White matter lesions (WMLs) are of considerable research interest because of their high prevalence and serious consequences, such as stroke and dementia. Most existing studies of WMLs have focused on severe WMLs, but mild WMLs, which are clinically and fundamentally significant, have been largely neglected. The present study is a comprehensive investigation on the injury pattern and on the anatomical, functional, and cognitive changes related to mild WMLs. These results may provide better understanding mild WMLs. Fifty-one human subjects with mild WMLs and 49 control participants completed serial neuropsychological tests and underwent a 3-T magnetic resonance imaging (MRI) scan that included diffusion tensor imaging, a resting-state functional MRI, and a structural MRI. We found declines in cognitive functions such as global function, executive function, and episodic memory in mild WMLs subjects. The white matter injuries in the mild WMLs subjects were mainly in the fibers that projected to frontal areas, while gray matter structures were relatively intact. The overall resting state function of the frontal area was significantly increased. The integrity of the neural fibers in the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus was significantly correlated with the cognitive scores in executive function and episodic memory in both the control and the mild WMLs group. These findings demonstrate that mild WMLs subjects exhibit abnormalities in both white matter structure and functional intrinsic brain activity and that such changes are related to several types of cognitive dysfunction.
The purpose of this study was to investigate the relationship between the expression of ribonucleotide reductase subunit M1 (RRM1) protein and the efficacy of gemcitabine/cisplatin (GP) adjuvant chemotherapy in postoperative non-small cell lung cancer (NSCLC) patients.
The use of photoluminescent probes for differentiating free amino acids from biomolecules containing the same amino acids is challenging. Photoluminescent probes generally present similar emission spectra when in the presence of either free-amino acids or protein containing those same amino acids. Probes based on cyclometalated iridium(III) complexes Ir(L)2(sol)2 (where L is 2-phenylpyridine, 2-(2,4-difluorophenyl)pyridine, or benzo[h]quinolone, and sol is a solvent molecule) present long-lived emission when bound to histidine. This emission is tuned by the microenvironment around the complex and therefore its lifetime is different for free histidine (487 ns) than from histidine-containing proteins such as bovine serum albumin (average lifetime > 700 ns). As a proof-of-concept we demonstrate that free histidine can be discerned from a mixture with histidine-containing proteins by using time-resolved photoluminescence decays. In the presence of multiple sources of histidine, iridium(III) probes display a multiexponential decay, which can be fitted by nonlinear least-squares methods to separate the different components. Because the pre-exponential factor of the 487 ns lifetime is proportional to the concentration of free histidine, we can use it to assess the amount of free histidine in solution even in the presence of proteins such as bovine serum albumin. We also show that iridium(III) probes displaying different photoluminescence maxima can be produced by modifying the ancillary ligands of the metal complex.
Features of path dependent energy transfer in a dual-ring light-harvesting (LH2) complexes (B850) system have been examined in detail systematically. The Frenkel-Dirac time dependent variational method with the Davydov D1 Ansatz is employed with detailed evolution of polaron dynamics in real space readily obtained. It is found that the phase of the transmission amplitude through the LH2 complexes plays an important role in constructing the coherent excitonic energy transfer. It is also found that the symmetry breaking caused by the dimerization of bacteriochlorophylls and coherence or correlation between two rings will be conducive in enhancing the exciton transfer efficiency.
Abstract Purpose: To determine the postoperative symptom by using inferior conjunctival autografting (ICA) rather than superior conjunctival autografting (SCA) after excision of pterygium. Methods: This prospective randomized control study evaluated 80 eyes of 80 consecutive patients undergoing primary pterygium surgery. Patients in each subgroup were then randomized into the ICA (n?=?40) or SCA (n?=?40) group. All patients were asked to return for follow up on days 1, 2, 3, 5, 7, and 14 then at months 1, 3, 6, and 12 postoperatively. Outcome measures were postoperative patient discomfort, corneal epithelial healing time, complications and recurrence rate. Results: Fluorescein staining revealed complete corneal epithelial healing time was 3.1?±?0.5 d (range 2-4) in the ICA group and 3.3?±?0.6 d (range 2-4) in the SCA group (p?=?0.11). Pain scores were significantly less in the ICA group than the SCA group on follow-up days 3 and 5 (p?0.05). Postoperative foreign body sensation scores on follow-up days 5 and 7 were significantly lower in the ICA group than the SCA group (p?0.05). Epiphora scores were significantly less in the ICA group than the SCA group on follow-up days 3, 5, and 7 (p?0.05). No statistically significant differences between two groups were found for the overall (conjunctival and corneal) recurrence rates (5% versus 7.5%, p?=?0.64). No serious complications were encountered. Conclusion: Pterygium excision with ICA led to less postoperative discomfort for patients with primary pterygium.
Organometal halide perovskites have recently attracted tremendous attention due to their potential for photovoltaic applications, and they are also considered as promising materials in light emitting and lasing devices. In this work, we investigated in detail the cryogenic steady state photoluminescence properties of a prototypical hybrid perovskite CH3NH3PbI3-xClx. The evolution of the characteristics of two excitonic peaks coincides with the structural phase transition around 160 K. Our results further revealed an exciton binding energy of 62.3 ± 8.9 meV and an optical phonon energy of 25.3 ± 5.2 meV, along with an abnormal blue-shift of the band gap in the high-temperature tetragonal phase.
The neural processes associated with becoming aware of sad mood are not fully understood. We examined the dynamic process of becoming aware of sad mood and recovery from sad mood. Sixteen healthy subjects underwent fMRI while participating in a sadness induction task designed to allow for variable mood induction times. Individualized regressors linearly modeled the time periods during the attainment of self-reported sad and baseline "neutral" mood states, and the validity of the linearity assumption was further tested using independent component analysis. During sadness induction the dorsomedial and ventrolateral prefrontal cortices, and anterior insula exhibited a linear increase in the blood oxygen level-dependent (BOLD) signal until subjects became aware of a sad mood and then a subsequent linear decrease as subjects transitioned from sadness back to the non-sadness baseline condition. These findings extend understanding of the neural basis of conscious emotional experience.
Since Apolipoprotein E (APOE) ?4 allele is a major genetic risk factor for sporadic Alzheimer's disease (AD), which has been suggested as a disconnection syndrome manifested by the disruption of white matter (WM) integrity and functional connectivity(FC), elucidating the subtle brain structural and functional network changes in cognitively normal ?4 carriers is essential for identifying sensitive neuroimaging based biomarkers and understanding the preclinical AD related abnormality development. We first constructed functional network based on the resting-state functional magnetic resonance imaging and structural network based on diffusion tensor image. Using global, local and nodal efficiencies of these two networks, we then examined 1) the differences of functional and WM structural network between cognitively normal ?4 carriers and non-carriers simultaneously, 2) the sensitivity of these indices as biomarkers, and 3) their relationship to behavior measurements as well as to cholesterol level. For ?4 carriers, we found reduced global efficiency significantly in WM and marginally in FC, regional FC dysfunctions mainly in medial temporal areas, and more widespread for WM network. Importantly, the right parahippocampal gyrus (PHG.R) was the only region with simultaneous functional and structural damage, and the nodal efficiency of PHG.R in WM network mediates the APOE ?4 effect on memory function. Finally, the cholesterol level correlated with WM network differently than with functional network in ?4 carriers. Our results demonstrated ?4-specific abnormal structural and functional patterns, which may potentially serve as biomarkers for early detection before the onset of the disease.Neuropsychopharmacology accepted article preview online, 18 November 2014. doi:10.1038/npp.2014.302.
