Acute Changes in the Resting Brain Networks in Concussion Patients: Small-World Topology Perspective.

BACKGROUND: The acute changes that occur in the small-world topology of the brain in concussion patients remain unclear. Here, we investigated acute changes in the small-world organization of brain networks in concussion patients and their influence on persistent post-concussion symptoms. METHODS: Eighteen concussion patients and eighteen age-matched controls were enrolled in this study. All participants underwent computed tomography, magnetic resonance imaging (MRI), susceptibility weighted imaging, and blood oxygen level-dependent functional MRI. A complex network analysis method based on graph theory was used to calculate the parameters of small-world networks under different degrees of network sparsity. All subjects were evaluated using the Glasgow Coma Scale and Rivermead Postconcussion Symptom Questionnaire. RESULTS: Compared with the controls, the normalized cluster coefficient (γ) of whole brain networks in patients and the "small-world" index (σ) was slightly enhanced, whereas the standardized minimum path (λ) was slightly shorter. Whole brain effect (Eglobal) and local effect (Elocal) changes were not pronounced. Under the condition of minimum network sparsity (Dmin = 0.13), the numbers of nodes in the "right intraorbital superior frontal gyrus" (Anatomical Automatic Labeling, AAL26), right globus pallidus (AAL76), and bilateral temporal transverse gyrus (AAL79,80) in brain concussion patients were significantly lower. The numbers of nodes in the left subcapital lobe (AAL61) and left occipital gyrus (AAL51) were significantly higher, and the normalized cluster coefficients of the right intraorbital supraphalus (AAL26) and left posterior cingulate gyrus (AAL35) were significantly increased. The normalized clustering coefficients of the right triangular subfrontal gyrus (AAL55) (based on the normalized clustering coefficients of nodes in AAL14) and left sub-parietal lobes (AAL61) were significantly reduced. The mean local effects of nodes in the right intraorbital upper frontal gyrus (AAL26), left posterior cingulate gyrus (AAL35), and bilateral auxiliary motor cortex (AAL19, 20) were enhanced, whereas the mean local effects of the bilateral triangular inferior frontal gyrus (AAL13,14) and left insular cap (AAL11) were reduced (p < 0.05). CONCLUSIONS: The overall trend of network topology abnormalities in patients was random, and generalized and local functional abnormalities were seen. Changes in the function and affective circuitry of the resting default network were particularly pronounced in these patients, which we speculate may be one of the main drivers of the cognitive dysfunction and mood changes seen in concussion patients.

KLF14/miR-1283/TFAP2C axis inhibits HER2-positive breast cancer progression via declining tumor cell proliferation.

MiR-1283 has been identified as a tumor suppressor in some malignancies. Whereas, the role of miR-1283 in HER2-positive (HER2+) breast cancer, particularly its role in regulating cell proliferation, one of the most significant features of tumor progression, is unclear. The related microRNA screened by the breast cancer sample GSE131599 dataset were detected in HER2+ breast cancer tissues and cell lines. Then, the obtained miR-1283 was overexpressed in SKBR3 and BT-474 cells followed by relevant functional assays concerning cell proliferation and apoptosis. The xenograft mouse model was induced and the effect of miR-1283 on tumor growth and cell proliferation was examined. The target of miR-1283 and the transcription factor regulating miR-1283 were predicted and identified. Finally, the influence of transcription factor KLF14 on cell proliferation and apoptosis was investigated. An integrated analysis confirmed that miR-1283 expression was significantly decreased in HER2+ breast cancer tissues. Also, by q-RT-PCR detection, miR-1283 expression was markedly reduced in HER2+ breast cancer tissues and cell lines. The miR-1283 overexpression prevented the proliferation and enhanced apoptosis of HER2+ breast cancer cells, as well as inhibited tumor growth. Mechanistically, miR-1283 inhibited TFAP2C expression by targeting the 3'-untranslated regions of TFAP2C messenger RNA, and the KLF14 enhanced miR-1283 level via binding to its promoter. The result subsequently confirmed the KLF14/miR-1283 signaling suppressed cell proliferation in HER2+ breast cancer. Our results suggested that the KLF14/miR-1283/TFAP2C axis inhibited HER2+ breast cancer progression, which might provide novel insight into mechanical exploration for this disease.

Circular RNA circ-ERBB2 promotes HER2-positive breast cancer progression and metastasis via sponging miR-136-5p and miR-198.

