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Background: Mitochondria-nuclear cross-talk and mitochondrial retrograde regulation are involved in the genesis and development of breast cancer (BC). Therefore, mitochondria can be regarded as a promising target for BC therapeutic strategies. The present study aimed to construct regulatory network and seek the potential biomarkers of BC diagnosis and prognosis as well as the molecular therapeutic targets from the perspective of mitochondrial dysfunction. Methods: The microarray data of mitochondria-related encoding genes in BC cell lines were downloaded from GEO including GSE128610 and GSE72319. GSE128610 was treated as test set and validation sets consisted of GSE72319 and TCGA tissue samples, intending to identify mitochondria-related differentially expressed genes (mrDEGs). We performed enrichment analysis, PPI network, hub mrDEGs and overall survival analysis and constructed transcription factor (TF)-miRNA-hub mrDEGs network. Results: A total of 23 up-regulated and 71 down-regulated mrDEGs were identified and validated in BC cell lines and tissues. Enrichment analyses indicated that mrDEGs were associated with several cancer-related biological processes. Moreover, 9 hub mrDEGs were identified and validated in BC cell lines and tissues. Finally, 5 hub coregulated mrDEGs, 21 miRNAs and 117 TFs were used to construct TF-miRNA-hub mrDEGs network. MYC associated zinc finger protein (MAZ), heparin binding growth factor (HDGF) and Sp2 transcription factor (SP2) regulated 3 hub mrDEGs. Hsa-mir-21-5p, hsa-mir-1-3p, hsa-mir-218-5p, hsa-mir-26a-5p and hsa-mir-335-5p regulated 2 hub mrDEGs. Overall survival analysis suggested that the up-regulation of fibronectin 1 (FN1), as well as the down-regulation of discoidin domain receptor tyrosine kinase 2 (DDR2) correlated with unfavorable prognosis in BC. Conclusion: TF-miRNA-hub mrDEGs had instruction significance for the exploration of BC etiology. The hub mrDEGs such as FN1 and DDR2 were likely to regulate mitochondrial function and be novel biomarkers for BC diagnosis and prognosis as well as the therapeutic targets.

The regenerative effect of Epimedium and its major bioactive flavonoid icariin (ICA) have been documented in traditional medicine, but their effect on sarcopenia has not been evaluated. The aim of this study was to investigate the effects of Epimedium extract (EE) on skeletal muscle as represented by differentiated C2C12 cells. Here we demonstrated that EE and ICA stimulated C2C12 myotube hypertrophy by activating several, including IGF-1 signal pathways. C2C12 myotube hypertrophy was demonstrated by enlarged myotube and increased myosin heavy chains (MyHCs). In similar to IGF-1, EE/ICA activated key components of the IGF-1 signal pathway, including IGF-1 receptor. Pre-treatment with IGF-1 signal pathway specific inhibitors such as picropodophyllin, LY294002, and rapamycin attenuated EE induced myotube hypertrophy and MyHC isoform overexpression. In a different way, EE induced MHyC-S overexpression can be blocked by AMPK, but not by mTOR inhibitor. On the level of transcription, EE suppressed myostatin and MRF4 expression, but did not suppress atrogenes MAFbx and MuRF1 like IGF-1 did. Differential regulation of MyHC isoform and atrogenes is probably due to inequivalent AKT and AMPK phosphorylation induced by EE and IGF-1. These findings suggest that EE/ICA stimulates pathways partially overlapping with IGF-1 signaling pathway to promote myotube hypertrophy.

Distance measurements for extragalactic objects are a fundamental problem in astronomy 1 , 2 and cosmology 3 , 4 . In the era of precision cosmology, we urgently need better measurements of cosmological distances to observationally test the increasing H 0 tension of the Hubble constant measured from different tools 5 – 7 . Using spectroastrometry 8 , GRAVITY at The Very Large Telescope Interferometer successfully revealed the structure, kinematics and angular sizes of the broad-line region (BLR) of 3C 273 with an unprecedentedly high spatial resolution 9 . Fortunately, reverberation mapping (RM) 10 of active galactic nuclei (AGNs) reliably provides linear sizes of their BLRs 11 . Here, we report a joint analysis of spectroastrometry and RM observations to measure AGN distances. We apply this analysis to 3C 273 observed by both GRAVITY 9 and an RM campaign 12 , and find an angular distance of 551 . 5 − 78.7 + 97.3  Mpc and H 0 = 71 . 5 − 10.6 + 11.9 km s − 1 Mpc − 1 . The advantages of the analysis are its pure geometrical measurements and that it simultaneously yields the mass of the central black hole. Moreover, we can conveniently repeat measurements of selected AGNs to efficiently reduce the statistical and systematic errors. Future observations of a reasonably sized sample (~30 AGNs) will provide the distances of the AGNs and hence a new way of measuring H 0 with a high precision (≲3%) to test the H 0 tension. A joint analysis of spectroastrometry and reverberation mapping observations independently measures the distance to the active galaxy nucleus 3C 273 and the value of H 0 . Future observations of about 30 such sources will measure H 0 to less than 3% precision.