Intrahepatic biliary cystadenoma (IHBCA) is a rare type of liver tumor. There are no specific diagnostic methods for IHBCA, so its preoperative diagnostic rate is still fairly low. The aims of this study were to evaluate the clinical manifestations, diagnosis, and treatment of IHBCA. We retrospectively analyzed data from 14 patients treated in our hospital from January 2004 to April 2014. Eleven patients (78.6 %) were female, and the average age was 48.0 years (range 16-77 years). The most common clinical symptoms were abdominal discomfort (i.e., abdominal pain), reported in seven cases (50 %), and fullness after eating, reported in two cases (14.3 %). Jaundice was a less common symptom reported in one case (7.1 %). Four patients (28.6 %) were asymptomatic. Enhanced computed tomography (CT) scan showed multilocular or internal septations in 11 cases (78.6 %) and papillary projections or mural nodules on the cyst wall in one case (7.1 %). After injection of a contrast agent, the cyst walls or septations were slightly enhanced in nine cases (64.3 %). All 14 patients underwent surgical resection. Only one case showed recurrence (2 years postoperatively); the remaining 13 patients were recurrence-free. Intrahepatic biliary cystadenoma often occurs in middle-aged women. The main clinical symptoms are abdominal fullness with a sense of pain and jaundice. Enhanced CT is the main preoperative diagnostic method. Radical resection is the best treatment for IHBCA and can effectively prevent recurrence.
Phosphate (Pi) deficiency has become a significant challenge to worldwide agriculture due to the depletion of accessible rock phosphate that is the major source of cheap Pi fertilizers. Previous research has identified a number of diverse adaptive responses to Pi starvation in the roots of higher plants. In this study, we found that accelerated axile root elongation of Pi-deprived maize plants resulted from enhanced cell proliferation. Comparative phosphoproteome and proteome profiles of maize axile roots were conducted in four stages in response to Pi deficiency by multiplex staining of high-resolution two dimensional gel separated proteins. Pro-Q DPS stained gels revealed that 6% of phosphoprotein spots displayed changes in phosphorylation state following low-Pi treatment. These proteins were involved in a large number of metabolic and cellular pathways including carbon metabolism and signal transduction. Changes in protein abundance of a number of enzymes indicated that low-Pi induced a number of carbon flux modifications in metabolic processes including sucrose breakdown and other downstream sugar metabolic pathways. A few key metabolic enzymes, including sucrose synthase (EC 220.127.116.11) and malate dehydrogenase (EC 18.104.22.168), and several signaling components involved in protein kinase or phosphatase cascades, auxin signaling and 14-3-3 proteins displayed low-Pi responsive changes in phosphorylation state or protein abundance. A variety of key enzymes and signaling components identified as potential targets for phosphorylation provide novel clues for comprehensive understanding of Pi regulation in plants. Protein phosphorylation, coordinating with changes in protein abundance, is required for maize root metabolic regulation and developmental acclimation to Pi starvation.
The ZnO/mpg-C3N4 composite photocatalyst with high visible light activity was successfully synthesized by a facile solvothermal method and characterized by thermogravimetric analysis (TGA), X-ray diffraction (XRD), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM) and UV-vis diffuse reflectance spectroscopy (DRS). The results indicated that ZnO particles dispersed uniformly on the mpg-C3N4 sheet. The photocatalytic activity of ZnO/mpg-C3N4 for photodegradation of MB was much higher than that of pure mpg-C3N4 both under the visible light and simulated solar irradiation. The optimal ZnO content for the photocatalytic activity of the ZnO/mpg-C3N4 composites is 24.9%, which is almost 2.3 times as high as that of pure mpg-C3N4 under visible light, and 1.9 times higher than that under simulated solar irradiation. The enhancement in photocatalytic activity should be assigned to the effective separation and transfer of photogenerated charges coming from the well-matched overlapping band-structure between mpg-C3N4 and ZnO. Radical trap experiments show that both ZnO/mpg-C3N4 composites and mpg-C3N4 have the same photodegradation mechanism, and the holes are their main oxidative species for MB degradation.
Pharmaceutical nanotechnology holds potential in cancer chemotherapy. In this research, the docetaxel-loaded D-alpha-tocopheryl polyethylene glycol 1000 succinate-b-poly(epsilon-caprolactone-ran-lactide) (TPGS-b-(PCL-ran-PLA)) nanoparticles were prepared by a modified nanoprecipitation method and then the particle size, surface morphology, nanoparticle stability, in vitro drug release and cellular uptake of nanoparticles were characterized. Finally, we evaluated the therapeutic effects of nanoparticle formulation in comparison with Taxotere both in vitro and in vivo. The size of TPGS-b-(PCL-ran-PLA) nanoparticles was about 150 nm and much smaller than PCL nanoparticles (about 185 nm) and the absolute value of zeta potential was higher than PCL nanoparticles (16.49 mV vs. 13.17 mV). FESEM images further confirmed the morphology and size of nanoparticles. The drug-loaded nanoparticles were considered to be stable, showing no change in the particle size and surface charge during three-month storage of its aqueous solution. In vitro drug release of TPGS-b-(PCL-ran-PLA) nanoparticles was much faster than PCL and PCL-TPGS nanoparticles. The cumulative drug release of docetaxel-loaded TPGS-b-(PCL-ran-PLA), PCL-TPGS, and PCL NPs were 38.00%, 34.48% and 29.04%, respectively. TPGS-b-(PCL-ran-PLA) nanoparticles showed an obvious increase of cellular uptake. Due to the advantages of TPGS-b-(PCL-ran-PLA) nanoparticles, it could achieve significantly higher level of cytotoxicity in vitro and better inhibition effect of tumor growth on xenograft BALB/c nude mice tumor model than commercial Taxotere at the same dose (1.49-fold more effective). The TPGS-b-(PCL-ran-PLA) could be used as a novel and potential biodegradable polymeric material for nanoformulation in cervical cancer chemotherapy.
To investigate structural covariance networks (SCNs) as measured by regional gray matter volumes with structural magnetic resonance imaging (MRI) from healthy young adults, and to examine their consistency and stability.
We present a microfabricated 10 by 10 array of microneedles for the treatment of a neurological disease called communicating hydrocephalus. Together with the previously reported microvalve array, the current implantable microneedle array completes the microfabricated arachnoid granulations (MAGs) that mimic the function of normal arachnoid granulations (AGs). The microneedle array was designed to enable the fixation of the MAGs through dura mater membrane in the brain and thus provide a conduit for the flow of cerebrospinal fluid (CSF). Cone-shaped microneedles with hollow channels were fabricated using a series of microfabrication techniques: SU-8 photolithography for tapered geometry, reactive ion etching for sharpening the microneedles, 248 nm deep UV excimer laser machining for creating through-hole inside the microneedles, and metal sputtering for improved rigidity. Puncture tests were conducted using porcine dura mater and the results showed that the fabricated microneedle array is strong enough to pierce the dura mater. The in-vitro biocompatibility test result showed that none of the 100 outlets of the microneedles exposed to the bloodstream were clogged significantly by blood cells. We believe that these test results demonstrate the potential use of the microneedle array as a new treatment of hydrocephalus.