BACKGROUND: Circular RNAs (circRNAs) are pivotal regulators of various human cancers and circ-ERBB2 is abnormally expressed in breast cancer cells. However, the role and mechanism of circ-ERBB2 in HER2-positive breast cancer are still unknown. METHODS: The circ-ERBB2 expressions in the tumor tissues of HER2-positive breast cancer patients were tested using quantitative real-time PCR. The circ-ERBB2 function was investigated by cell counting kit 8 assay, Transwell, flow cytometry and Western blot. Mechanistically, fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and dual-luciferase reporter gene assays were conducted to confirm the interaction between circ-ERBB2 and miR-136-5p or miR-198 in HER2-positive breast cancer cells. RESULTS: Circ-ERBB2 was elevated in the tumor tissues of HER2-positive breast cancer patients. Functionally, the interference with circ-ERBB2 repressed HER2-positive breast cancer cell proliferation, migration, invasion and accelerated cell apoptosis. Furthermore, the mechanistic analysis corroborated that circ-ERBB2 acted as a competing endogenous RNA for miR-136-5p or miR-198 to relieve the repressive influence of miR-136-5p or miR-198 on its target transcription factor activator protein 2C (TFAP2C). Meanwhile, in vivo assays further corroborated the oncogenic function of circ-ERBB2 in HER2-positive breast cancer. CONCLUSIONS: Circ-ERBB2 accelerated HER2-positive breast cancer progression through the circ-ERBB2/miR-136-5p/TFAP2C axis or the circ-ERBB2/miR-198/TFAP2C axis.

Differential diagnosis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma based on spatial and channel attention mechanisms.

BACKGROUND: The pre-operative non-invasive differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) mainly depends on imaging. However, the accuracy of conventional imaging and radiomics methods in differentiating between the two carcinomas is unsatisfactory. In this study, we aimed to establish a novel deep learning model based on computed tomography (CT) images to provide an effective and non-invasive pre-operative differential diagnosis method for HCC and ICC. MATERIALS AND METHODS: We retrospectively investigated the CT images of 395 HCC patients and 99 ICC patients who were diagnosed based on pathological analysis. To differentiate between HCC and ICC we developed a deep learning model called CSAM-Net based on channel and spatial attention mechanisms. We compared the proposed CSAM-Net with conventional radiomic models such as conventional logistic regression, least absolute shrinkage and selection operator regression, support vector machine, and random forest models. RESULTS: With respect to differentiating between HCC and ICC, the CSAM-Net model showed area under the receiver operating characteristic curve (AUC) values of 0.987 (accuracy = 0.939), 0.969 (accuracy = 0.914), and 0.959 (accuracy = 0.912) for the training, validation, and test sets, respectively, which were significantly higher than those of the conventional radiomics models (0.736-0.913 [accuracy = 0.735-0.912], 0.602-0.828 [accuracy = 0.647-0.818], and 0.638-0.845 [accuracy = 0.618-0.849], respectively. The decision curve analysis showed a high net benefit of the CSAM-Net model, which suggests potential efficacy in differentiating between HCC and ICC in the diagnosis of liver cancers. CONCLUSIONS: The proposed CSAM-Net model based on channel and spatial attention mechanisms provides an effective and non-invasive tool for the differential diagnosis of HCC and ICC on CT images, and has potential applications in diagnosis of liver cancers.

Effects of amiloride on potassium and calcium currents in guinea pig ventricular myocytes.

AIM: To elucidate the possible mechanisms underlying antiarrhythmia of the non-selective Na+/H+ exchanger inhibitor--amiloride. METHODS: Single ventricular cells were isolated using a double-enzyme method. Effects of amiloride on voltage-dependent potassium and calcium currents in isolated guinea pig ventricular myocyte were recorded by using whole-cell patch clamp techniques. RESULTS: Exposure to amiloride (10 -100 micromol x L(-1)), the L-type and T-type calcium currents were depressed. Amiloride resulted in a concentration-dependent inhibition of peak (Ca,L), But amiloride did not change the shape of their I - V curves. It only decreased the amplitudes of the currents of the two types. When myocytes were incubated with 100 micromol x L(-1) amiloride, I(Kr) was slightly depressed and I(Ks) did not change. Amiloride (1 - 100 micromol x L(-10) depressed I(K1) in a concentration-dependent manner. CONCLUSION: Amiloride depressed potassium and calcium currents, which may give support to its uses in some diseases of the cardiovascular system.

Effects of benzyltetrahydropalmatine on the rapidly activating component of delayed rectifier potassium current in guinea pig ventricular myocytes.

AIM: To investigate the effect of benzyltetrahydropalmatine (BTHP) on the rapidly activating component of delayed rectifier K+ current (Ikr) in single guinea pig ventricular myocytes. METHODS: Whole-cell patch clamp technique was used to record Ikr. RESULTS: Ikr was blocked by 1-100 mumol.L-1 BTHP in concentration-, voltage-, and specifically frequency-dependent fashion, with IC50 of 13.5 mumol.L-1 (95% confidence range: 11.2-15.8 mumol.L-1). 30 mumol.L-1 BTHP reduced Ikr and Ikr.tail by (31 +/- 4)% and (36 +/- 5)% (n = 6, P < 0.01), respectively. The time constant for deactivation (tau') of the tail current was decreased by 30 mumol.L-1 BTHP from (238 +/- 16) ms to (196 +/- 14) ms, while drug had no any effect on the time constant for activation (tau) of Ikr,tail. CONCLUSION: BTHP inhibited Ikr in a frequency-dependent fashion.

