The effect of dapagliflozin on myocardial ischemia-reperfusion injury in diabetic rats.

The incidence of ischemic heart disease is 2-3 times higher in diabetic patients. However, the effect of dapagliflozin on ischemia-reperfusion myocardial injury in diabetic rats has not been studied. We examined the effects of dapagliflozin on myocardial IR injury in streptozotocin-nicotinamide-induced diabetic rats. Rats were divided into four groups (n = 7 in each group): control, control-dapagliflozin, diabetes, and diabetes-dapagliflozin. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water for 2 months. The hearts were perfused in a Langendorff's apparatus at 2 months and assessed before (baseline) and after myocardial IR for the following parameters: left ventricular developed pressure (LVDP), minimum and maximum rates of pressure change in the left ventricle (±dP/dt), endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) mRNA expressions, creatine kinase MB (CK-MB) and troponin imyocardial enzyme extravasation, and lactate dehydrogenase. The recovery of LVDP and ±dP/dt in diabetic rats was lower than that in controls but near normal after dapagliflozin treatment. Diabetic rats had decreased eNOS expression and increased iNOS expression at baseline and after IR, whereas dapagliflozin normalized these parameters after IR. Compared with controls, cardiac NOx levels were initially lower in diabetic patients but higher after IR. Baseline MDA levels were higher in diabetic rats after IR, whereas cardiac NOx levels decreased after treatment with dapagliflozin. Dapagliflozin protects the diabetic rat heart from ischemia-reperfusion myocardial injury by regulating the expression of eNOS and iNOS and inhibiting cardiac lipid peroxidation.

Computational discovery of microstructured composites with optimal stiffness-toughness trade-offs.

The conflict between stiffness and toughness is a fundamental problem in engineering materials design. However, the systematic discovery of microstructured composites with optimal stiffness-toughness trade-offs has never been demonstrated, hindered by the discrepancies between simulation and reality and the lack of data-efficient exploration of the entire Pareto front. We introduce a generalizable pipeline that integrates physical experiments, numerical simulations, and artificial neural networks to address both challenges. Without any prescribed expert knowledge of material design, our approach implements a nested-loop proposal-validation workflow to bridge the simulation-to-reality gap and find microstructured composites that are stiff and tough with high sample efficiency. Further analysis of Pareto-optimal designs allows us to automatically identify existing toughness enhancement mechanisms, which were previously found through trial and error or biomimicry. On a broader scale, our method provides a blueprint for computational design in various research areas beyond solid mechanics, such as polymer chemistry, fluid dynamics, meteorology, and robotics.

Low-cost dual-energy CBCT by spectral filtration of a dual focal spot X-ray source.

Dual-energy cone beam computed tomography (DE-CBCT) has been shown to provide more information and improve performance compared to a conventional single energy spectrum CBCT. Here we report a low-cost DE-CBCT by spectral filtration of a carbon nanotube x-ray source array. The x-ray photons from two focal spots were filtered respectively by a low and a high energy filter. Projection images were collected by alternatively activating the two beams while the source array and detector rotated around the object, and were processed by a one-step materials decomposition and reconstruction method. The performance of the DE-CBCT scanner was evaluated by imaging a water-equivalent plastic phantom with inserts containing known densities of calcium or iodine and an anthropomorphic head phantom with dental implants. A mean energy separation of 15.5 keV was achieved at acceptable dose rates and imaging time. Accurate materials quantification was obtained by materials decomposition. Metal artifacts were reduced in the virtual monoenergetic images synthesized at high energies. The results demonstrated the feasibility of high quality DE-CBCT imaging by spectral filtration without using either an energy sensitive detector or rapid high voltage switching.

Improving the accuracy of bone mineral density using a multisource CBCT.