The polar lipid fraction E (PLFE) isolated from the thermoacidophilic archaeon Sulfolobus acidocaldarius contains exclusively bipolar tetraether lipids, which are able to form extraordinarily stable vesicular membranes against a number of chemical, physical, and mechanical stressors. PLFE liposomes have thus been considered appealing biomaterials holding great promise for biotechnology applications such as drug delivery and biosensing. Here we demonstrated that PLFE can also form free-standing "planar" membranes on micropores (?100 ?m) of polydimethylsiloxane (PDMS) thin films embedded in printed circuit board (PCB)-based fluidics. To build this device, two novel approaches were employed: (i) an S1813 sacrificial layer was used to facilitate the fabrication of the PDMS thin film, and (ii) oxygen plasma treatment was utilized to conveniently bond the PDMS thin film to the PCB board and the PDMS fluidic chamber. Using electrochemical impedance spectroscopy, we found that the dielectric properties of PLFE planar membranes suspended on the PDMS films are distinctly different from those obtained from diester lipid and triblock copolymer membranes. In addition to resistance (R) and capacitance (C) that were commonly seen in all the membranes examined, PLFE planar membranes showed an inductance (L) component. Furthermore, PLFE planar membranes displayed a relatively large membrane resistance, suggesting that, among the membranes examined, PLFE planar membrane would be a better matrix for studying channel proteins and transmembrane events. PLFE planar membranes also exhibited a sharp decrease in phase angle with the frequency of the input AC signal at ?1 MHz, which could be utilized to develop sensors for monitoring PLFE membrane integrity in fluidics. Since the stability of free-standing planar lipid membranes increases with increasing membrane packing tightness and PLFE lipid membranes are more tightly packed than those made of diester lipids, PLFE free-standing planar membranes are expected to be considerably stable. All these salient features make PLFE planar membranes particularly attractive for model studies of channel proteins and transmembrane events and for high-throughput drug screening and artificial photosynthesis. This work can be extended to nanopores of PDMS thin films in microfluidics and eventually aid in membrane-based new lab-on-a-chip applications.
Silent or asymptomatic lacunar infarcts (LACI) are common in elderly individuals, but it remains largely unclear how these often neglected silent brain infarcts lead to multiple domain cognitive deficits and even Alzheimer's disease (AD). In this study, we investigated the difference between patients with silent LACI in basal ganglia region and healthy controls for the structural and functional changes in the aspects of alterations of gray matter (GM) volume and intra-/inter-default mode network (DMN) and salience network (SN) connectivity. Thirty patients with silent LACI in the basal ganglia region and thirty healthy controls participated in the study. Voxel-based morphometry analysis was employed to measure the GM volume. We further investigated the intra/inter-network connectivity of DMN and SN using resting-state functional magnetic resonance imaging. Compared with healthy controls, patients performed worse in cognitive function in the aspects of general mental status, attention, and memory. The LACIs showed more severe GM atrophy in insula, anterior cingulate cortex, caudate, and superior temporal pole than controls. The connectivity within and between two networks was also reduced in patients. Importantly, the disrupted connectivity correlated with the patients' cognitive performance. Our findings support the hypothesis that silent lacunar infarcts result in cognitive decline, GM, and functional connectivity loss.
The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China.
Although a number of studies have indicated that the positive expression of nucleophosmin (NPM) and trefoil factor 3 (TFF3) is associated with oncogenesis and poor prognosis in several tumor types, the prognostic value of the co-expression of NPM and TFF3 in gastric cancer (GC) has not been fully elucidated. Therefore, in this study, we aimed to investigate the role of NPM and TFF3 in GC and determine their prognostic value. We retrospectively reviewed 108 patients who had undergone radical gastric tumor resection. The expression of NPM and TFF3 was detected by immunohistochemistry and the association of NPM and TFF3 with clinicopathological characteristics was investigated using the Chi-square test. Furthermore, univariate and multivariate analyses were conducted to determine the prognostic value of these markers. Of the 108 samples, NPM was positive in 57 (53%) and TFF3 was positive in 54 samples (50%). The positive expression of NPM was correlated with advanced tumor stage and recurrence (P=0.0333 and P<0.0001, respectively), whereas the expression of TFF3 was associated with larger tumor size (P=0.0005), poor differentiation (P=0.0435), lymph node metastasis (P=0.0116), advanced tumor stage (P=0.0244) and recurrence (P=0.0116). The univariate analysis revealed that the expression of NPM, the expression of TFF3 and the co-expression of the two were associated with poor survival (P=0.0004, 0.0028 and 0.0020, respectively). By multivariate analysis, all three factors were identified as independent prognostic factors in postoperative GC patients (hazard ratio = 1.970, 2.021 and 2.339, respectively). In conclusion, the expression of NPM and TFF3 and, particularly, the co-expression of the two, may serve as independent prognostic factors in postoperative GC patients.
With a longer life expectancy and an increased prevalence of neurodegenerative diseases, investigations on trajectories of cognitive aging have become exciting and promising. This study aimed to estimate the patterns of age-related cognitive decline and the potential associated factors of cognitive function in community-dwelling residents of Beijing, China. In this study, 1248 older adults aged 52-88 years [including 175 mild cognitive impairment (MCI) subjects] completed a battery of neuropsychological scales. The personal information, including demographic information, medical history, eating habits, lifestyle regularity and leisure activities, was also collected. All cognitive function exhibited an agerelated decline in normal volunteers. Piece-wise linear fitting results suggested that performance on the Auditory Verbal Learning Test remained stable until 58 years of age and continued to decline thereafter. The decline in processing speed and executive function began during the early 50's. Scores on visual-spatial and language tests declined after 66 years of age. The decline stage of the general mental status ranged from 63 to 70 years of age. However, the MCI group did not exhibit an obvious age-related decline in most cognitive tests. Multivariate linear regression analyses indicated that education, gender, leisure activities, diabetes and eating habits were associated with cognitive abilities. These results indicated various trajectories of age-related decline across multiple cognitive domains. We also found different patterns of agerelated cognitive decline between MCI and normal elderly. These findings could help improve the guidance of cognitive intervention program and have implications for public policy issues.
Mild Cognitive Impairment (MCI) is a transitional stage between normal aging and dementia and people with MCI are at high risk of progression to dementia. MCI is attracting increasing attention, as it offers an opportunity to target the disease process during an early symptomatic stage. Structural magnetic resonance imaging (MRI) measures have been the mainstay of Alzheimer's disease (AD) imaging research, however, ventricular morphometry analysis remains challenging because of its complicated topological structure. Here we describe a novel ventricular morphometry system based on the hyperbolic Ricci flow method and tensor-based morphometry (TBM) statistics. Unlike prior ventricular surface parameterization methods, hyperbolic conformal parameterization is angle-preserving and does not have any singularities. Our system generates a one-to-one diffeomorphic mapping between ventricular surfaces with consistent boundary matching conditions. The TBM statistics encode a great deal of surface deformation information that could be inaccessible or overlooked by other methods. We applied our system to the baseline MRI scans of a set of MCI subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI: 71 MCI converters vs. 62 MCI stable). Although the combined ventricular area and volume features did not differ between the two groups, our fine-grained surface analysis revealed significant differences in the ventricular regions close to the temporal lobe and posterior cingulate, structures that are affected early in AD. Significant correlations were also detected between ventricular morphometry, neuropsychological measures, and a previously described imaging index based on fluorodeoxyglucose positron emission tomography (FDG-PET) scans. This novel ventricular morphometry method may offer a new and more sensitive approach to study preclinical and early symptomatic stage AD.
Polyvinyl alcohol functionalized carbon black with H2S-sensor moieties can be pumped through oil and water in porous rock and the H2S content can be determined based on the fluorescent enhancement of the H2S-sensor addends.
To investigate effects and functional mechanism of compound Congrongyizhi Capsule (CCRC), a Chinese medicine, on cognitive functions against amnestic mild cognitive impairment (aMCI) patients with functional magnetic resonance imaging (fMRI) based on n-back task.
Hepatic apoptosis is thought of as a prevalent mechanism in most forms of liver injury. However, the role of hepatic apoptosis is often intermixed with the cellular necrosis. It remains unknown how apoptosis is relevant to the progression of the liver injury. This review summarizes the characteristics of both hepatic apoptosis and necrosis in pathogenesis of liver diseases. Apoptosis and necrosis represent alternative outcomes of different etiology during liver injury. Apoptosis is a main mode of cell death in chronic viral hepatitis, but is intermingled with necrosis in cholestatic livers. Necrosis is the principal type of liver cell killing in acetaminophen-induced hepatotoxicity. Anti-apoptosis as a strategy is beneficial to liver repair response. Therapeutic options of liver disease depend on the understanding toward pathogenic mechanisms of different etiology.
