Percutaneous gallbladder drainage as a bridge to concomitant coronary artery bypass grafting and laparoscopic cholecystectomy.

A 74-year-old woman with left main and three-vessel coronary artery disease was scheduled for off-pump coronary artery bypass grafting and developed acute severe cholecystitis preoperatively. Percutaneous gallbladder drainage was placed to achieve gallbladder decompression and infection control. Two weeks later, CABG and laparoscopic cholecystectomy were successfully performed at the same time.

Mesenchymal stem cell-derived conditioned medium attenuate angiotensin II-induced aortic aneurysm growth by modulating macrophage polarization.

Mesenchymal stem cells (MSCs) exhibit therapeutic benefits on aortic aneurysm (AA); however, the molecular mechanisms are not fully understood. The current study aimed to investigate the therapeutic effects and potential mechanisms of murine bone marrow MSC (BM-MSCs)-derived conditioned medium (MSCs-CM) on angiotensin II (AngII)-induced AA in apolipoprotein E-deficient (apoE-/- ) mice. Murine BM-MSCs, MSCs-CM or control medium were intravenously administrated into AngII-induced AA in apoE-/- mice. Mice were sacrificed at 2 weeks after injection. BM-MSCs and MSCs-CM significantly attenuated matrix metalloproteinase (MMP)-2 and MMP-9 expression, aortic elastin degradation and AA growth at the site of AA. These treatments with BM-MSCs and MSCs-CM also decreased Ly6chigh monocytes in peripheral blood on day 7 and M1 macrophage infiltration in AA tissues on day 14, whereas they increased M2 macrophages. In addition, BM-MSCs and MSCs-CM reduced MCP-1, IL-1Ra and IL-6 expression and increased IL-10 expression in AA tissues. In vitro, peritoneal macrophages were co-cultured with BM-MSCs or fibroblasts as control in a transwell system. The mRNA and protein expression of M2 macrophage markers were evaluated. IL-6 and IL-1ß were reduced, while IL-10 was increased in the BM-MSC systems. The mRNA and protein expression of M2 markers were up-regulated in the BM-MSC systems. Furthermore, high concentration of IGF1, VEGF and TGF-ß1 was detected in MSCs-CM. Our results suggest that MSCs-CM could prevent AA growth potentially through regulating macrophage polarization. These results may provide a new insight into the mechanisms of BM-MSCs in the therapy of AA.

Diverse roles of macrophage polarization in aortic aneurysm: destruction and repair.

Aortic aneurysm (AA) is defined as an enlargement of the aorta greater than 1.5 times its normal size. Early diagnosis of AA is challenging and mortality of AA is high. Curative pharmacological treatments for AA are still lacking, highlighting the need for better understanding of the underlying mechanisms of AA progression. Accumulating studies have proven that the polarization state of circulating monocyte-derived macrophages plays a crucial role in regulating the development of AA. Distinct macrophage subtypes display different functions. Several studies targeting macrophage polarization during AA formation and progression showed potential treatment effects. In this review, we focus on the recent advances of research on macrophage polarization in the progression of AA and propose that targeting macrophage polarization could hold great promise for preventing and treating AA.

Altered attention networks and DMN in refractory epilepsy: A resting-state functional and causal connectivity study.

