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1.  Which type of social activities may reduce cognitive decline in the elderly?: a longitudinal population-based study 
BMC Geriatrics  2016;16:165.
Background
Previous studies have found that social activities are beneficial for the reduction of cognitive decline (CD) in the elderly. However, knowledge regarding the types of social activities that reduce CD in later life is limited. The aim of this study is to examine which type of social activities reduce CD 4 years later among young-old (Y-O) and old-old (O-O) adults.
Methods
We conducted a secondary analysis using data from cognitively intact adults 65 years of age or older who participated in the Korean Longitudinal Study of Aging (KLoSA). Cognitive function was assessed using the Korean version of the Mini-Mental State Examination (MMSE). We computed CD between 2008 and 2012 by subtracting the Wave 4 MMSE score from the Wave 2 MMSE score. Multivariate linear regression analysis was conducted regarding the effects of social activities on CD after adjusting for age, sex, education, income, marital status, activities of daily living (ADL), instrumental activities of daily living (IADL), chronic diseases, quality of life, depressive symptom, change in depressive symptom, and cognitive functioning at baseline.
Results
Subjects who participated in senior citizen clubs or senior centers at baseline had a lower risk of CD 4 years later than those who did not in Y-O adults. Frequent contact with offspring by phone or letters was associated with reduced CD in O-O adults. Frequent face-to-face contact with offspring was positively associated with CD in O-O adults. Participating in two or more formal social activities was associated with reduced CD compared with nonparticipation in O-O adults.
Conclusion
Encouraging older adults to participate in senior citizen clubs or to have frequent contacts with adult children by phone or letters may help reduce CD in later life among older adults. Participation in a variety of formal social activities may also have a beneficial effect on preventing CD in older adults.
Electronic supplementary material
The online version of this article (doi:10.1186/s12877-016-0343-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12877-016-0343-x
PMCID: PMC5039914  PMID: 27677321
Cognitive impairment; Social activity; Elderly; Korea
2.  Inducing mitophagy in diabetic platelets protects against severe oxidative stress 
EMBO Molecular Medicine  2016;8(7):779-795.
Abstract
Diabetes mellitus (DM) is a growing international concern. Considerable mortality and morbidity associated with diabetes mellitus arise predominantly from thrombotic cardiovascular events. Oxidative stress‐mediated mitochondrial damage contributes significantly to enhanced thrombosis in DM. A basal autophagy process has recently been described as playing an important role in normal platelet activation. We now report a substantial mitophagy induction (above basal autophagy levels) in diabetic platelets, suggesting alternative roles for autophagy in platelet pathology. Using a combination of molecular, biochemical, and imaging studies on human DM platelets, we report that platelet mitophagy induction serves as a platelet protective mechanism that responds to oxidative stress through JNK activation. By removing damaged mitochondria (mitophagy), phosphorylated p53 is reduced, preventing progression to apoptosis, and preserving platelet function. The absence of mitophagy in DM platelets results in failure to protect against oxidative stress, leading to increased thrombosis. Surprisingly, this removal of damaged mitochondria does not require contributions from transcription, as platelets lack a nucleus. The considerable energy and resources expended in “prepackaging” the complex mitophagy machinery in a short‐lived normal platelet support a critical role, in anticipation of exposure to oxidative stress.
doi:10.15252/emmm.201506046
PMCID: PMC4931291  PMID: 27221050
diabetes mellitus; mitophagy; oxidative stress; platelets; Haematology; Metabolism; Vascular Biology & Angiogenesis
3.  Aldose Reductase-Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction, and Damage in Diabetic Platelets 
Circulation  2014;129(15):1598-1609.
Background
Platelet abnormalities are well-recognized complications of diabetes mellitus (DM). Mitochondria play a central role in platelet metabolism and activation. Mitochondrial dysfunction is evident in DM. The molecular pathway for hyperglycemia-induced mitochondrial dysfunction in DM platelets is unknown.