Various amnestic mild cognitive impairment (aMCI) subtypes have been identified as single domain (SD) or multiple domain (MD), with differential probabilities of progression to Alzheimer disease (AD). Detecting the differences in the alterations in gray matter (GM) and intrinsic brain activity between the subtypes of aMCI help to understand their pathophysiological mechanisms and was conducive to construct such potential biomarkers to monitor the progression of aMCI.
Biosensors for in situ detection of pathogenic bacteria in liquid are developed using magnetostrictive particles (MSP) as the sensor platform. The sensing elements used are phage E2 against Salmonella typhimurium, monoclonal antibody against Listeria monocytogenes, polyclonal antibody against Escherichia coli, and polyclonal antibody against Staphylococcus aureus, respectively. These biosensors were characterized in cultures with different populations ranging from 5?×?10(1) to 5?×?10(8) ?cfu/mL. It is found that the MSP-based biosensors work well in water and have a rapid response with a response time in minutes, which makes the MSP-based sensors suitable for in situ and real-time detection of pathogenic bacteria in liquid. The experimental results show that all MSP-phage and MSP-antibody biosensors in size of 1.0?mm?×?0.3?mm?×?15?µm exhibit a detection limit better than 100?cfu/mL. Based on the Hill plot, it is concluded that each bacterial cell is bound onto the sensor surface through about four-to-five sites. When the cultures with low population (<10(6) ?cfu/mL) are tested, both MSP-phage and MSP-antibody sensors exhibit the similar response. However, the phage-MSP sensors exhibit a higher capability in the capture of target bacterial cell.
Based on previous studies, a preclinical classification for Alzheimer's disease (AD) has been proposed. However, 1) specificity of the different neuronal injury (NI) biomarkers has not been studied, 2) subjects with subtle cognitive impairment but normal NI biomarkers (SCINIB) have not been included in the analyses and 3) progression to mild cognitive impairment (MCI) or dementia of the AD type (DAT), referred to here as MCI/DAT, varies between studies. Therefore, we analyzed data from 486 cognitively normal (CN) and 327 DAT subjects in the AD Neuroimaging Initiative (ADNI)-1/GO/2 cohorts.
Lung cancer is an inflammation-associated epithelial carcinoma. A highly active interleukin 6 (IL-6)/glycoprotein 130 (gp130)/signal transducer and activator of transcription 3 (STAT3) pathway has been identified in a subset of primary lung cancer and closely correlated with tumor progression and poor prognosis. In a previous study, the frequent occurrence of somatic gain-of-function mutations was observed in the gp130-encoding IL6ST gene in exon 6 in 60% of inflammatory hepatocellular adenomas. Prompted by this finding, we assessed 110 Chinese lung carcinomas using PCR and direct DNA sequencing but found no somatic mutation of IL6ST in exon 6. However, one new potential germline missense mutation c.599C>G was identified in one adenocarcinoma that harbors wild-type epidermal growth factor receptor and KRAS. Protein modeling analysis showed that this mutation might not affect the gp130 protein conformation. Moreover, activated STAT3 was observed in most of the lung tumor tissues at a higher level than that in matched normal lung tissues. In conclusion, the c.599C>G mutation may be a new single nucleotide polymorphism of IL6ST, but mutations in exon 6 of this gene are not apparently common genetic variations occurring and leading to constitutive activation of STAT3 in lung cancer.
A-type Kv4 potassium channels undergo a conformational change toward a nonconductive state at negative membrane potentials, a dynamic process known as pre-open closed states or closed-state inactivation (CSI). CSI causes inhibition of channel activity without the prerequisite of channel opening, thus providing a dynamic regulation of neuronal excitability, dendritic signal integration, and synaptic plasticity at resting. However, the structural determinants underlying Kv4 CSI remain largely unknown. We recently showed that the auxiliary KChIP4a subunit contains an N-terminal Kv4 inhibitory domain (KID) that directly interacts with Kv4.3 channels to enhance CSI. In this study, we utilized the KChIP4a KID to probe key structural elements underlying Kv4 CSI. Using fluorescence resonance energy transfer two-hybrid mapping and bimolecular fluorescence complementation-based screening combined with electrophysiology, we identified the intracellular tetramerization (T1) domain that functions to suppress CSI and serves as a receptor for the binding of KID. Disrupting the Kv4.3 T1-T1 interaction interface by mutating C110A within the C3H1 motif of T1 domain facilitated CSI and ablated the KID-mediated enhancement of CSI. Furthermore, replacing the Kv4.3 T1 domain with the T1 domain from Kv1.4 (without the C3H1 motif) or Kv2.1 (with the C3H1 motif) resulted in channels functioning with enhanced or suppressed CSI, respectively. Taken together, our findings reveal a novel (to our knowledge) role of the T1 domain in suppressing Kv4 CSI, and that KChIP4a KID directly interacts with the T1 domain to facilitate Kv4.3 CSI, thus leading to inhibition of channel function.
Survivin is a promising anticancer therapeutic target due to its important role in the inhibition of apoptosis of tumor cells. However, little is currently known about its role in non small cell lung cancer (NSCLC). The present study evaluated whether the downregulation of survivin expression would affect cell proliferation, cell cycle distribution, apoptosis and colony formation of NSCLC. A recombinant lentiviral small hairpin RNA (shRNA) expression vector, which specifically targeted survivin, was constructed and transfected into the A549 human NSCLC cell line. Quantitative polymerase chain reaction and western blotting were used to determine the mRNA and protein expression levels of survivin, 48 h following the knockdown of survivin expression. Cell proliferation, apoptosis, cell cycle distribution and colony formation were determined following the downregulation of survivin by shRNA. In addition, A549 cells were injected into nude mice, and the effects of shRNA targeting the survivin gene on tumor growth were assessed. Downregulation of survivin expression, using the RNA silencing approach in A549 tumor cells, significantly suppressed the proliferation and colony formation ability of the cells, and induced tumor apoptosis in vitro. The nude mice inoculated with A549 cells developed cancer, and treatment with shRNA targeting survivin markedly inhibited the growth of these cancers, with no obvious side effects. The results of the present study suggest that suppression of survivin expression by RNA interference may induce NSCLC apoptosis, and provide a novel approach for anticancer gene therapy.
There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials.
Cytokinins are a major group of phytohormones regulating plant growth, development and stress responses. However, in contrast to the well-defined polar transport of auxins, the molecular basis of cytokinin transport is poorly understood. Here we show that an ATP-binding cassette transporter in Arabidopsis, AtABCG14, is essential for the acropetal (root to shoot) translocation of the root-synthesized cytokinins. AtABCG14 is expressed primarily in the pericycle and stelar cells of roots. Knocking out AtABCG14 strongly impairs the translocation of trans-zeatin (tZ)-type cytokinins from roots to shoots, thereby affecting the plant's growth and development. AtABCG14 localizes to the plasma membrane of transformed cells. In planta feeding of C(14) or C(13)-labelled tZ suggests that it acts as an efflux pump and its presence in the cells directly correlates with the transport of the fed cytokinin. Therefore, AtABCG14 is a transporter likely involved in the long-distance translocation of cytokinins in planta.
The Independent Component Analysis (ICA)-linear non-Gaussian acyclic model (LiNGAM), an algorithm that can be used to estimate the causal relationship among non-Gaussian distributed data, has the potential value to detect the effective connectivity of human brain areas. Under the assumptions that (a): the data generating process is linear, (b) there are no unobserved confounders, and (c) data have non-Gaussian distributions, LiNGAM can be used to discover the complete causal structure of data. Previous studies reveal that the algorithm could perform well when the data points being analyzed is relatively long. However, there are too few data points in most neuroimaging recordings, especially functional magnetic resonance imaging (fMRI), to allow the algorithm to converge. Smith's study speculates a method by pooling data points across subjects may be useful to address this issue (Smith et al., 2011). Thus, this study focus on validating Smith's proposal of pooling data points across subjects for the use of LiNGAM, and this method is named as pooling-LiNGAM (pLiNGAM). Using both simulated and real fMRI data, our current study demonstrates the feasibility and efficiency of the pLiNGAM on the effective connectivity estimation.