PURPOSE: Epilepsy is considered a disorder of neural networks. Patients diagnosed with refractory epilepsy frequently experience attention impairments. Seizure activity in epilepsy may disturb brain networks and damage the brain function of attention. The aims of this study were to assess functional and causal connectivities of the attention networks and default mode network using resting-state functional magnetic resonance imaging (fMRI). METHOD: Resting-state fMRI data were gathered from 19 patients with refractory epilepsy (mixed localization and aetiologies) and 21 healthy people. The fMRI data were analyzed by group independent component analysis (ICA) fMRI toolbox to extract dorsal attention network (DAN), ventral attention network (VAN), and default mode network (DMN). The components of the selected networks were compared between patients and healthy controls to explore the change in functional connectivity (FC). Granger causality analysis was performed by taking the aforementioned significant brain areas as regions of interest (ROIs) to calculate autoregression coefficients of each pair of ROIs. Comparisons were done to find the significantly different causal connectivity when FC was changed between patients and healthy controls. RESULTS: In DAN, the FC values of the bilateral frontal eye field (FEF) and left intraparietal sulcus (IPS) were decreased. In VAN, the FC values of the double-side ventral prefrontal cortex (vPFC) and the temporoparietal junction (TPJ) were reduced. As for DMN, the FC values of the bilateral medial prefrontal cortices (mPFC) were decreased whereas those for the bilateral precuneus (PCUN) were increased. Granger causal connectivity values were correlated: causal influence was decreased significantly from the left IPS (in DAN) to the double side of the vPFC but remained the same for the right FEF (in DAN) to the right TPJ. The value was decreased from the left PCUN (in DMN) to the right TPJ and FEF, and the causal flow from the right PCUN to the right TPJ and bilateral vPFC was also significantly inhibited (p < 0.05). CONCLUSION: Frequent seizures in patients with refractory epilepsy may damage the cortex and disturb DAN, VAN, and DMN, leading to functional and causal connectivity alteration. In addition, epileptic activity may disrupt network interactions and further influence information communication.

Bone marrow-derived innate macrophages attenuate oxazolone-induced colitis.

Previous studies have shown that a subpopulation of granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent F4/80high CD11bhigh innate macrophages could be derived from bone marrow cells by continuous in vitro culturing. These cells could be induced to differentiate into M1 or M2 macrophages in vitro. In the current study, we sought to determine whether bone marrow cell-derived innate macrophages (BMIMs) could be used to fulfill an anti-inflammatory purpose by intravenous transplantation in vivo after being stimulated to differentiate into M2 macrophages. Because Th2 cytokines, such as interleukin IL-4 and IL-13, can induce macrophage polarization into M2 macrophages, we treated the BMIMs with IL-4 and IL-13 in vitro. Next, the M2 macrophages were intravenously transplanted into a typical Th2-mediated inflammatory disease model, oxazolone (OXZ)-induced colitis, to assess the anti-inflammatory activity of BMIM-derived M2 macrophages (BMIM-M2Ms) in vivo. After transplantation, the severity of intestinal inflammation was attenuated. In addition, colon lengths and mouse body weights were noticeably improved. F4/80+ CD206+ double-positive cells (displaying the markers of M2 macrophages) had accumulated in the colon tissue of BMIM-M2M-transplanted mice. This evidence demonstrated that bone marrow-derived BMIM-M2Ms could be used to alleviate OXZ-induced Th2-mediated inflammation in a mouse model in vivo.

Resting-state functional connectivity predicts impulsivity in economic decision-making.

Increasing neuroimaging evidence suggests an association between impulsive decision-making behavior and task-related brain activity. However, the relationship between impulsivity in decision-making and resting-state brain activity remains unknown. To address this issue, we used functional MRI to record brain activity from human adults during a resting state and during a delay discounting task (DDT) that requires choosing between an immediate smaller reward and a larger delayed reward. In experiment I, we identified four DDT-related brain networks. The money network (the striatum, posterior cingulate cortex, etc.) and the time network (the medial and dorsolateral prefrontal cortices, etc.) were associated with the valuation process; the frontoparietal network and the dorsal anterior cingulate cortex-anterior insular cortex network were related to the choice process. Moreover, we found that the resting-state functional connectivity of the brain regions in these networks was significantly correlated with participants' discounting rate, a behavioral index of impulsivity during the DDT. In experiment II, we tested an independent group of subjects and demonstrated that this resting-state functional connectivity was able to predict individuals' discounting rates. Together, these findings suggest that resting-state functional organization of the human brain may be a biomarker of impulsivity and can predict economic decision-making behavior.

Intravenous administration of mesenchymal stem cells prevents angiotensin II-induced aortic aneurysm formation in apolipoprotein E-deficient mouse.