Methods and Results
Using both human and humanized mouse models, we report that hyperglycemia-induced aldose reductase (AR) activation, and subsequent reactive oxygen species (ROS) production, leads to increased p53 phosphorylation (Ser15), which promotes mitochondrial dysfunction, damage and rupture by sequestration of the anti-apoptotic protein Bcl-xL. In a glucose dose dependent manner, severe mitochondrial damage leads to loss of mitochondrial membrane potential and platelet apoptosis (cytochrome c release, caspase 3 activation and phosphatidylserine exposure). Although platelet hyperactivation, mitochondrial dysfunction, AR activation, ROS production and p53 phosphorylation are all induced by hyperglycemia, we demonstrate that platelet apoptosis and hyperactivation are two distinct states, dependent upon the severity of the hyperglycemia and mitochondrial damage. Combined, both lead to increased thrombus formation in a mouse blood stasis model.
Conclusions
AR contributes to diabetes-mediated mitochondrial dysfunction and damage through the activation of p53. The degree of mitochondrial dysfunction and damage determines whether hyperactivity (mild damage) or apoptosis (severe damage) will ensue. These signaling components provide novel therapeutic targets for DM thrombotic complications.
doi:10.1161/CIRCULATIONAHA.113.005224
PMCID: PMC3989377  PMID: 24474649
aldose reductase; p53; platelet; diabetes mellitus; mitochondria; apoptosis
4.  Transnational collaboration for faculty development in health professions education in Mongolia 
Purpose
The Mongolian National University of Medical Sciences is the only national university in Mongolia and has produced more than 90% of health professionals in the country. Experts from Mongolia and Korea embarked on a collaborative effort to develop educational programs for faculty development based on the personal and professional needs of faculty members. This study aimed to evaluate the outcomes of those educational programs to determine whether this transnational collaboration was successful.
Methods
A needs assessment survey was conducted among 325 faculty members. Based on the results of this survey, the joint expert team developed educational programs on seven core topics: clinical teaching, curriculum development, e-learning, item writing, medical research, organizational culture, and resident selection. Surveys evaluating the satisfaction and the attitudes of the participants were conducted for each program.
Results
Throughout the 17-day program, 16 experts from Korea and 14 faculty members from Mongolia participated as instructors, and a total of 309 participants attended the program. The average satisfaction score was 7.15 out of 8.0, and the attitudes of the participants towards relevant competencies significantly improved after each educational program.
Conclusion
The faculty development programs that were developed and implemented as part of this transnational collaboration between Mongolia and Korea are expected to contribute to the further improvement of health professions education in Mongolia. Future studies are needed to evaluate the long-term outcomes of these educational programs.
doi:10.3946/kjme.2016.43
PMCID: PMC5138573  PMID: 27907984
Transnational collaboration; Faculty development; Health professions education
5.  Cytokine-Like 1 Regulates Cardiac Fibrosis via Modulation of TGF-β Signaling 
PLoS ONE  2016;11(11):e0166480.
Cytokine-like 1 (Cytl1) is a secreted protein that is involved in diverse biological processes. A comparative modeling study indicated that Cytl1 is structurally and functionally similar to monocyte chemoattractant protein 1 (MCP-1). As MCP-1 plays an important role in cardiac fibrosis (CF) and heart failure (HF), we investigated the role of Cytl1 in a mouse model of CF and HF. Cytl1 was upregulated in the failing mouse heart. Pressure overload-induced CF was significantly attenuated in cytl1 knock-out (KO) mice compared to that from wild-type (WT) mice. By contrast, adeno-associated virus (AAV)-mediated overexpression of cytl1 alone led to the development of CF in vivo. The endothelial-mesenchymal transition (EndMT) and the transdifferentiation of fibroblasts (FBs) to myofibroblasts (MFBs) have been suggested to contribute considerably to CF. Adenovirus-mediated overexpression of cytl1 was sufficient to induce these two critical CF-related processes in vitro, which were completely abrogated by co-treatment with SB-431542, an antagonist of TGF-β receptor 1. Cytl1 induced the expression of TGF-β2 both in vivo and in vitro. Antagonizing the receptor for MCP-1, C-C chemokine receptor type 2 (CCR2), with CAS 445479-97-0 did not block the pro-fibrotic activity of Cytl1 in vitro. Collectively, our data suggest that Cytl1 plays an essential role in CF likely through activating the TGF-β-SMAD signaling pathway. Although the receptor for Cyt1l remains to be identified, Cytl1 provides a novel platform for the development of anti-CF therapies.
doi:10.1371/journal.pone.0166480
PMCID: PMC5105950  PMID: 27835665
6.  Children in Chronic Pain: Promoting Pediatric Patients’ Symptom Accounts in Tertiary Care 
Social science & medicine (1982)  2008;66(6):1418-1428.