Recent multivariate neuroimaging studies have revealed aging-related alterations in brain structural networks. However, the sensory/motor networks such as the auditory, visual and motor networks, have obtained much less attention in normal aging research. In this study, we used Gaussian Bayesian networks (BN), an approach investigating possible inter-regional directed relationship, to characterize aging effects on structural associations between core brain regions within each of these structural sensory/motor networks using volumetric MRI data. We then further examined the discriminability of BN models for the young (N = 109; mean age =22.73 years, range 20-28) and old (N = 82; mean age =74.37 years, range 60-90) groups. The results of the BN modeling demonstrated that structural associations exist between two homotopic brain regions from the left and right hemispheres in each of the three networks. In particular, compared with the young group, the old group had significant connection reductions in each of the three networks and lesser connection numbers in the visual network. Moreover, it was found that the aging-related BN models could distinguish the young and old individuals with 90.05, 73.82, and 88.48% accuracy for the auditory, visual, and motor networks, respectively. Our findings suggest that BN models can be used to investigate the normal aging process with reliable statistical power. Moreover, these differences in structural inter-regional interactions may help elucidate the neuronal mechanism of anatomical changes in normal aging.
PET (positron emission tomography) imaging researches of functional metabolism using fluorodeoxyglucose (18F-FDG) of animal brain are important in neuroscience studies. FDG-PET imaging studies are often performed on groups of rats, so it is desirable to establish an objective voxel-based statistical methodology for group data analysis.
Recent neuroimaging studies have revealed normal aging-related alterations in functional and structural brain networks such as the default mode network (DMN). However, less is understood about specific brain structural dependencies or interactions between brain regions within the DMN in the normal aging process. In this study, using Bayesian network (BN) modeling, we analyzed gray matter volume data from 109 young and 82 old subjects to characterize the influence of aging on associations between core brain regions within the DMN. Furthermore, we investigated the discriminability of the aging-associated BN models for the young and old groups. Compared to their young counterparts, the old subjects showed significant reductions in connections from right inferior temporal cortex (ITC) to medial prefrontal cortex (mPFC), right hippocampus (HP) to right ITC, and mPFC to posterior cingulate cortex and increases in connections from left HP to mPFC and right inferior parietal cortex to right ITC. Moreover, the classification results showed that the aging-related BN models could predict group membership with 88.48% accuracy, 88.07% sensitivity, and 89.02% specificity. Our findings suggest that structural associations within the DMN may be affected by normal aging and provide crucial information about aging effects on brain structural networks.
Phosphorus deficiency limits plant growth and development. To better understand the mechanisms behind how maize responds to phosphate stress, we compared the proteome analysis results of two groups of maize leaves that were treated separately with 1,000 µM (control, +P) and 5 µM of KH2PO4 (intervention group, -P) for 25 days. In total, 1,342 protein spots were detected on 2-DE maps and 15.43% had changed (P<0.05; ?1.5-fold) significantly in quantity between the +P and -P groups. These proteins are involved in several major metabolic pathways, including photosynthesis, carbohydrate metabolism, energy metabolism, secondary metabolism, signal transduction, protein synthesis, cell rescue and cell defense and virulence. The results showed that the reduction in photosynthesis under low phosphorus treatment was due to the down-regulation of the proteins involved in CO2 enrichment, the Calvin cycle and the electron transport system. Electron transport and photosynthesis restrictions resulted in a large accumulation of peroxides. Maize has developed many different reactive oxygen species (ROS) scavenging mechanisms to cope with low phosphorus stress, including up-regulating its antioxidant content and antioxidase activity. After being subjected to phosphorus stress over a long period, maize may increase its internal phosphorus utilization efficiency by altering photorespiration, starch synthesis and lipid composition. These results provide important information about how maize responds to low phosphorus stress.
Clinical trials on early stage Alzheimers disease (AD) are reaching a bottleneck because none of the current disease markers changes appreciably early in the disease process and therefore a huge sample is required to adequately power such trials. We propose a method to combine multiple markers so that the longitudinal rate of progression can be improved. The criterion is to maximize the probability that the combined marker will be decreased over time (assuming a negative mean slope for each marker). We propose estimates to the weights of markers in the optimum combination and a confidence interval estimate to the combined rate of progression through the maximum likelihood estimates and a bootstrap procedure. We conduct simulations to assess the performance of our estimates and compare our approach with the first principal component from a principal component analysis. The proposed method is applied to a real world sample of individuals with preclinical AD to combine measures from two cognitive domains. The combined cognitive marker is finally used to design future clinical trials on preclinical AD, demonstrating a significant improvement in reducing the sample sizes needed to power such trials when compared with individual markers alone.
Transient receptor potential vanilloid type 1 (TRPV1) channel responds to a wide spectrum of physical and chemical stimuli. In doing so, it serves as a polymodal cellular sensor for temperature change and pain. Many chemicals are known to strongly potentiate TRPV1 activation, though how this is achieved remains unclear. In this study we investigated the molecular mechanism underlying the gating effects of divalent cations Mg(2+) and Ba(2+). Using a combination of fluorescence imaging and patch-clamp analysis, we found that these cations potentiate TRPV1 gating by most likely promoting the heat activation process. Mg(2+) substantially lowers the activation threshold temperature; as a result, a significant fraction of channels are heat-activated at room temperature. Although Mg(2+) also potentiates capsaicin- and voltage-dependent activation, these processes were found either to be not required (in the case of capsaicin) or insufficient (in the case of voltage) to mediate the activating effect. In support of a selective effect on heat activation, Mg(2+) and Ba(2+) cause a Ca(2+)-independent desensitization that specifically prevents heat-induced channel activation but does not prevent capsaicin-induced activation. These results can be satisfactorily explained within an allosteric gating framework in which divalent cations strongly promote the heat-dependent conformational change or its coupling to channel activation, which is further coupled to the voltage- and capsaicin-dependent processes.
Divalent cations Mg(2+) and Ba(2+) selectively and directly potentiate transient receptor potential vanilloid type 1 heat activation by lowering the activation threshold into the room temperature range. We found that Mg(2+) potentiates channel activation only from the extracellular side; on the intracellular side, Mg(2+) inhibits channel current. By dividing the extracellularly accessible region of the channel protein into small segments and perturbing the structure of each segment with sequence replacement mutations, we observed that the S1-S2 linker, the S3-S4 linker, and the pore turret are all required for Mg(2+) potentiation. Sequence replacements at these regions substantially reduced or eliminated Mg(2+)-induced activation at room temperature while sparing capsaicin activation. Heat activation was affected by many, but not all, of these structural alternations. These observations indicate that extracellular linkers and the turret may interact with each other. Site-directed fluorescence resonance energy transfer measurements further revealed that, like heat, Mg(2+) also induces structural changes in the pore turret. Interestingly, turret movement induced by Mg(2+) precedes channel activation, suggesting that Mg(2+)-induced conformational change in the extracellular region most likely serves as the cause of channel activation instead of a coincidental or accommodating structural adjustment.
Structure learning of Bayesian Networks (BNs) is an important topic in machine learning. Driven by modern applications in genetics and brain sciences, accurate and efficient learning of large-scale BN structures from high-dimensional data becomes a challenging problem. To tackle this challenge, we propose a Sparse Bayesian Network (SBN) structure learning algorithm that employs a novel formulation involving one L1-norm penalty term to impose sparsity and another penalty term to ensure that the learned BN is a Directed Acyclic Graph--a required property of BNs. Through both theoretical analysis and extensive experiments on 11 moderate and large benchmark networks with various sample sizes, we show that SBN leads to improved learning accuracy, scalability, and efficiency as compared with 10 existing popular BN learning algorithms. We apply SBN to a real-world application of brain connectivity modeling for Alzheimers disease (AD) and reveal findings that could lead to advancements in AD research.