BACKGROUND: Mesenchymal stem cells (MSCs) are known to be capable of suppressing inflammatory responses. We previously reported that intra-abdominal implantation of bone marrow-derived MSCs (BM-MSCs) sheet by laparotomy attenuated angiotensin II (AngII)-induced aortic aneurysm (AA) growth in apolipoprotein E-deficient (apoE-/-) mice through anti-inflammation effects. However, cell delivery by laparotomy is invasive; we here demonstrated the effects of multiple intravenous administrations of BM-MSCs on AngII-induced AA formation. METHODS: BM-MSCs were isolated from femurs and tibiae of male apoE-/- mice. Experimental AA was induced by AngII infusion for 28 days in apoE-/- mice. Mice received weekly intravenous administration of BM-MSCs (n=12) or saline (n=10). After 4 weeks, AA formation incidence, aortic diameter, macrophage accumulation, matrix metalloproteinase (MMP)' activity, elastin content, and cytokines were evaluated. RESULTS: AngII induced AA formation in 100% of the mice in the saline group and 50% in the BM-MSCs treatment group (P < 0.05). A significant decrease of aortic diameter was observed in the BM-MSCs treatment group at ascending and infrarenal levels, which was associated with decreased macrophage infiltration and suppressed activities of MMP-2 and MMP-9 in aortic tissues, as well as a preservation of elastin content of aortic tissues. In addition, interleukin (IL)-1ß, IL-6, and monocyte chemotactic protein-1 significantly decreased while insulin-like growth factor-1 and tissue inhibitor of metalloproteinases-2 increased in the aortic tissues of BM-MSCs treatment group. CONCLUSIONS: Multiple intravenous administrations of BM-MSCs attenuated the development of AngII-induced AA in apoE-/- mice and may become a promising alternative therapeutic strategy for AA progression.

A comparative study of two types of sternal pins used for sternal closure: poly-L-lactide sternal pins versus uncalcined hydroxyapatite poly-L-lactide sternal pins.

Bioabsorbable poly-L-lactide (PLLA) sternal pins are applied to reinforce sternal closure during cardiac surgery. However, these pins lack osteoconductivity. A new bioabsorbable sternal pin with osteoconductivity, made of uncalcined hydroxyapatite and poly-L-lactide (u-HA-PLLA) has been developed. This study was conducted to compare the two types of sternal pins in terms of sternal stability and healing after median sternotomy. Between October 2006 and January 2012, 105 patients underwent aortic surgery for aortic aneurysms or dissection via median sternotomy and sternal closure with sternal pins. Among these patients, 75 were followed for 12 months using serial computed tomography (CT). PLLA sternal pins were used in 30 patients (group A) and u-HA-PLLA sternal pins were used in 45 patients (group B). The incidence rates of transverse sternal dehiscence, anteroposterior displacement and complete sternal fusion were evaluated using CT. The cross-sectional cortical bone density area (CBDA) of the sternum around the sternal pins was examined to evaluate the osteoconductivity of the sternal pins. There were no significant differences between groups A and B in the sternal dehiscence rate (6.7 vs 4.4 %), sternal displacement rate (6.7 vs 2.2 %) or 12-month sternal fusion rate (63.3 vs 73.3 %). The CBDA around the sternal pins significantly increased between discharge and 12 months after surgery in group B (P < 0.001) but not in group A. These results show that u-HA-PLLA sternal pins exhibit certain osteoconductivity; however, both PLLA and u-HA-PLLA sternal pins provide comparable clinical outcomes regarding sternal stability and healing.

[Impulsive decision-making behaviors in heroin addicts: a study of functional magnetic resonance imaging].

OBJECTIVE: To explore the brain regions associated with impulsive decision-making behaviors and interpret the nervous mechanism for addiction and relapse in heroin abusers. METHODS: Using the paradigms of psychological experiment, the subjects in both heroin addiction group (HA group) and normal control group (HC group) performed Iowa gambling task (IGT) and simultaneously underwent functional magnetic resonance imaging (fMRI) scan. All the above data were gathered and then analyzed by SPM5 software to explore both the brain regions and their functional changes correlated with impulsive decision-making. RESULTS: Evidence by IGT behavioral consequences demonstrated that the net scores in HC group increased with numbers of decision-making whereas no increment (fluctuating between-1 and 0) was observed in HA group. Based on the results of fMRI analysis, right orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), left ventromedial prefrontal cortex (MPFC) and anterior cingulate cortex (ACC) were activated in both groups. But the right OFC was more active while the right DLPFC and left MPFC were weaker in HA group versus the HC group. Meanwhile, activation of right lenticular nucleus, right thalamus, right insula, hippocampus and left caudate nucleus were observed in HA group. CONCLUSION: Heroin abusers are incapable of impulsive decision-making in behavioral studies. Such a brain region as prefrontal cortex participates in the decision-making performance and control of impulsiveness. Functionally abnormal brain regions correlated with impulsive decision-making may be one cause of genesis, maintenance and relapse of heroin addiction.