Background To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) have cardiovascular and renal protective effects in patients with advanced diabetic kidney disease (DKD) with an estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m 2 . Methods In this cohort study, patients with type 2 diabetes mellitus and eGFR < 30 mL/min per 1.73 m 2 with a first prescription for GLP-1RAs or dipeptidyl peptidase 4 inhibitors (DPP-4is) from 2012 to 2021 (n = 125,392) were enrolled. A Cox proportional hazard model was used to assess the cardiorenal protective effects between the GLP-1RA and DDP-4i groups. Results A total of 8922 participants [mean (SD) age 68.4 (11.5) years; 4516 (50.6%) males; GLP-1RAs, n = 759; DPP-4is, n = 8163] were eligible for this study. During a mean follow-up of 2.1 years, 78 (13%) and 204 (13.8%) patients developed composite cardiovascular events in the GLP-1RA and DPP-4i groups, respectively [hazard ratio (HR) 0.88, 95% confidence interval CI 0.68–1.13]. Composite kidney events were reported in 134 (38.2%) and 393 (44.2%) patients in the GLP-1RA and DPP-4i groups, respectively (subdistribution HR 0.72, 95% CI 0.56–0.93). Conclusions GLP-1RAs had a neutral effect on the composite cardiovascular outcomes but reduced composite kidney events in the patients with advanced DKD compared with DPP-4is.

Type 1 active galactic nuclei display broad emission lines, which are regarded as arising from photoionized gas moving in the gravitational potential of a supermassive black hole 1 , 2 . However, the origin of this broad-line region gas is unresolved so far 1 – 3 . Another component is the dusty torus 4 beyond the broad-line region—probably an assembly of discrete clumps 5 – 7 —which can hide the region from some viewing angles and make them observationally appear as type 2 objects. Here, we report that these clumps moving within the dust sublimation radius, such as the molecular cloud G2 discovered in the Galactic Centre 8 , will be tidally disrupted by the black hole, resulting in some gas becoming bound at smaller radii while other gas is ejected and returns to the torus. The clumps fulfill necessary conditions to be photoionized 9 . Specific dynamical components of tidally disrupted clumps include spiral-in gas as inflow, circularized gas and ejecta as outflow. We calculated various profiles of emission lines from these clouds, and found that they generally agree with H β profiles of Palomar–Green quasars 10 . We found that the asymmetry, shape and shift of the profiles strongly depend on [O  iii ] luminosity, which we interpret as a proxy of dusty torus angles. Tidally disrupted clumps from the torus may represent the source of the broad-line region gas. The origin of the broad-line emission from type-1 active galactic nuclei is unclear. Calculations of emission lines from dusty clumps that are tidally disrupted by the central black hole suggest that these clumps give rise to the broad-line emission.

Despite huge efforts have been devoted to investigating ultrathin layers of two-dimensional (2D) transition-metal dichalcogenides (TMDs), their realistic applications in electronics and optoelectronics are hindered by limited scalability and uniformity of 2D thin layers. In this work, a two-step synthesis method was adopted to produce wafer-scale molybdenum diselenide (MoSe 2 ) nanosheets. Molybdenum oxide (MoO 3 ) thin film was initially prepared via atomic layer deposition (ALD) and followed by a selenization process in chemical vapor deposition (CVD) tube furnace. MoSe 2 nanosheets with desired thickness can be obtained by tuning ALD cycles in preparing MoO 3 layers. The synthesized MoSe 2 films exhibited excellent layer controllability, homogeneity and wafer-scale uniformity. Few-layer structure of our MoSe 2 with a polycrystalline crystal structure was verified by means of Raman and transmission electron microscopy (TEM) measurements. Moreover, arrays of MoSe 2 -based photodetectors with different device dimension were fabricated and the photo-responses of the devices were studied. The device exhibited a fast photo-response time of 50 ms, a high on/off ratio of ~ 24 and a good photo-responsivity of 11.7 mA/W, and it is found that the effective illumination area was a critical factor for application. The work opens up an attractive approach to realize the application of wafer-scale 2D materials in integrated optoelectronic-systems.

Many patients with papillary thyroid cancer (PTC) demonstrate satisfactory outcomes. However, 8%-28% of patients with PTC show tumor recurrence, which may affect prognosis. Therefore, identifying factors associated with tumor recurrence in patients with PTC may be helpful to refine therapeutic strategies. To identify factors associated with PTC recurrence, we retrospectively reviewed demographic features (sex and age), operation method, image character, serum thyroglobulin (Tg), accumulated radioactive iodine (I-131) therapeutic dose, I-131 uptake, and metastases at diagnosis in 829 patients with PTC. Patients were grouped into early (stage I and II; n = 698) and advanced (stage III and IV; n = 131) tumor-node-metastasis (TNM) stages. Recurrence rate, mortality rate, risk factors of recurrence, recurrent free survival and overall survival curve were compared between two groups. Patients in the early stage demonstrated a lower recurrence rate (7.2%) than did those in the advanced stage (28.2%, p < 0.05). The mortality rate of patients with recurrence in the advanced stage was higher than that of those in the early stage (51.4% vs. 12.0%). The major impact factors on tumor recurrence in early TNM stage were distant metastasis and lymph node metastasis, while in advanced TNM stage were distant metastasis, male gender, total thyroidectomy with limited lymph node dissection, and a high serum Tg level. Strategies to monitor tumor recurrence might be refined according to the TNM stages of PTC patients.