We report a strategy to make use of poly(lactic-co-glycolic acid) nanoparticle (PLGA NPs) for co-delivery of docetaxel (DTX) as a model anticancer drug together with vitamin E TPGS. The latter plays a dual role as a pore-forming agent in the nanoparticles that may result in smaller particle size, higher drug encapsulation efficiency and faster drug release, and also as a bioactive agent that could inhibit P-glycoprotein to overcome multi-drug resistance of the cancer cells, The DTX-loaded PLGA NPs of 0, 10, 20 and 40% TPGS were prepared by the nanoprecipitation method and then characterized for their size and size distribution, surface morphology, physical status and encapsulation efficiency of the drug in the NPs. All four NPs were found of size ranged 100-120 nm and EE ranged 85-95% at drug loading level around 10%. The in vitro evaluation showed that the 48 h IC50 values of the free DTX and the DTX-loaded PLGA NPs of 0, 10, 20% TPGS were 2.619 and 0.474, 0.040, 0.009 ?g/mL respectively, which means that the PLGA NPs formulation could be 5.57 fold effective than the free DTX and that the DTX-loaded PLGA NPs of 10 or 20% TPGS further be 11.85 and 52.7 fold effective than the DTX-loaded PLGA NPs of no TPGS (therefore, 66.0 and 284 fold effective than the free DTX). Xenograft tumor model and immunohistological staining analysis further confirmed the advantages of the strategy of co-delivery of anticancer drugs with TPGS by PLGA NPs.
The aberrant expression of microRNAs is associated with development and progression of cancers. Down-regulation of miR-124 has been demonstrated in the hepatocellular carcinoma (HCC), but the underlying mechanism by which miR-124 suppresses tumorigenesis in HCC remains elusive. In this study, we found that miR-124 suppresses the tumor growth of HCC through targeting the signal transducers and activators of transcription 3 (STAT3). Overexpression of miR-124 suppressed proliferation and induced apoptosis in HepG-2 cells. Luciferase assay confirmed that miR-124 binding to the 3-UTR region of STAT3 inhibited the expression of STAT3 and phosphorylated STAT3 proteins in HepG-2 cells. Knockdown of STAT3 by siRNA in HepG-2 cells mimicked the effect induced by miR-124. Overexpression of STAT3 in miR-124-transfected HepG-2 cells effectively rescued the inhibition of cell proliferation caused by miR-124. Furthermore, miR-124 suppressed xenograft tumor growth in nude mice implanted with HepG-2 cells by reducing STAT3 expression. Taken together, our findings show that miR-124 functions as tumor suppressor in HCC by targeting STAT3, and miR-124 may therefore serve as a biomarker for diagnosis and therapeutics in HCC.
This work presents a novel semi-automated renal region-of-interest (ROI) determination method that is user friendly, time saving, and yet provides a robust glomerular filtration rate (GFR) estimation highly consistent with the reference method.
Context: Human brown adipose tissue (BAT) is activated with cold exposure, but it is unknown whether overfeeding activates BAT. Objective: We determined BAT activation with cold, fasting, and overfeeding and the relationship of BAT activation with future weight change. Design, Setting, Participants, and Interventions: Sixteen healthy adults were evaluated during energy balance, fasting, and 24 hours of 200% overfeeding. All subjects had a fluorodeoxyglucose-positron emission tomography (PET) scan after exposure to 16°C to determine cold-induced BAT activity (CIBA). The first six subjects had a second PET scan after 36 hours of fasting to establish the lack of BAT activation at 22°C. The other subjects second PET scan occurred after 24 hours of overfeeding at 22°C but only if they demonstrated CIBA. Twelve subjects returned at 6 months for reassessment of body composition. Main Outcome Measures: BAT was defined in cool scans as voxels with a standardized uptake value (SUV) of 2.0 or greater and Hounsfield units between -250 and -10. Body composition was assessed by dual-energy x-ray absorptiometry. Results: Although 75% of the subjects demonstrated visible CIBA, none had visual BAT activity after overfeeding. CIBA was greater than that observed in the same defined BAT voxels after fasting (n = 6; 2.9 ± 0.5 vs 1.2 ± 0.2; ? = -1.7; 95% confidence interval -2.4, -1.0 SUV; P < .01). In the second cohort, CIBA was also higher than observed BAT voxel activity after 24 hours overfeeding (n = 8; 3.5 ± 0.7 vs 0.9 ± 0.2; ? = -2.6; 95% confidence interval -3.2, -1.9 SUV; P < .01). Baseline CIBA negatively correlated with changes in fat mass after 6 months (r = -0.72, P = .009). Conclusions: BAT may be important in weight regulation unrelated to the response to overeating.
The specific binding of auxiliary Kv channel-interacting proteins (KChIPs) to the N-teriminus of Kv4 pore-forming -subunits results in modulation of gating properties, surface expression and subunit assembly of Kv4 channels. However, the interactions between KChIPs and Kv4 remain elusive. Thus, ACE was employed to quantitatively evaluate the interactions between KChIPs and Kv4.3 N-teriminus (KvN) and between KChIP4a/related mutants and Ca(2+)for the first time. The mobility ratio, derivatives calculated from mobility shift method, was used to deduce the binding constants (Kb). As a result, the binding constants for KChIP4a/KvN and KChIP1/KvN complexes were (8.32 ± 1.66) × 10(6) L mol(-1) and (5.26 ± 0.71) × 10(6) L mol(-1), respectively. And in the presence of calcium (10 ?mol L(-1)), the binding constant of KChIP4a/KvN increased to (6.72 ± 1.66) × 10(7) L mol(-1). In addition, the binding constant of KChIP4a with Ca(2+) was (7.1 ± 1.5) × 10(7) L mol(-1). Besides, studies on the effect of structures truncated mutants revealed that the third EF-hand of KChIP4a was related to high affinity binding with Ca(2+), and the integrity of molecular structure of KChIP4a was important for Ca(2+) binding. This method profits from small samples, rapid analysis and simple operation without time consuming.
Autopsy series commonly report a high percentage of coincident pathologies in demented patients, including patients with a clinical diagnosis of dementia of the Alzheimer type (DAT). However many clinical and biomarker studies report cases with a single neurodegenerative disease. We examined multimodal biomarker correlates of the consecutive series of the first 22 Alzheimers Disease Neuroimaging Initiative autopsies. Clinical data, neuropsychological measures, cerebrospinal fluid A?, total and phosphorylated tau and ?-synuclein and MRI and FDG-PET scans.
We report a one-pot synthesis of urchin-like FePd-Fe3O4 nanocomposites, spherical clusters of FePd nanoparticles (NPs) with spikes of Fe3O4 nanorods (NRs), via controlled thermal decomposition of Fe(CO)5 and reduction of Pd(acac)2. The FePd NPs with sizes between 6 and 9 nm self-aggregate into 60 nm superparticles (SPs), and Fe3O4 NRs grow on the surface of these SPs. Reductive annealing at 500 °C converts the FePd-Fe3O4 into exchange-coupled nanocomposites L1(0)-FePd-Fe with their Hc tunable from 0.8 to 2.6 kOe and Ms controlled from 90 to 190 emu/g. The work provides a general approach to L1(0)-FePd-Fe nanocomposite magnets for understanding exchange coupling at the nanoscale. The concept may be extended to other magnetic nanocomposite systems and may help to build superstrong magnets for magnetic applications.
Reconstruction of parametric images from dynamic single photon emission computed tomography (SPECT) data acquired with slow rotating cameras is a challenge because the estimation of the time-activity curves (TACs) may involve fitting data to an inconsistent underdetermined system of equations. This work presents a novel algorithm for the estimation of the blood input function and myocardial TAC with high accuracy and high efficiency directly from these projections.