[A voxel-based morphometric analysis of brain gray matter in online game addicts].

OBJECTIVE: To explore the possible brain mechanism of online game addiction (OGA) in terms of brain morphology through voxel-based morphometric (VBM) analysis. METHODS: Seventeen subjects with OGA and 17 age- and gender-matched healthy controls (HC group) were recruited from Department of Psychology at our hospital during February-December 2011. The internet addiction scale (IAS) was used to measure the degree of OGA tendency. Magnetic resonance imaging (MRI) scans were performed to acquire 3-dimensional T1-weighted images. And FSL 4.1 software was employed to confirm regional gray matter volume changes. For the regions where OGA subjects showed significantly different gray matter volumes from the controls, the gray matter volumes of these areas were extracted, averaged and regressed against the scores of IAS. RESULTS: The OGA group had lower gray matter volume in left orbitofrontal cortex (OFC), left medial prefrontal cortex (mPFC), bilateral insula (INS), left posterior cingulate cortex (PCC) and left supplementary motor area (SMA). Gray matter volumes of left OFC and bilateral INS showed a negative correlation with the scores of IAS (r = -0.65, r = -0.78, P < 0.05). CONCLUSION: Gray matter volume changes are present in online game addicts and they may be correlated with the occurrence and maintenance of OGA.

Case Report: 3D Printing Guided Cardiac Autotransplantation for Treatment of a Giant Complex Primary Left Atrial Tumor.

Primary cardiac tumors are rare and complete surgical resection is the optimal treatment. However, it is a great challenge to resect some malignant or complex benign left-sided cardiac tumors situated on the posterior aspect of the heart using conventional surgical resection techniques. Previous studies reported that cardiac autotransplantation is a feasible and safe technique for resection of such cardiac tumors. We report a successful case of cardiac autotransplantation with 3-dimensional (3D) printing technique for complete resection of a giant complex primary left atrial tumor.

Down-regulating microRNA-20a regulates CDH1 to protect against cerebral ischemia/reperfusion injury in rats.

Studies have extensively focused on the involvement of microRNAs (miRNAs) in cerebral ischemia/reperfusion (I/R) injury but not much on the specific role of miR-20a. Hence, this study is purposed to decipher whether miR-20a could regulate cadherin 1 (CDH1) to affect cerebral I/R injury in rats. Rat transient middle cerebral artery occlusion model (MCAO) was established. Rats were injected with lentiviral solution containing miR-20a inhibitor, or overexpressed CDH1 or combined depleted miR-20a and CDH1 to explore their roles in cerebral I/R injury. Oxidative stress-related factors, miR-20a, CDH1, nuclear factor-kappaB (NF-κB) and Nestin expression in brain tissues were detected by RT-qPCR and western blot assay. The target relation between miR-20a and CDH1 was predicted by online website and further confirmed by luciferase activity assay. In rats with cerebral I/R injury, increased miR-20a and decreased CDH1 were found in brain tissues. Reduction of miR-20a or elevation of CDH1 attenuated behavior function in MCAO rats. Inhibiting miR-20a or restoring CDH1 restrained oxidative stress, attenuated pathological damage of neurons, promoted neuron survival, and down-regulated NF-κB and Nestin expression in brain tissues of MCAO rats. CDH1 was determined to a target gene of miR-20a. This study elucidates that down-regulating miR-20a elevates CDH1 to protect neurons from cerebral I/R injury, which paves a new way for treatment of cerebral I/R injury.

Addiction related alteration in resting-state brain connectivity.