Multisource cone beam computed tomography CBCT (ms-CBCT) has been shown to overcome some of the inherent limitations of a conventional CBCT. The purpose of this study was to evaluate the accuracy of ms-CBCT for measuring the bone mineral density (BMD) of mandible and maxilla compared to the conventional CBCT. The values measured from a multi-detector CT (MDCT) were used as substitutes for the ground truth. An anthropomorphic adult skull and tissue equivalent head phantom and a homemade calibration phantom containing inserts with varying densities of calcium hydroxyapatite were imaged using the ms-CBCT, the ms-CBCT operating in the conventional single source CBCT mode, and two clinical CBCT scanners at similar imaging doses; and a clinical MDCT. The images of the anthropomorphic head phantom were reconstructed and registered, and the cortical and cancellous bones of the mandible and the maxilla were segmented. The measured CT Hounsfield Unit (HU) and Greyscale Value (GV) at multiple region-of-interests were converted to the BMD using scanner-specific calibration functions. The results from the various CBCT scanners were compared to that from the MDCT. Statistical analysis showed a significant improvement in the agreement between the ms-CBCT and MDCT compared to that between the CBCT and MDCT.

Selective vulnerability of hippocampal sub-regions in patients with subcortical vascular mild cognitive impairment.

Early diagnosis of subcortical vascular mild cognitive impairment (svMCI) is clinically essential because it is the most reversible subtype of all cognitive impairments. Since structural alterations of hippocampal sub-regions have been well studied in neurodegenerative diseases with pathophysiological cognitive impairments, we were eager to determine whether there is a selective vulnerability of hippocampal sub-fields in patients with svMCI. Our study included 34 svMCI patients and 34 normal controls (NCs), with analysis of T1 images and Montreal Cognitive Assessment (MoCA) scores. Gray matter volume (GMV) of hippocampal sub-regions was quantified and compared between the groups, adjusting for age, sex, and education. Additionally, we explored correlations between altered GMV in hippocampal sub-fields and MoCA scores in svMCI patients. Patients with svMCI exhibited selectively reduced GMV in several left hippocampal sub-regions, such as the hippocampal tail, hippocampal fissure, CA1 head, ML-HP head, CA4 head, and CA3 head, as well as decreased GMV in the right hippocampal tail. Specifically, GMV in the left CA3 head was inversely correlated with MoCA scores in svMCI patients. Our findings indicate that the atrophy pattern of patients with svMCI was predominantly located in the left hippocampal sub-regions. The left CA3 might be a crucial area underlying the distinct pathophysiological mechanisms of cognitive impairments with subcortical vascular origins.

Volumetric computed tomography with carbon nanotube X-ray source array for improved image quality and accuracy.

Cone beam computed tomography (CBCT) is widely used in medical and dental imaging. Compared to a multidetector CT, it provides volumetric images with high isotropic resolution at a reduced radiation dose, cost and footprint without the need for patient translation. The current CBCT has several intrinsic limitations including reduced soft tissue contrast, inaccurate quantification of X-ray attenuation, image distortions and artefacts, which have limited its clinical applications primarily to imaging hard tissues and made quantitative analysis challenging. Here we report a multisource CBCT (ms-CBCT) which overcomes the short-comings of the conventional CBCT by using multiple narrowly collimated and rapidly scanning X-ray beams from a carbon nanotube field emission source array. Phantom imaging studies show that, the ms-CBCT increases the accuracy of the Hounsfield unit values by 60%, eliminates the cone beam artefacts, extends the axial coverage, and improves the soft tissue contrast-to-noise ratio by 30-50%, compared to the CBCT configuration.

Fat- and iron-corrected ADC to assess liver fibrosis in patients with chronic hepatitis B.