This paper examines how clinicians promote pediatric patients’ symptom accounts at the beginning of visits in three pediatric tertiary care clinics at a university hospital in the US: pain, gastroenterology and neurology. Quantitative and qualitative data were collected for 69 patient-parent pairs, including videotaped intake visits. Two forms of child account promotion, together with their corresponding distribution across clinics, were identified: (1) Epistemic prefaces were used to upgrade the patient’s epistemic status and to establish the child as primary informant; and, (2) non-focused questioning was used to permit children latitude in the formulation of symptoms and experiences. In general, epistemic prefaces were characteristic of the gastroenterology and neurology visits, while non-focused questioning was found overwhelmingly in the pain encounters.
doi:10.1016/j.socscimed.2007.11.015
PMCID: PMC3014257  PMID: 18272275
USA; Children; Chronic condition; Pain; Communication; Biopsychosocial; Patient Participation
7.  Retrospective Case Series of Aripiprazole Augmentation in Pervasive Developmental Disorders 
Psychiatry Investigation  2010;7(3):220-223.
Due to co-morbidities and treatment resistant nature of pervasive developmental disorder (PDD), diverse combinations of regimens have been tried. This retrospective study aimed to explore adjunctive use of aripiprazole in children with PDD. Changes in illness severity were measured by Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) in 14 aripiprazole-treated patients with PDD. Improvement of illness severity was observed after aripiprazole add-on (5.8±0.8 to 4.9±1.0, Z=-2.75, p=0.001). Mean dosage was 7.7 mg/day [standard deviation (SD) 3.3, range 5-15]. A higher mean dosage was observed in group with improvement in symptoms (t=-2.33, df =12, p=0.004). The target symptoms most effectively improved after using aripiprazole were positive psychotic symptoms (mean CGI-I: 2.0±1.4, 3 responders/4 patients, 75% response) followed by aggressive behavior (2.5±1.7, 3/4, 75%), self-injurious behavior (2.0±1.0, 2/3, 67%), stereotypic behavior (2.7±1.2, 2/3, 67%), tic (2.8±1.0, 2/4, 50%), irritability (3.5±2.1, 1/2, 50%), obsessive behavior (2.5±2.1, 1/3, 33%), hyperactivity (3.4±1.6, 3/7, 43%) and mood fluctuation (3, 0/1, no response). Five patients (35%) discontinued aripiprazole due to treatment-emergent adverse effects (akathisia, insomnia, withdrawal). The results of this study suggest that aripiprazole augmentation may be used safely in maladaptive behaviors of some populations of PDD. However, future studies are required to confirm these preliminary findings.
doi:10.4306/pi.2010.7.3.220
PMCID: PMC2947811  PMID: 20927312
Aripiprazole; Augmentation; Autism; Pervasive developmental disorder
9.  Islet Specific Wnt Activation in Human Type II Diabetes 
Experimental Diabetes Research  2009;2008:728763.
The Wnt pathway effector gene TCF7L2 has been linked to type II diabetes, making it important to study the role of Wnt signaling in diabetes pathogenesis. We examined the expression of multiple Wnt pathway components in pancreases from normal individuals and type II diabetic individuals. Multiple members of the Wnt signaling pathway, including TCF7L2, Wnt2b, β-catenin, pGSK3β, TCF3, cyclinD1, and c-myc, were undetectable or expressed at low levels in islets from nondiabetic individuals, but were also upregulated specifically in islets of type II diabetic patients. Culture of pancreatic tissue and islet isolation led to Wnt activation that was reversed by the Wnt antagonist sFRP, demonstrating that Wnt activation in that setting was due to soluble Wnt factors. These data support a model in which the Wnt pathway plays a dynamic role in the pathogenesis of type II diabetes and suggest manipulation of Wnt signaling as a new approach to β-cell-directed diabetes therapy.
doi:10.1155/2008/728763
PMCID: PMC2628766  PMID: 19165345
10.  ApCPEB4, a non-prion domain containing homolog of ApCPEB, is involved in the initiation of long-term facilitation 
Molecular Brain  2016;9:91.