It is widely accepted that addictive drug use is related to abnormal functional organization in the user's brain. The present study aimed to identify this type of abnormality within the brain networks implicated in addiction by resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI). With fMRI data acquired during resting state from 14 chronic heroin users (12 of whom were being treated with methadone) and 13 non-addicted controls, we investigated the addiction related alteration in functional connectivity between the regions in the circuits implicated in addiction with seed-based correlation analysis. Compared with controls, chronic heroin users showed increased functional connectivity between nucleus accumbens and ventral/rostral anterior cingulate cortex (ACC), between nucleus accumbens and orbital frontal cortex (OFC), and between amygdala and OFC and reduced functional connectivity between prefrontal cortex and OFC and between prefrontal cortex and ACC. These observations of altered resting-state functional connectivity suggested abnormal functional organization in the addicted brain and may provide additional evidence supporting the theory of addiction that emphasizes enhanced salience value of a drug and its related cues but weakened cognitive control in the addictive state.

A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy.

Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammation-related signaling pathways of JAK2/STAT3 and NF-κB, as well as regulate autophagy. However, its role in vascular inflammation and AAA progression remains to be elucidated. In the present study, the effect and potential mechanisms of BP-1-102 on angiotensin II (AngII) induced AAA in ApoE-/- mice were investigated. AAA was induced in ApoE-/- mice with infusion of AngII for 28 days. BP-1-102 was administrated orally to mice every other day. Mice were sacrificed on day 7, day 14, and day 28 to evaluate the treatment effects. BP-1-102 markedly decreased AAA incidence and aortic diameter, maintained elastin structure and volume, reduced the expression of pro-inflammatory cytokines and MMPs, and inhibited inflammatory cells infiltration. Moreover, BP-1-102 dramatically reduced the expression of JAK2, p-STAT3, p-NF-κB, and Bcl-xL but maintained the expression of LC3B and Beclin in AAA tissues. In vitro, vascular smooth muscle cells (VSMCs) were treated with AngII and/or BP-1-102 at indicated time and concentration. BP-1-102 inhibited AngII-induced JAK2/STAT3 and NF-κB signaling activation and maintained autophagy-related proteins expression in VSMCs. Taken together, our findings suggest that BP-1-102 inhibits vascular inflammation and AAA progression through decreasing JAK2/STAT3 and NF-κB activation and maintaining autophagy.

Decision-making and prepotent response inhibition functions in excessive internet users.

INTRODUCTION: Excessive Internet use (EIU), also described as Internet addiction or pathological Internet use, has already become a serious social problem around the world. Some researchers consider EIU as a kind of behavioral addiction. However, there are few experimental studies on the cognitive functions of excessive Internet users (EIUers) and limited data are available to compare EIU with other addictive behaviors, such as drug abuse and pathological gambling. METHODS: In the present study, we examined EIUers' functions of decision-making and prepotent response inhibition. Two groups of participants, EIUers and controls, were compared on these two functions by using a Gambling Task and a Go/no-go Task, respectively. RESULTS: Compared with controls, EIUers selected significantly less net decks in the Gambling Task (P=.007). Furthermore, the EIUers made progress in selecting strategy, but more slowly than did the control group (EIUers, chunk 3 > chunk 1, P<.001; controls, chunk 2 > chunk 1, P<.001). Interestingly, EIUers' accuracy during the no-go condition was significantly higher than that of controls (P=.018). CONCLUSION: These results showed some similarities and dissimilarities between EIU and other addictive behaviors such as drug abuse and pathological gambling. The findings from the Gambling Task indicated that EIUers have deficits in decision-making function, which are characterized by a strategy learning lag rather than an inability to learn from task contingencies. EIUers' better performance in the Go/no-go Task suggested some dissociation between mechanisms of decision-making and those of prepotent response inhibition. However, EIUers could hardly suppress their excessive online behaviors in real life. Their ability of inhibition still needs to be further studied with more specific assessments.

Prefrontal cortex involvement in the event-based prospective memory: evidence from patients with lesions in the prefrontal cortex.