PURPOSE: We aimed to evaluate the diagnostic performance of apparent diffusion coefficient (ADC) in assessing liver fibrosis after correcting for the effects of hepatic steatosis or iron deposition. METHODS: Seventy-three patients with chronic hepatitis B (CHB) were included in this retrospective study. The aspartate aminotransferase-to-platelet ratio index (APRI) was calculated for classification of the fibrosis grade. Significant fibrosis and cirrhosis were diagnosed with the APRI. The proton density fat fraction (PDFF), R2*, and ADC values were measured. The impact of the PDFF and R2* on the ADC was analyzed. The PDFF- and R2*-corrected ADC values (ADCPDFF and ADCR2*) were calculated according to linear regression equations. The diagnostic performance of uncorrected ADC (ADCu), ADCPDFF and ADCR2* in predicting significant fibrosis and cirrhosis was assessed, and the area under the curve (AUC) values were compared. RESULTS: Among the 73 patients in this study, the mean ADC was 0.866 ± 0.084×10-3 mm2/s, the mean R2* was 60.24 (42.77, 85.37) 1/s, and the mean PDFF was 2.90% (1.60%- 4.80%). The ADC was negatively correlated with the PDFF (r= -0.298, P = .010) and R2* (r = -0.457, P < .001). Linear regression analysis showed that the PDFF and R2* were independent factors of the ADC (ß= -0.315, P = .007, R2= 0.099 and ß= -0.493, P < .001, R2= 0.243, respectively). Compared with the uncorrected ADC (r= -0.307, P = .022), the correlation between the ADCPDFF and fibrosis grade increased (r= -0.513, P < .001), and the correlation between the ADCR2* and fibrosis grade decreased (r=-0.168, P = .215). The AUC of the ADCPDFF was significantly larger than that of the ADCu in the diagnosis of significant fibrosis and cirrhosis, which increased from 0.68 to 0.81 (P = .003) for predicting significant fibrosis and from 0.75 to 0.84 (P = .009) for predicting cirrhosis. The AUCs for the ADCR2* in the diagnosis of significant fibrosis and cirrhosis were both lower than that for the uncorrected ADC (P = .206 and P = .109, respectively). CONCLUSION: After correcting for the effects of steatosis, the diagnostic performance of the ADC for signifi-cant fibrosis and cirrhosis increased. The ADC corrected for the effects of steatosis may be more reliable for identifying liver fibrosis.

Performance of Single-Shot Echo-Planar Imaging in Diffusion Tensor Imaging in Rat Sciatic Nerve Compared With Readout-Segmented Echo-Planar Imaging.

Objectives: To compare the performances of single-shot echo-planar imaging (SS-EPI) and readout-segmented echo-planar imaging (RS-EPI) for diffusion tensor imaging (DTI) of the rat sciatic nerve. Methods: Eight healthy adult male Sprague-Dawley rats were anesthetized and scanned with a 3T MRI scanner using SS-EPI and RS-EPI DTI sequences. The image quality in terms of the morphology of the nerve, distortions of the nearby femur, muscles, and homogeneity of neuromuscular were evaluated and scored. The correlations between the DTI parameters including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), apparent diffusion coefficient (ADC), and histopathological parameters were calculated by using the Pearson correlation coefficient and compared by the modified Fisher Z-transform, respectively. Results: The quality scores were higher for the images from the SS-EPI sequence compared with the RS-EPI sequence for characteristics such as sharpness of the sciatic nerve margin (P = 0.008), artifacts of the sciatic nerve (P = 0.008), and homogeneity of the neuromuscular region (P = 0.007), as well as the contrast-to-noise ratio (CNR) of DW images (P < 0.001). The correlation coefficients were higher for the FA and RD values from the SS-EPI sequence compared with those from the RS-EPI sequence. Furthermore, the correlation coefficients between FA and myelin thickness (P = 0.027), FA and diameter of the myelinated fiber (P = 0.036), as well as RD and myelin thickness (P = 0.05) were statistically higher for the SS-EPI sequence compared with those for the RS-EPI sequence. Conclusion: Diffusion tensor imaging analysis of the rat sciatic nerve showed that the image quality from the SS-EPI sequence was significantly higher compared with that from the RS-EPI sequence. Furthermore, the FA and RD derived from the SS-EPI sequence are promising and sensitive biomarkers to detect the histopathological changes in the rat sciatic nerve.

Fast Independent Component Analysis Algorithm-Based Diagnosis of L5 Nerve Root Compression and Changes of Brain Functional Areas Using 3D Functional Magnetic Resonance Imaging.