Two pharmacologically distinct types of local protein synthesis are required for synapse- specific long-term synaptic facilitation (LTF) in Aplysia: one for initiation and the other for maintenance. ApCPEB, a rapamycin sensitive prion-like molecule regulates a form of local protein synthesis that is specifically required for the maintenance of the LTF. However, the molecular component of the local protein synthesis that is required for the initiation of LTF and that is sensitive to emetine is not known. Here, we identify a homolog of ApCPEB responsible for the initiation of LTF. ApCPEB4 which we have named after its mammalian CPEB4-like homolog lacks a prion-like domain, is responsive to 5-hydroxytryptamine, and is translated (but not transcribed) in an emetine-sensitive, rapamycin-insensitive, and PKA-dependent manner. The ApCPEB4 binds to different target RNAs than does ApCPEB. Knock-down of ApCPEB4 blocked the induction of LTF, whereas overexpression of ApCPEB4 reduces the threshold of the formation of LTF. Thus, our findings suggest that the two different forms of CPEBs play distinct roles in LTF; ApCPEB is required for maintenance of LTF, whereas the ApCPEB4, which lacks a prion-like domain, is required for the initiation of LTF.
Electronic supplementary material
The online version of this article (doi:10.1186/s13041-016-0271-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13041-016-0271-x
PMCID: PMC5075418  PMID: 27770822
Aplysia; Long-term facilitation; CPEB; CPEB4
11.  Flexoelectric effect in an in-plane switching (IPS) liquid crystal cell for low-power consumption display devices 
Scientific Reports  2016;6:35254.
Technology of displaying static images in portable displays, advertising panels and price tags pursues significant reduction in power consumption and in product cost. Driving at a low-frequency electric field in fringe-field switching (FFS) mode can be one of the efficient ways to save powers of the recent portable devices, but a serious drop of image-quality, so-called image-flickering, has been found in terms of the coupling of elastic deformation to not only quadratic dielectric effect but linear flexoelectric effect. Despite of the urgent requirement of solving the issue, understanding of such a phenomenon is yet vague. Here, we thoroughly analyze and firstly report the flexoelectric effect in in-plane switching (IPS) liquid crystal cell. The effect takes place on the area above electrodes due to splay and bend deformations of nematic liquid crystal along oblique electric fields, so that the obvious spatial shift of the optical transmittance is experimentally observed and is clearly demonstrated based on the relation between direction of flexoelectric polarization and electric field polarity. In addition, we report that the IPS mode has inherent characteristics to solve the image-flickering issue in the low-power consumption display in terms of the physical property of liquid crystal material and the electrode structure.
doi:10.1038/srep35254
PMCID: PMC5059722  PMID: 27731372
12.  Cell type-specific long-range connections of basal forebrain circuit 
eLife  null;5:e13214.
The basal forebrain (BF) plays key roles in multiple brain functions, including sleep-wake regulation, attention, and learning/memory, but the long-range connections mediating these functions remain poorly characterized. Here we performed whole-brain mapping of both inputs and outputs of four BF cell types – cholinergic, glutamatergic, and parvalbumin-positive (PV+) and somatostatin-positive (SOM+) GABAergic neurons – in the mouse brain. Using rabies virus -mediated monosynaptic retrograde tracing to label the inputs and adeno-associated virus to trace axonal projections, we identified numerous brain areas connected to the BF. The inputs to different cell types were qualitatively similar, but the output projections showed marked differences. The connections to glutamatergic and SOM+ neurons were strongly reciprocal, while those to cholinergic and PV+ neurons were more unidirectional. These results reveal the long-range wiring diagram of the BF circuit with highly convergent inputs and divergent outputs and point to both functional commonality and specialization of different BF cell types.
DOI: http://dx.doi.org/10.7554/eLife.13214.001
doi:10.7554/eLife.13214
PMCID: PMC5095704  PMID: 27642784
basal forebrain; anatomy; rabies virus; somatostatin; cholinergic; parvalbumin; Mouse
13.  Highly photoresponsive and wavelength-selective circularly-polarized-light detector based on metal-oxides hetero-chiral thin film 
Scientific Reports  2016;6:19580.