PRIMARY OBJECTIVE: The aim of the present study was to investigate the event-based prospective memory (EBPM) and time-based prospective memory (TBPM) in patients with lesion in prefrontal cortex (PFC) and test the hypothesis that the prefrontal cortex is involved in the prospective memory (PM) network. RESEARCH DESIGN: The performance of patients with lesion in PFC (n = 30) was compared with that of a demographically matched control group (n = 30). METHODS AND PROCEDURES: A neuropsychological battery of tests including EBPM and TBPM tasks were administered to both groups. MAIN OUTCOME AND RESULTS: The group with lesion in PFC were significantly impaired in EBPM, but insignificantly impaired in TBPM tasks. There was no difference in performance of EBPM and TBPM tasks between the patients with lesion in the left and the right PFC. CONCLUSIONS: These results suggest that the patients with lesion in PFC were impaired in EBPM, but not in TBPM, implying that EBPM and TBPM may have different neural substrates. It is possible that PFC is more selectively involved in EBPM, but less in TBPM.

Stroke and peripheral embolisms in a pediatric patient with giant atrial myxoma: Case report and review of current literature.

RATIONALE: Cerebral stroke with peripheral embolism due to left atrial myxoma is very rare in children. Misdiagnosis may occur because of nonspecific symptoms in the heart. PATIENT CONCERNS: We present a case of a 16-year-old boy who presented with ischemic stroke and embolisms in the lower extremity, caused by a giant left atrial myxoma. DIAGNOSES: Left atrial myxoma. INTERVENTIONS: A giant gelatinous mass was completely excised, and the histopathological findings confirmed the diagnosis of atrial myxoma. OUTCOMES: The temperature of the right lower extremity recovered gradually, and pulse of the right dorsalis pedis artery became palpable 10 days after the surgery. The strength of the bilateral lower extremity was level 5 at discharge. LESSONS: Our case, along with the review of the literature, highlights the fact that myxomas often initially present with multiple embolisms but with few cardiac symptoms. Transthoracic echocardiography should be performed immediately to make a definitive diagnosis.

Rejuvenation of Cardiac Tissue Developed from Reprogrammed Aged Somatic Cells.

Induced pluripotent stem cells (iPSCs) derived via somatic cell reprogramming have been reported to reset aged somatic cells to a more youthful state, characterized by elongated telomeres, a rearranged mitochondrial network, reduced oxidative stress, and restored pluripotency. However, it is still unclear whether the reprogrammed aged somatic cells can function normally as embryonic stem cells (ESCs) during development and be rejuvenated. In the current study, we applied the aggregation technique to investigate whether iPSCs derived from aged somatic cells could develop normally and be rejuvenated. iPSCs derived from bone marrow myeloid cells of 2-month-old (2 M) and 18-month-old (18 M) C57BL/6-Tg (CAG-EGFP)1Osb/J mice were aggregated with embryos derived from wild-type ICR mice to produce chimeras (referred to as 2 M CA and 18 M CA, respectively). Our observations focused on comparing the ability of the iPSCs derived from 18 M and 2 M bone marrow cells to develop rejuvenated cardiac tissue (the heart is the most vital organ during aging). The results showed an absence of p16 and p53 upregulation, telomere length shortening, and mitochondrial gene expression and deletion in 18 M CA, whereas slight changes in mitochondrial ultrastructure, cytochrome C oxidase activity, ATP production, and reactive oxygen species production were observed in CA cardiac tissues. The data implied that all of the aging characteristics observed in the newborn cardiac tissue of 18 M CA were comparable with those of 2 M CA newborn cardiac tissue. This study provides the first direct evidence of the aging-related characteristics of cardiac tissue developed from aged iPSCs, and our observations demonstrate that partial rejuvenation can be achieved by reprogramming aged somatic cells to a pluripotent state.

Aggregation of quaternary ammonium gemini surfactants C12-s-C12.2Br in n-heptane/n-hexanol solution: effect of the spacer chains on the critical reverse micelle concentrations.

The critical reverse micelle concentrations of C(12)-s-C(12).2Br (s=2,3,4,5,6,8,12) in n-heptane/n-hexanol solutions, cmc(I)s, have been determined by absorption spectrum method using iodine as probe. The values of cmc(I)s are smaller than those of the critical micelle concentrations (cmc(aq)s) in aqueous solution and reach a maximum at s=4, which is similar to the variation of cmc(aq) with s. The variation of cmc(I) with s is attributed to the alteration in the spacer chain conformation, i.e. when the spacer is short enough, it may adopt stretch configuration and when the spacer is long, it tends to bend towards the continuous oil phase to achieve a more densely packing of the quaternary ammonium heads on the surface of the core.