In all six members of TRPV channel subfamily, there is an ankyrin repeat domain (ARD) in their intracellular Ntermini. Ankyrin (ANK) repeat, a common motif with typically 33 residues in each repeat, is primarily involved in protein-protein interactions. Despite the sequence similarity among the ARDs of TRPV channels, the structure of TRPV3-ARD, however, remains unknown. Here, we report the crystal structure of TRPV3-ARD solved at 1.95 Å resolution, which reveals six-ankyrin repeats. While overall structure of TRPV3-ARD is similar to ARDs from other members of TRPV subfamily; it, however, features a noticeable finger 3 loop that bends over and is stabilized by a network of hydrogen bonds and hydrophobic packing, instead of being flexible as seen in known TRPV-ARD structures. Electrophysiological recordings demonstrated that mutating key residues R225, R226, Q255, and F249 of finger 3 loop altered the channel activities and pharmacology. Taken all together, our findings show that TRPV3-ARD with characteristic finger 3 loop likely plays an important role in channel function and pharmacology.
The plant hormone salicylic acid (SA) plays critical roles in plant defense, stress responses, and senescence. Although SA biosynthesis is well understood, the pathways by which SA is catabolized remain elusive. Here we report the identification and characterization of an SA 3-hydroxylase (S3H) involved in SA catabolism during leaf senescence. S3H is associated with senescence and is inducible by SA and is thus a key part of a negative feedback regulation system of SA levels during senescence. The enzyme converts SA (with a Km of 58.29 µM) to both 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-DHBA in vitro but only 2,3-DHBA in vivo. The s3h knockout mutants fail to produce 2,3-DHBA sugar conjugates, accumulate very high levels of SA and its sugar conjugates, and exhibit a precocious senescence phenotype. Conversely, the gain-of-function lines contain high levels of 2,3-DHBA sugar conjugates and extremely low levels of SA and its sugar conjugates and display a significantly extended leaf longevity. This research reveals an elegant SA catabolic mechanism by which plants regulate SA levels by converting it to 2,3-DHBA to prevent SA overaccumulation. The research also provides strong molecular genetic evidence for an important role of SA in regulating the onset and rate of leaf senescence.
Most experts consider that memantine has a symptomatic treatment, but clinical trials have not yet provided compelling evidence to support a disease-modifying effect. We investigate the effects of memantine on clinical ratings; fluorodeoxyglucose positron emission tomography (FDG-PET) measurements, which can monitor disease-modifying effect; and cerebrospinal fluid (CSF) assays in patients with moderate to severe probable Alzheimer disease (AD) dementia. Twenty-two patients completed a 24-week, double-blind, placebo-controlled, randomized clinical trial of memantine, titrated up to 10 mg twice per day using the Severe Impairment Battery, AD Assessment Scale-Cognitive subscale, Mini-Mental State Examination, FDG-PET measurements of the regional cerebral metabolic rate for glucose (CMRgl), and CSF amyloid ? (A?) and tau assays. An automated brain mapping algorithm and predefined regions of interest were each used to analyze treatment-related regional CMRgl effects. In comparison with the placebo group, the memantine treatment group had significantly less cognitive decline on the Severe Impairment Battery and significantly less CMRgl declines in regions preferentially affected by AD. There were no significant treatment effects on CSF A?????, CSF A?????, total tau, or phosphor-tau levels or ratios. This relatively small and brief randomized clinical trial suggests an association between memantines clinical benefit and its effects on FDG-PET measurements in AD-affected brain regions. Larger and longer studies are needed to confirm these findings, extend them to earlier clinical and preclinical stages of AD, and help determine the extent to which FDG-PET should be qualified for use as a reasonably likely surrogate end point in the evaluation of putative AD-modifying treatments.
While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques.
Coal is the most abundant and readily combustible energy resource being used worldwide. However, its structural characteristic creates a perception that coal is only useful for producing energy via burning. Here we report a facile approach to synthesize tunable graphene quantum dots from various types of coal, and establish that the unique coal structure has an advantage over pure sp(2)-carbon allotropes for producing quantum dots. The crystalline carbon within the coal structure is easier to oxidatively displace than when pure sp(2)-carbon structures are used, resulting in nanometre-sized graphene quantum dots with amorphous carbon addends on the edges. The synthesized graphene quantum dots, produced in up to 20% isolated yield from coal, are soluble and fluorescent in aqueous solution, providing promise for applications in areas such as bioimaging, biomedicine, photovoltaics and optoelectronics, in addition to being inexpensive additives for structural composites.
Pain in masticatory muscles is among the most prominent symptoms of temperomandibular disorders (TMDs) that have diverse and complex etiology. A common complaint of TMD is that unilateral pain of craniofacial muscle can cause a widespread of bilateral pain sensation, although the underlying mechanism remains unknown. To investigate whether unilateral inflammation of masseter muscle can cause a bilateral allodynia, we generated masseter muscle inflammation induced by unilateral injection of complete Freunds adjuvant (CFA) in rats, and measured the bilateral head withdrawal threshold at different time points using a von Frey anesthesiometer. After behavioral assessment, both right and left trigeminal ganglia (TRG) were dissected and examined for histopathology and transient receptor potential vanilloid 1 (TRPV1) mRNA expression using quantitative real-time PCR analysis. A significant increase in TRPV1 mRNA expression occurred in TRG ipsilateral to CFA injected masseter muscle, whereas no significant alteration in TRPV1 occurred in the contralateral TRG. Interestingly, central injection of TRPV1 antagonist 5-iodoresiniferatoxin into the hippocampus significantly attenuated the head withdrawal response of both CFA injected and non-CFA injected contralateral masseter muscle. Our findings show that unilateral inflammation of masseter muscle is capable of inducing bilateral allodynia in rats. Upregulation of TRPV1 at the TRG level is due to nociception caused by inflammation, whereas contralateral nocifensive behavior in masticatory muscle nociception is likely mediated by central TRPV1, pointing to the involvement of altered information processing in higher centers.
Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.
Given a single index, the receiver operational characteristic (ROC) curve analysis is routinely utilized for characterizing performances in distinguishing two conditions/groups in terms of sensitivity and specificity. Given the availability of multiple data sources (referred to as multi-indices), such as multimodal neuroimaging data sets, cognitive tests, and clinical ratings and genomic data in Alzheimer’s disease (AD) studies, the single-index-based ROC underutilizes all available information. For a long time, a number of algorithmic/analytic approaches combining multiple indices have been widely used to simultaneously incorporate multiple sources. In this study, we propose an alternative for combining multiple indices using logical operations, such as “AND,” “OR,” and “at least n” (where n is an integer), to construct multivariate ROC (multiV-ROC) and characterize the sensitivity and specificity statistically associated with the use of multiple indices. With and without the “leave-one-out” cross-validation, we used two data sets from AD studies to showcase the potentially increased sensitivity/specificity of the multiV-ROC in comparison to the single-index ROC and linear discriminant analysis (an analytic way of combining multi-indices). We conclude that, for the data sets we investigated, the proposed multiV-ROC approach is capable of providing a natural and practical alternative with improved classification accuracy as compared to univariate ROC and linear discriminant analysis.
IAPs are a group of regulatory proteins that are structurally related. Their conserved homologues have been identified in various organisms. In human, eight IAP members have been recognized based on baculoviral IAP repeat (BIR) domains. IAPs are key regulators of apoptosis, cytokinesis and signal transduction. The antiapoptotic property of IAPs depends on their professional role for caspases. IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. IAPs impede apoptotic process via membrane receptor-dependent (extrinsic) cascade and mitochondrial dependent (intrinsic) pathway. IAP-mediated apoptosis affects the progression of liver diseases. Therapeutic options of liver diseases may depend on the understanding toward mechanisms of the IAP-mediated apoptosis.