Mitochondria determine the physiological status of most eukaryotes. Mitochondrial dynamics plays an important role in maintaining mitochondrial homeostasis, and the disorder in mitochondrial dynamics could affect cellular energy metabolism leading to tumorigenesis. In recent years, disrupted mitochondrial dynamics has been found to influence the biological behaviors of gastrointestinal cancer with the potential to be a novel target for its individualized therapy. This review systematically introduced the role of mitochondrial dynamics in maintaining mitochondrial homeostasis, and further elaborated the effects of disrupted mitochondrial dynamics on the cellular biological behaviors of gastrointestinal cancer as well as its association with cancer progression. We aim to provide clues for elucidating the etiology and pathogenesis of gastrointestinal cancer from the perspective of mitochondrial homeostasis and disorder.

Angiotensin receptor blockers (ARBs) may have protective effects against dementia occurrence in patients with hypertension (HTN). However, whether telmisartan, an ARB with peroxisome proliferator-activated receptor [gamma] (PPAR-[gamma])-modulating effects, has additional benefits compared to other ARBs remains unclear. Between 1997 and 2013, 2,166,944 type 2 diabetes mellitus (T2DM) patients were identified from the National Health Insurance Research Database of Taiwan. Patients with HTN using ARBs were included in the study. Patients with a history of stroke, traumatic brain injury, or dementia were excluded. Finally, 65,511 eligible patients were divided into 2 groups: the telmisartan group and the non-telmisartan ARB group. Propensity score matching (1:4) was used to balance the distribution of baseline characteristics and medications. The primary outcome was the diagnosis of dementia. The secondary outcomes included the diagnosis of Alzheimer disease and occurrence of symptomatic ischemic stroke (IS), any IS, and all-cause mortality. The risks between groups were compared using a Cox proportional hazard model. Statistical significance was set at p < 0.05. There were 2,280 and 9,120 patients in the telmisartan and non-telmisartan ARB groups, respectively. Patients in the telmisartan group had a lower risk of dementia diagnosis (telmisartan versus non-telmisartan ARBs: 2.19% versus 3.20%; HR, 0.72; 95% CI, 0.53 to 0.97; p = 0.030). They also had lower risk of dementia diagnosis with IS as a competing risk (subdistribution HR, 0.70; 95% CI, 0.51 to 0.95; p = 0.022) and with all-cause mortality as a competing risk (subdistribution HR, 0.71; 95% CI, 0.53 to 0.97; p = 0.029). In addition, the telmisartan users had a lower risk of any IS (6.84% versus 8.57%; HR, 0.79; 95% CI, 0.67 to 0.94; p = 0.008) during long-term follow-up. Study limitations included potential residual confounding by indication, interpretation of causal effects in an observational study, and bias caused by using diagnostic and medication codes to represent real clinical data. The current study suggests that telmisartan use in hypertensive T2DM patients may be associated with a lower risk of dementia and any IS events in an East-Asian population.

Background Sodium-glucose co-transporter 2 inhibitors (SGLT2i) has shown evidence of cardiovascular benefit in patients with type 2 diabetes mellitus (T2DM). Currently metformin is the guideline-recommended first-line treatment. We aimed to investigate the benefit of SGLT2i vs metformin as first-line therapy. Methods Electronic medical records from Chang Gung Research Database during 2016–2019 were retrieved for patients with T2DM. Patients aged < 20, not receiving anti-diabetic medication, first-line treatment neither metformin nor SGLT2i were excluded. Primary outcomes were heart failure hospitalization, acute coronary syndrome, ischemic stroke, and all-cause mortality. Patients were followed up for events or December 31, 2019, whichever comes first. Results After exclusion criteria, a total of 41,020 patients with T2DM were eligible for analysis. There were 1100 patients with SGLT2i as first-line and 39,920 patients with metformin as first-line treatment. IPTW was used for propensity score matching. During one year follow-up, the hazard ratio (HR) of patients on SGLT2i as first-line treatment to patients on metformin as first-line treatment were HR 0.47 (95% CI 0.41–0.54, p < 0.0001) in heart failure hospitalization, HR 0.50 (95% CI 0.41–0.61, p < 0.0001) in acute coronary syndrome, HR 1.21 (95% CI 1.10–1.32, p < 0.0001) in ischemic stroke, and HR 0.49 (95% CI 0.44–0.55, p < 0.0001) in all-cause mortality. Conclusions In patients with T2DM, SGLT2i as first-line treatment may be associated with decreased events of heart failure hospitalization, acute coronary syndrome, and all-cause mortality, compared with metformin as first-line treatment. However, there may be an increased events of ischemic stroke using SGLT2i compared to metformin.