In this paper, the application of 3-dimensional (3D) functional magnetic resonance imaging (FMRI) in the diagnosis of the 5th lumbar (L5) nerve root compression and brain functional areas in patients with lumbar disc herniation (LDH) was analyzed. The traditional fast independent component analysis (Fast ICA) algorithm was optimized based on the modified whitening matrix to establish a new type of Modified-Fast ICA (M-Fast ICA) algorithm that was compared with the introduced traditional Fast ICA and ICA. M-Fast ICA was applied to the 3D FMRI diffusion tensor imaging (DTI) evaluation of 65 patients with L5 nerve root pain due to LDH (group A) and 50 healthy volunteers (group B). The values of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the lumbar nerve roots (L3, L4, L5, and the 1st sacral vertebra (S1)) were recorded among subjects from the two groups. Besides, the score of edema degree in the lumbar nerve roots (L5 and S1) and activity of brain functional areas were also recorded among all subjects of the two groups. The results showed that the mean square error of M-Fast ICA was smaller than that of traditional Fast ICA and ICA, while its signal-to-noise ratio (SNR) was greater than that of Fast ICA and ICA (P < 0.05). The FA of L5 and S1 nerve roots in patients of group A was sharply lower than the values of group B, while the ADC of patients in group A was greater than that of the control group (P < 0.05). Besides, the score of edema in L5 and S1 nerve roots of patients in group A increased in contrast to group B (P < 0.05). The brain areas were activated after surgery including bilateral temporal lobe, left thalamus, splenium of corpus callosum, and right internal capsule. In conclusion, the 3D image denoising performance of M-Fast ICA optimized and constructed in this study was superior to that of the traditional Fast ICA and ICA. The FA of patients with L5 nerve root pain due to LDH decreased steeply, while the ADC increased dramatically. L5 nerve root pain caused by LDH resulted in changes in brain functional areas of the patients to inhibit the resting state default network activity, and the corresponding brain functional areas could be activated through treatment.

Different patterns of functional and structural alterations of hippocampal sub-regions in subcortical vascular mild cognitive impairment with and without depression symptoms.

In addition to cognitive impairments, depression symptoms were reported in subcortical vascular mild cognitive impairment. Although hippocampal alterations were associated with cognitive decline in subcortical vascular mild cognitive impairment, the neural mechanism underlying depression symptoms remains unclear. Thus, a cohort of 18 patients with depression symptoms, 17 patients without depression symptoms, and 23 normal controls was used. Functionally, significantly altered resting-state functional connectivity between hippocampal emotional sub-region and right posterior cingulate cortex, between hippocampal cognitive sub-region and right inferior parietal gyrus and between hippocampal perceptual sub-region and left inferior temporal gyrus were identified among three groups. Structurally, significantly altered structural associations between hippocampal emotional sub-region and 6 frontal regions/right pole part of superior temporal gyrus/right inferior occipital gyrus, between hippocampal cognitive sub-region and right orbital part of inferior frontal gyrus /right anterior cingulate cortex, and between hippocampal perceptual and right orbital part of inferior frontal gyrus / left inferior temporal gyrus / left thalamus were identified among the three groups. Further analyses also showed correlations between functional connectivity and depression symptoms and/or cognitive impairments of patients. Together, these results showed different patterns of functional and structural alterations of the hippocampal sub-regions in the subcortical vascular mild cognitive impairment with and without depression, which might be specially associated with the depression symptoms and cognitive impairments in these patients.

Alterations of White Matter Microstructure in Subcortical Vascular Mild Cognitive Impairment with and without Depressive Symptoms.

BACKGROUND: Depressive symptoms were thought to increase the risk of vascular dementia. Previous studies reported widespread white matter damages in the subcortical vascular mild cognitive impairment (svMCI), but little is known about the mechanism of depressive symptoms in svMCI. OBJECTIVE: In the current study, we aim to explore the white matter microstructural alterations in svMCI with depressive symptoms, and their associations with clinical measurements. METHODS: Fifty-eight subjects including 18 svMCI with depression (svMCI+D), 17 svMCI without depression (svMCI-D), and 23 normal controls (NC) were included in the study. Voxel-based analyses were performed on fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: Compared to NC, both svMCI groups showed decreased FA in the bilateral insula and the left precentral gyrus, and increased MD in the cerebellum. Compared to svMCI-D, svMCI+D showed increased FA in left precentral gyrus. Moreover, svMCI+D showed significant correlation between the increased MD in the cerebellum and the Hamilton Depression Rating Scale (HAMD) scores. CONCLUSION: Our findings of white matter alterations might be associated with executive function and memory performance in the svMCI patients. Moreover, the structural alterations in the cerebellum might underlie the mechanism of depressive symptoms in svMCI patients.

