). A total of seven patients with TRD underwent surgical implantation of a VNS device were followed over a 9-month period. The 24-item Hamilton Rating Scale for Depression (HAMD-24) and the 14-item Hamilton Anxiety Scale (HAMA) were used to assess depressive and anxiety symptoms, respectively. Neurocognitive function was measured with the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scale (WMS). After 3 months of treatment with VNS, the antidepressant response and remission rates were 42.9% and 28.6%, respectively. After 9 months of treatment with VNS, the response and remission rates increased to 85.7% and 57.1%, respectively. Significant time main effects were identified for HAMD-24 scores, HAMA scores, the WMS memory quotient, and the full intelligence quotients measured with the WAIS (all ps < 0.05). The most frequent adverse effects of VNS treatment were voice alteration (100%) and cough frequency increase (71.4%). This preliminary study indicated that adjunctive VNS was effective and safe in treating Chinese patients who were suffering from TRD, and its efficacy increased with time. There is positive evidence to support the role of VNS as an adjunctive treatment in Chinese patients with TRD. The antidepressant efficacy of adjunctive VNS for Chinese patients with TRD increased with time. The most frequent adverse effects of VNS treatment were voice alteration and cough frequency increase. [ABSTRACT FROM AUTHOR]

Our recent studies suggest that 1,25-dihydroxyvitamin [D.sub.3] functions as an endocrine suppressor of renin biosynthesis. Genetic disruption of the vitamin D receptor (VDR) results in overstimulation of the reninangiotensin system (RAS), leading to high blood pressure and cardiac hypertrophy. Consistent with the higher heart-to-body weight ratio, the size of left ventricular cardiomyocytes in VDR knockout (KO) mice was markedly increased compared with wild-type (WT) mice. As expected, levels of atrial natriuretic peptide (ANP) mRNA and circulating ANP were also increased in VDRKO mice. Treatment of VDRKO mice with captopril reduced cardiac hypertrophy and normalized ANP expression. To investigate the role of the cardiac RAS in the development of cardiac hypertrophy, the expression of renin, angiotensinogen, and AT-1a receptor in the heart was examined by real-time RT-PCR and immunostaining. In VDRKO mice, the cardiac renin mRNA level was significantly increased, and this increase was further amplified by captopril treatment. Consistently, intense immunostaining was detected in the left ventricle of captopril-treated WT and VDRKO mice by use of an anti-renin antibody. Levels of cardiac angiotensinogen and AT-1a receptor mRNAs were unchanged in the mutant mice. These data suggest that the cardiac hypertrophy seen in VDRKO mice is a consequence of activation of both the systemic and cardiac RAS and support the notion that 1,25-dihydroxyvitamin [D.sub.3] regulates cardiac functions, at least in part, through the RAS. atrial natriuretic peptide; cardiomyocyte; hypertension; captopril

Peritoneal fibrosis (PF) is a disease caused by prolonged exposure of the peritoneum to high levels of dialysis fluid. Astragalus total saponins (ATS) is a phytochemical naturally occurring in Radix Astragali that has anti-inflammatory and anti-oxidant properties. In this study, we constructed an in vivo model of PF using 4.25% glucose-containing administered intraperitoneally to rats and incubated peritoneal mesothelial cells (PMCs) with 4.25% glucose-containing peritoneal dialysis fluid to construct an in vitro model of PF. Furthermore, siRNA of PGC-1 α was used to inhibit the expression of PGC-1 α to further investigate the mechanism of the protective effect of ATS on PF. In both in vivo and in vitro models, ATS treatment showed a protective effect against PF, with ATS reducing the thickness of peritoneal tissues in PF rats, increasing the viability of PMCs, increasing the mitochondrial membrane potential and reducing apoptosis ratio. ATS treatment also reduced the expressions of peritoneal fibrosis markers (Smad2, p-Smad2 and α -SMA) and apoptosis markers (Caspase3, cleaved-Caspase3 and Bax) and restored the expressions of mitochondrial synthesis proteins (PGC-1 α , NRF1 and TFAM) in ATS-treated peritoneal tissues or PMCs. Furthermore, in the presence of PGC-1 α inhibition, the protective effect of ATS on PF was blocked. In conclusion, ATS treatment may be an effective therapeutic agent to inhibit high glucose-induced in peritoneal fibrosis through PGC-1 α -mediated apoptosis. [ABSTRACT FROM AUTHOR]

Abstract Background Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2) activity have been suggested to contribute to the pathogenesis of HD, however unique casp2 cleavage substrates have remained elusive. We thus utilized mice completely lacking casp2 (casp2-/-) to examine the role played by casp2 in the progression of HD. This 'substrate agnostic' approach allows us to query the effect of casp2 on HD progression without pre-defining proteolytic substrates of interest. Results YAC128 HD model mice lacking casp2 show protection from well-validated motor and cognitive features of HD, including performance on rotarod, swimming T-maze, pre-pulse inhibition, spontaneous alternation and locomotor tasks. However, the specific pathological features of the YAC128 mice including striatal volume loss and testicular degeneration are unaltered in mice lacking casp2. The application of high-resolution magnetic resonance imaging (MRI) techniques validates specific neuropathology in the YAC128 mice that is not altered by ablation of casp2. Conclusions The rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD.

Inspired by the specific optical properties of DNA photonic nanowires (PNs) on which fluorescent dyes are to be precisely positioned and photonic energy transfer over nanometers can be achieved, herein, we develop a DNA PN-based homogeneous entropy-driven biomolecular assay (HEBA). Using homogeneous Förster resonance energy transfer (FRET) of Cy3, we constructed a DNA PN capable of transferring energy from the green donor dye (FAM) to the red acceptor fluorophore (Cy5) across a total distance of 10.2 nm with an end-to-end transfer efficiency of 13.2%. By taking DNA PNs as the substrate of entropy-driven circuit, thrombin was detected as a proof-of-principle target. The trigger of HEBA by thrombin, during which separation of Cy3, FAM, and Cy5 occurred and the FRET of the PN got interrupted, resulted in a high value of signal-to-background ratio (S/B, signal and background were FFAM/FCy5 in the presence and absence of thrombin, respectively), giving a detection dynamic range of 5–25 nM with a detection limit of 2.7 nM. This strategy offers an alternative platform for biomarker clinical diagnosis, greatly expanding the application fields of DNA PNs to analytical chemistry. [ABSTRACT FROM AUTHOR]

The glucagon-like peptide-1 receptor agonist exenatide (EXT) is an effective treatment for type 2 diabetes. However, this peptide has a short biological half-life and the delayed release characteristic of current formulations limit its clinical application. Herein, we prepared EXT-loaded inside-porous poly(d,l-lactic-co-glycolic acid (PLGA) microspheres with outside layers (EXT-PMS) using a W1/O/W2 emulsion method with a microfluidic technique and its fabrication and formulation conditions were systematically investigated. In vitro dissolution experiments showed that the PLGA concentration, proportion of drug and oil phase, and the number and size of pores strongly affected the release behaviors of EXT-PMS. In vitro, the optimized EXT-PMS with large internal pores exhibited rapid and stable release without a lag phase. In a rat model, subcutaneous administration of the product yielded plasma concentrations of EXT that was sustained for 30 days with low burst and no delayed-release effect. The preparation of inside-porous microspheres is lighting up the development of long-acting drug delivery systems for other drugs with favorable release characteristics. [ABSTRACT FROM AUTHOR]