Effects of benzyltetrahydropalmatine on potassium currents in guinea pig and rat ventricular myocytes.

AIM: To investigate the effects of benzyltetrahydropalmatine (BTHP) on rapidly activating component (I(Kr)), slowly activating component (I(Ks)) of delayed rectifier potassium current, inward rectifier potassium current (I(K1)), and transient outward potassium current (I(to)) in single ventricular myocytes. METHODS: Whole-cell patch clamp technique was used to record ionic currents. RESULTS: (1) BTHP 30 micromol/L reduced I(Kr) and I(Kr,tail) by 31 %+/-4 % and 36 %+/-5 % (n=6, P <0.01), respectively and inhibited I(Ks) and I(Ks,tail) by 40 %+/-6 % and 45 %+/-5 % (n=7, P <0.01), respectively. I(Kr) and I(Ks) were blocked by BTHP 1-100 micromol/L in a concentration-dependent fashion (IC50 value was 13.5 micromol/L and 95 % confidence limit: 11.2-15.8 micromol/L for I(Kr), 9.3 micromol/L and 95 % confidence limit: 7.8-11.8 micromol/L for I(Ks), respectively). (2) BTHP 5 micromol/L inhibited I(to) by 63 %+/-6 % (n=6, P <0.01). BTHP 1-100 micromol/L reduced I(to) in a concentration-dependent manner (IC50 value was 3.6 micromol/L and 95 % confidence limit: 2.9-4.3 micromol/L). (3) BTHP 200 micromol/L did not affect I(K1). CONCLUSION: BTHP inhibited I(Kr), I(Ks), and I(to), but not I(K1). The antiarrhythmic effects of BTHP may be mainly due to its blockade on potassium channels.

Perforated patch recording of L-type calcium current with beta-escin in guinea pig ventricular myocytes.

AIM: To establish a perforated patch recording (PPR) mode with beta-escin and compare L-type calcium current (I(Ca,L)) recorded under PPR and normal whole-cell recording (WCR) condition in isolated guinea-pig ventricular myocytes. METHODS: Single myocytes were dissociated by enzymatic dissociation method. beta-escin was added to the pipette solution to perforate the cell membrane and obtain PPR mode. I(Ca,L) was recorded using PPR and WCR techniques. RESULTS: beta-Escin 20, 25, and 30 micromol/L could permeabilize the cell membrane and obtain PPR mode. With beta-escin 25 micromol/L, the success rate was highest (16/17, 94 %) and the time required for permibilization was 2-15 (8+/-4) min. Run-down of I(Ca,L) was considerably slower in PPR than in WCR condition. The amplitude of I(Ca,L) was decreased by 36 % at 20 min after the formation of WCR, while it was slowly decreased by 8 % at 30 min after the formation of PPR. The current-voltage relation (I-V) curves, activation and inactivation curves of I(Ca,L) were not significantly different between WCR and PPR. The inactivation rate of ICa,L was slower in PPR than in WCR, the faster inactivation time constant (tau(f)) was longer in PPR than in WCR at membrane potentials of -20 mV -- +10 mV (n=6, P<0.05), and the slower time constant (tau(s)) was also longer in PPR than in WCR at membrane potentials of -10 mV to +10 mV (n=6, P<0.05). There was no significant difference between the activation rate in WCR and PPR. CONCLUSION: Using beta-escin 25 micromol/L can easily obtain stable PPR in isolated guinea-pig ventricular myocytes, and this method is useful in dealing with channels, which show run-down under normal WCR such as L-type Ca channel.

Effects of anthopleurin-Q on myocardial hypertrophy in rats and physiologic properties of isolated atria in guinea pigs.

AIM: To study effects of anthopleurin-Q (AP-Q) on myocardial hypertrophy in rats and isolated atria in guinea pigs. METHODS: Two myocardial hypertrophy models in rats were established, one introduced by levothyroxine, the other by stenosis of abdominal aorta. Cardiac myocytes morphometry and functional experiments were employed to investigate effects of AP-Q. RESULTS: Low dose of AP-Q (1 microg/kg/d, ip) reduced morphologic changes of myocardial hypertrophy in both rat models. While high dose of AP-Q (10 microg/kg/d, ip) did not, and caused mild hydropic degeneration in cardiomyocytes. High concentration of AP-Q (30 nmol/L) enhanced the contractility, raised automaticity, and prolonged the functional refractory period (FRP) in isolated left atria of guinea pigs; higher concentration (100 nmol/L) triggered arrhythmia in right atria; low concentration of AP-Q (1 nmol/L)did not affect any myocardial properties above. CONCLUSION: Low dose of AP-Q without inotropic effect can hinder the experimental myocardial hypertrophy in rats; high dose with positive inotropic effect may be responsible for its toxic reaction.