A highly efficient circularly-polarized-light detector with excellent wavelength selectivity is demonstrated with an elegant and simple microelectronics-compatible way. The circularly-polarized-light detector based on a proper combination of the geometry-controlled TiO2-SnO2 hetero-chiral thin film as an effective chiroptical filter and the Si active layer shows excellent chiroptical response with external quantum efficiency as high as 30% and high helicity selectivity of ~15.8% in an intended wavelength range. Furthermore, we demonstrated the ability of manipulating both bandwidth and responsivity of the detector simultaneously in whole visible wavelength range by a precise control over the geometry and materials constituting hetero-chiral thin film. The high efficiency, wavelength selectivity and compatibility with conventional microelectronics processes enabled by the proposed device can result in remarkable developments in highly integrated photonic platforms utilizing chiroptical responses.
doi:10.1038/srep19580
PMCID: PMC4726136  PMID: 26795601
14.  Small Retailer Perspectives of the 2009 Women, Infants and Children Program Food Package Changes 
Objective
To understand vendor perspectives regarding changes made in 2009 to the Special Supplemental Nutrition Program for Women, Infant, and Children (WIC) food package.
Methods
Fifty-two in-depth, qualitative interviews with owners or managers of small stores in 8 urban areas across 7 states conducted 6-12 months after the changes.
Results
Store owners experienced implementation challenges, but felt the changes increased the number of customers, sales, and profits.
Conclusion
This research provides vendor perspectives on the 2009 WIC policy changes and may enhance policy implementation directed at increasing healthy food availability, particularly in urban communities.
doi:10.5993/AJHB.36.5.8
PMCID: PMC4703098  PMID: 22584093
WIC; qualitative research; storeowner perspectives; food policy; sales
15.  Mucinous Borderline Ovarian Tumor in Very Old Aged Postmenopausal Woman 
Journal of Menopausal Medicine  2015;21(3):160-164.
Mucinous borderline ovarian tumors (BOTs) occur most often in women between the ages of 20 and 30. Early-stage detection of the condition has a more favorable prognosis. In this case report, the authors present an elderly 93-year old woman who visited our hospital due to severe abdominal pain after being diagnosed with a pelvic mass 2 years ago and not undergoing any treatment since the diagnosis was made. She underwent emergency left salpingo-oophorectomy and was diagnosed with mucinous BOT according to biopsy results.
doi:10.6118/jmm.2015.21.3.160
PMCID: PMC4719091  PMID: 26793682
Aged; Cystadenoma mucinous; Female; Ovarian neoplasms
16.  The Effect of Formative Program Evaluation on Continuous Program Improvement: A Case Study of a Clinical Training Program in Lao PDR 
Journal of Korean Medical Science  2015;30(12):1743-1747.
This study aimed to evaluate the effect of the formative program evaluation on the continuous improvement of a clinical training program for Lao health professionals. The training program was conducted 4 times consecutively for total 48 health professionals, and the formative program evaluation was carried out during the whole process. To evaluate the satisfaction and the transfer of the trainees, the questionnaire survey, the focus group interview, and the trainees' medical records were used. After the end of each batch of the program, the evaluation data were analyzed, and its results were shared with the training management committee and the trainers, who, based on the results, reached a consensus on how to improve the program. The evaluation results and the comparison of them among the four batches of the program showed that there was a continuous increase of the satisfaction and the transfer of the trainees, especially in the early period of the program. The formative program evaluation which was conducted during the whole process of the clinical training program had a positive effect on the improvement of the program, especially in the early phase, by increasing the satisfaction and transfer of the trainees.
Graphical Abstract
doi:10.3346/jkms.2015.30.12.1743
PMCID: PMC4689817  PMID: 26713048
Formative Program Evaluation; Clinical Training Program; Lao PDR
17.  Three-Dimensional Metal-Oxide Nanohelix Arrays Fabricated by Oblique Angle Deposition: Fabrication, Properties, and Applications 
Three-dimensional (3D) nanostructured thin films have attracted great attention due to their novel physical, optical, and chemical properties, providing tremendous possibilities for future multifunctional systems and for exploring new physical phenomena. Among various techniques to fabricate 3D nanostructures, oblique angle deposition (OAD) is a very promising method for producing arrays of a variety of 3D nanostructures with excellent controllability, reproducibility, low cost, and compatibility with modern micro-electronic processes. This article presents a comprehensive overview of the principle of OAD, and unique structural and optical properties of OAD-fabricated thin films including excellent crystallinity, accurate tunability of refractive indices, and strong light scattering effect which can be utilized to remarkably enhance performances of various systems such as antireflection coatings, optical filters, photoelectrodes for solar-energy-harvesting cells, and sensing layers for various sensors.
doi:10.1186/s11671-015-1057-2
PMCID: PMC4577498  PMID: 26391174
Three-dimensional nanostructured thin films; Oblique angle deposition
18.  Evaluation of Dual-Color Fluorescence In Situ Hybridization With Peptide Nucleic Acid Probes for the Detection of Mycobacterium tuberculosis and Non-Tuberculous Mycobacteria in Clinical Specimens 
Annals of Laboratory Medicine  2015;35(5):500-505.