To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ?4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease.
In the brain and heart, auxiliary Kv channel-interacting proteins (KChIPs) co-assemble with pore-forming Kv4 ?-subunits to form a native K(+) channel complex and regulate the expression and gating properties of Kv4 currents. Among the KChIP1-4 members, KChIP4a exhibits a unique N terminus that is known to suppress Kv4 function, but the underlying mechanism of Kv4 inhibition remains unknown. Using a combination of confocal imaging, surface biotinylation, and electrophysiological recordings, we identified a novel endoplasmic reticulum (ER) retention motif, consisting of six hydrophobic and aliphatic residues, 12-17 (LIVIVL), within the KChIP4a N-terminal KID, that functions to reduce surface expression of Kv4-KChIP complexes. This ER retention capacity is transferable and depends on its flanking location. In addition, adjacent to the ER retention motif, the residues 19-21 (VKL motif) directly promote closed-state inactivation of Kv4.3, thus leading to an inhibition of channel current. Taken together, our findings demonstrate that KChIP4a suppresses A-type Kv4 current via ER retention and enhancement of Kv4 closed-state inactivation.
To investigate whether higher fasting serum glucose levels in cognitively normal, nondiabetic adults were associated with lower regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer disease (AD).
Activation of ?-catenin and PI3K pathways are crucial for the oncogenesis of colorectal cancer (CRC). It remains controversial whether these two pathways function independently or cooperatively in the development and progression of CRC. We showed previously that ?-catenin inhibited NF-?B activation by interacting with p65 and this inhibitory interaction involved an unidentified cellular protein. In this study, we found that the PI3K effect on NF-?B activity is dependent on the level of ?-catenin in CRC cells. PI3K promoted NF-?B activity in the ?-catenin-low RKO cells; whereas it inhibited NF-?B activity in the ?-catenin-high HCT116, DLD-1, and SW480 cells. We showed that PI3K is required for the physical interaction and functional inhibition of NF-?B by ?-catenin. Inhibition of PI3K released NF-?B suppression in ?-catenin-high CRC cells, which conferred these cells with susceptibility to TNF?- and Fas-induced apoptosis. This is consistent with the observation showing that the level of ?-catenin and activated Akt are both inversely correlated with the expression of Fas, a downstream target of NF-?B, in CRC specimens. Mechanistically, the PI3K subunit p85 formed a complex with ?-catenin and NF-?B. Inhibition of PI3K disrupted the complex formation, leading to NF-?B activation. Our study not only provides new insight into the cross-talk among PI3K, ?-catenin and NF-?B signaling pathways but also indicates that targeting PI3K may yield therapeutic efficacy in treating ?-catenin-high CRC.
The key circulating pro-inflammatory cytokines and their interaction in peripheral inflammation after acute cerebral ischemia are poorly understood. CD40L, IFN-?, IL-1?, IL-1?, IL-6, IL-8, IL-17 and TNF-? were determined using multi-ELISA kit in stroke patients within 72 h of an acute ischemic attack. Leukocyte mRNAs were determined using real-time polymerase chain reactions (PCR). Stroke severity and clinical outcomes were evaluated by National Institutes of Health Stroke Scores (NIHSS) and modified Rankin Scale (mRS). Plasma/mRNA cytokine interactions were analyzed using the Bayesian network learning procedure. Compared to controls, stroke patients had higher IL-6, IL-8 and TNF? protein in plasma and lower IL-6, IL-8, TNF?, IL-1?, and IL-1? mRNA in leukocyte within 72 h after stroke. However, only the elevation of IL-6 correlated with the severity and prognosis of their stroke. This was associated with a decreased IL-6 mRNA in leukocyte. Further study showed that Bayesian network analysis revealed that changes in the other cytokines were subsequent to IL-6 leukocyte cytokine RNA. The change of other cytokines in plasma proteins after ischemic brain injury appeared secondary to IL-6. Pro-inflammatory cytokines up-regulation in plasma and compensatory immunity depression in leukocyte involve in peripheral inflammation response to cerebral ischemia. IL-6 appears to be the key mediator of circulating pro-inflammatory cytokines network.
Apoptotic injury participates in hepatic fibrosis, but the molecular mechanisms are not well understood. The present study aimed to investigate the role of inducible TIMP1 in the pathogenesis of hepatic apoptosis-fibrosis. Apoptosis was induced with GCDC, LPS, and alcohol in precision-cut liver slices or bile duct ligation (BDL) in rats, as reflected by caspase-3 activity, TUNEL assay, and apoptosis-related gene profiles. The hepatic fibrosis was detected with Picrosirius staining, hydroxyproline determination, and expression profiling of fibrosis-related genes. Levels of TIMP1 were upregulated by the hepatic apoptosis, but downregulated by caspase inhibitor. The inducible TIMP1 was apoptosis-dependent. Once TIMP1 was inhibited with treatment of TIMP1-siRNA, the fibrotic response was reduced as demonstrated by hydroxyproline assay. In addition, the expression of fibrosis-related genes aSMA, CTGF, and TGFb2r were down-regulated subsequent to the treatment of TIMP1-siRNA. TIMP1 could mediate the expression of fibrosis-related genes. TIMP1 was transcriptionally regulated by nuclear factor c-Jun as demonstrated by EMSA and ChIP assay. The treatment of c-Jun siRNA could significantly decrease the expression of TIMP1 induced by alcohol, GCDC, or LPS treatment. Hepatic apoptosis induces the expression of TIMP1. Inducible TIMP1 can modulate the expression of fibrosis-related genes in liver. TIMP1 pathway is a potential target for therapeutic intervention of fibrotic liver diseases.
The Ca(2+)-permeable transient receptor potential vanilloid subtype 4 (TRPV4) channel mediates crucial physiological functions, such as calcium signaling, temperature sensing, and maintaining cell volume and energy homeostasis. Noticeably, most disease-causing genetic mutations are concentrated in the cytoplasmic domains. In the present study, we focused on the role of the TRPV4 C terminus in modulating protein folding, trafficking, and activity. By examining a series of C-terminal deletions, we identified a 20-amino acid distal region covering residues 838-857 that is critical for channel folding, maturation, and trafficking. Surface biotinylation, confocal imaging, and fluorescence-based calcium influx assay demonstrated that mutant proteins missing this region were trapped in the endoplasmic reticulum and unglycosylated, leading to accelerated degradation and loss of channel activity. Rosetta de novo structural modeling indicated that residues 838-857 assume a defined conformation, with Gly(849) and Pro(851) located at critical positions. Patch clamp recordings confirmed that lowering the temperature from 37 to 30 °C rescued channel activity of folding-defective mutants. Moreover, biochemical tests demonstrated that, in addition to participating in C-C interaction, the C terminus also interacts with the N terminus. Taken together, our findings indicate that the C-terminal region of TRPV4 is critical for channel protein folding and maturation, and the short distal segment plays an essential role in this process. Therefore, selectively disrupting the folding-sensitive region may present therapeutic potential for treating overactive TRPV4-mediated diseases, such as pain and skeletal dysplasias.
The degree of Granger causal modeling estimated influence for a brain region was reported to predict its blood oxygenation level-dependent (BOLD) activity level in the resting-state default mode network (DMN). Many brain disorders, such as Alzheimers disease (AD), may alter the influence strength, activity levels, or both. Whether the relationship or prediction between these two will be affected under disease condition is unknown. In this study, the spontaneous brain activity, and inter-regional Granger causality connection were investigated over eight core DMN regions in AD patients in contrast to that in normal controls. Compared to normal control (NC), AD patients had both decreased BOLD activity level and Granger causal influence in medial prefrontal cortex and decreased activity level in inferior parietal cortex showed. However, the positive correlation between the BOLD activity level and the degree of the Granger causal modeling defined influence was found not altered by AD.
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