Cortical Alterations Are Associated with Depression in Subcortical Vascular Mild Cognitive Impairment Revealed by Surface-Based Morphometry.

BACKGROUND: Late-life depression often coexists with vascular cognitive impairment and affects the quality of life for elders. However, little is known about cortical morphometric interactions between subcortical vascular mild cognitive impairment (svMCI) and concomitant mild depressive symptoms at the early stage. OBJECTIVE: We aimed to investigate cortical alterations of svMCI with and without depressive symptoms and determine whether these parameters are associated with depression symptoms and/or cognitive impairments. METHODS: Surface based morphometry was performed on 18 svMCI patients with depressive symptoms (svMCI + D), 16 svMCI patients without depressive symptoms (svMCI-D), and 23 normal controls (NC). RESULTS: Compared to NC, both svMCI + D and svMCI-D patients exhibited significantly decreased surface area (SA) in many cortical areas. Interestingly, svMCI + D patients showed significantly increased rather than decreased SA in right lateral occipital gyrus (LOG.R), and a consistent trend of increased SA in these areas compared to svMCI-D. In addition, the svMCI + D showed increased gray matter volume of left pericalcarine (periCAL.L) than svMCI-D, whereas svMCI-D showed decreased gray matter volume of periCAL.L than NC. Further correlation analyses revealed that the SA of left superior temporal gyrus (STG.L) and right lateral orbital part of frontal gyrus (lorbFG.R) were significantly correlated with Hamilton depression rating scale of svMCI + D. CONCLUSION: In conclusion, these results extend our insight into svMCI and add weight to reevaluation of concomitant early stage depressive symptoms. Moreover, we suggest that LOG.R∖periCAL.L∖STG.L∖lorbFG.R might serve as sensitive and trait-dependent biomarkers to detect concomitant depressive symptoms in svMCI patients.

Structural and Functional Disruptions in Subcortical Vascular Mild Cognitive Impairment With and Without Depressive Symptoms.

Many previous studies have revealed structural and functional abnormalities in patients with the subcortical vascular mild cognitive impairment (svMCI). Although depression symptoms were suggested to serve as a potential marker of conversion to dementia in patients with svMCI, whether these disruptions or other new findings will be identified in the svMCI comorbid with depression symptoms has not been established. In the current study, we combined voxel-based morphometry (VBM) and the resting-state functional magnetic resonance imaging (fMRI) to investigate the structural and functional disruptions in the svMCI with and without depression symptoms using a cohort of 18 svMCI with depression symptoms (svMCI+D), 17 svMCI without depression symptoms (svMCI-D), and 23 normal controls (NC). As a result, we identified significantly decreased gray matter density in the left parahippocampus (ParaHIPP.L), the right hippocampus (HIPP.R), and the right middle cingulate cortex (MCC.R) in both svMCI+D and svMCI-D compared to NC. Most importantly, we also identified increased gray matter density in the MCC.R accompanied by increased resting-state functional connectivity (RSFC) with right parahippocampus (ParaHIPP.R) in the svMCI+D compared to svMCI-D. Moreover, the gray matter density of MCC.R and ParaHIPP.L was correlated with cognitive impairments and depression symptoms in the svMCI, respectively. In conclusion, these results extended previous studies and added weight to considerations of depression symptoms in the svMCI. Moreover, we suggested that a processing loop associated with HIPP, ParaHIPP, and MCC might underlie the mechanism of depression symptoms in the svMCI.

Alterations in White Matter Integrity in Young Adults with Smartphone Dependence.

Smartphone dependence (SPD) is increasingly regarded as a psychological problem, however, the underlying neural substrates of SPD is still not clear. High resolution magnetic resonance imaging provides a useful tool to help understand and manage the disorder. In this study, a tract-based spatial statistics (TBSS) analysis on diffusion tensor imaging (DTI) was used to measure white matter integrity in young adults with SPD. A total of 49 subjects were recruited and categorized into SPD and control group based on their clinical behavioral tests. To localize regions with abnormal white matter integrity in SPD, the voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) on the whole brain was performed by TBSS. The correlation between the quantitative variables of brain structures and the behavior measures were performed. Our result demonstrated that SPD had significantly lower white matter integrity than controls in superior longitudinal fasciculus (SLF), superior corona radiata (SCR), internal capsule, external capsule, sagittal stratum, fornix/stria terminalis and midbrain structures. Correlation analysis showed that the observed abnormalities in internal capsule and stria terminalis were correlated with the severity of dependence and behavioral assessments. Our finding facilitated a primary understanding of white matter characteristics in SPD and indicated that the structural deficits might link to behavioral impairments.

Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia.

OBJECTIVE: Retrovirus has been suggested as one of agents involved in the development of schizophrenia. In the present study, we examined the role of the human endogenous retrovirus W family (HERV-W) env gene in the etiopathogenesis of recent-onset schizophrenia, using molecular and epidemiological approaches. METHODS: Nested RT-PCR was used to detect the messenger RNA (mRNA) of the HERV-w env gene in plasmas. Quantitative real-time polymerase chain reaction (PCR) was employed to detect the viral reverse transcriptase activity in human sera. Human U251 glioma cells were used to study the potential role of the HERV-W env gene in the etiopathogenesis of recent-onset schizophrenia. RESULTS: We identified genes with mRNA sequences homologous to HERV-W env gene from plasmas of 42 out of 118 individuals with recent-onset schizophrenia but not from any of 106 normal persons (P < .01, t test). Quantitative real-time PCR showed a significantly increase in the reverse transcriptase activity in the sera of patients (by 35.59%) compared with controls (by 2.83%) (P < .05, t test). Overexpression of HERV-w env in human U251 glioma cells upregulated brain-derived neurotrophic factor (BDNF), an important schizophrenia-associated gene, neurotrophic tyrosine kinase receptor type 2 (NTRK2, also called TrkB), and dopamine receptor D3 and increased the phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein. BDNF promoter reporter gene assays showed that the HERV-W env triggers BDNF production in human U251 glioma cells. Using gene knockdown, we found that CREB is required for the expression of BDNF that is regulated by env. CONCLUSION: Our data revealed that the transcriptional activation of HERV is associated with the development of schizophrenia in some patients and indicated that HERV-W env regulates the expression of schizophrenia-associated genes. This report is the first to elucidate the signaling pathway responsible for the upregulation of HERV-W env-triggered BDNF. Our study provides new evidence for the involvement of HERV-W in the central nervous system, which will benefit the diagnosis and treatment of the devastating schizophrenia and related disorders.

R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer.

Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P < 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors.

Identification and functional characterization of a novel human misshapen/Nck interacting kinase-related kinase, hMINK beta.

Misshapen/NIKs-related kinase (MINK) is a member of the germinal center family of kinases that are homologous to the yeast sterile 20 (Ste20) kinases and regulate a wide variety of cellular processes, including cell morphology, cytoskeletal rearrangement, and survival. Here, we present the cloning and functional characterization of a novel human Misshapen/NIKs-related kinase beta (hMINK beta) that encodes a polypeptide of 1312 amino acids. hMINK beta is ubiquitously expressed in most tissues with at least five alternatively spliced isoforms. Similar to Nck interacting kinase (NIK) and Traf2 and Nck-interacting kinase (TNIK), hMINK beta moderately activates c-Jun N-terminal kinase (JNK) and associates with Nck via the intermediate domain in the yeast two-hybrid system and in a glutathione S-transferase (GST) pull-down assay. Interestingly, overexpression of the kinase domain deleted and kinase-inactive mutants of hMINK beta in human fibrosarcoma HT1080 cells enhanced cell spreading, actin stress fiber formation, and adhesion to extracellular matrix, as well as decreased cell motility and cell invasion. Furthermore, these mutants also promoted cell-cell adhesion in human breast carcinoma MCF7 cells, evidenced with cell growth in clusters and increased membrane localization of beta-catenin, a multifunctional protein involved in E-cadherin-mediated cell adhesion. Finally, hMINK beta protein was found to colocalize with the Golgi apparatus, implicating that hMINK beta might exert its functions, at least in part, through the modulation of intracellular protein transport. Taken together, these results suggest that hMINK beta plays an important role in cytoskeleton reorganization, cell adhesion, and cell motility.