Background
Peptide nucleic acid (PNA) probes are artificial DNA analogues with a hydrophobic nature that can penetrate the mycobacterial cell wall. We evaluated a FISH method for simultaneous detection and identification of Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacteria (NTM) in clinical respiratory specimens using differentially labeled PNA probes.
Methods
PNA probes targeting the mycobacterial 16S ribosomal RNA were synthesized. The cross-reactivity of MTB- and NTM-specific probes was examined with reference strains and 10 other frequently isolated bacterial species. A total of 140 sputum specimens were analyzed, comprising 100 MTB-positive specimens, 21 NTM-positive specimens, and 19 MTB/NTM-negative specimens; all of them were previously confirmed by PCR and culture. The PNA FISH test results were graded by using the United States Centers for Disease Control and Prevention-recommended scale and compared with the results from the fluorochrome acid-fast bacterial stain.
Results
The MTB- and NTM-specific PNA probes showed no cross-reactivity with other tested bacterial species. The test results demonstrated 82.9% agreement with the culture results with diagnostic sensitivity of 80.2% and diagnostic specificity of 100.0% (kappa=0.52, 95% confidence interval: 0.370-0.676).
Conclusions
Dual-color PNA FISH showed high specificity for detecting and identifying mycobacteria in clinical specimens. However, because of its relatively low sensitivity, this method could be more applicable to culture confirmation. In application to direct specimens, the possibility of false-negative results needs to be considered.
doi:10.3343/alm.2015.35.5.500
PMCID: PMC4510502  PMID: 26206686
Peptide nucleic acids; Fluorescence in situ hybridization; Mycobacterium tuberculosis; Non-tuberculous mycobacteria
19.  Clinical Relevance of High-Resolution Single Nucleotide Polymorphism Array in Patients with Relapsed Acute Lymphoblastic Leukemia with Normal Karyotype: A Report of Three Cases 
Annals of Laboratory Medicine  2014;35(1):132-136.
We report three patients with normal karyotype (NK) ALL, who showed genetic aberrations as determined by high-resolution single nucleotide polymorphism array (SNP-A) analysis at both diagnosis and relapse. We evaluated the clinical relevance of the SNP-A assay for the detection of subtle changes in the size of affected genetic lesions at relapse as well as the prognostic value of the assay. In our patients, application of the SNP-A assay enabled sensitive detection of cryptic changes affecting clinically important genes in NK ALL. Therefore, this assay seems to be more advantageous compared to other conventional methods such as FISH assay, HemaVision (DNA Technology, Denmark), and conventional karyotyping for the detection of an "unstable genotype" at relapse, which may be associated with microscopic clonal evolution and poor prognosis. Further comprehensive studies are required to confirm the issues presented by our case patients in this report.
doi:10.3343/alm.2015.35.1.132
PMCID: PMC4272944  PMID: 25553294
Acute lymphoblastic leukemia; Array; Clonal evolution; Normal karyotype; Prognosis; Single nucleotide polymorphism
20.  Fast Modulation of Visual Perception by Basal Forebrain Cholinergic Neurons 
Nature neuroscience  2013;16(12):1857-1863.
The basal forebrain provides the primary source of cholinergic input to the cortex, and it plays a crucial role in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking, which could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception.
doi:10.1038/nn.3552
PMCID: PMC4201942  PMID: 24162654
21.  Reversal of Lipotoxic Effects on the Insulin Promoter by Alverine and Benfluorex: Identification as HNF4α Activators 
ACS chemical biology  2013;8(8):1730-1736.
The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings and previously unknown to share mechanistic or structural similarity, activated the nuclear receptor transcription factor HNF4α. Both were hits in a high-throughput screen for compounds that reversed the inhibitory effect of the fatty acid palmitate on human insulin promoter activity. Alverine is used in the treatment of irritable bowel syndrome, while benfluorex (Mediator) was used to treat hyperlipidemia and type II diabetes. Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity. Strikingly, alverine and benfluorex have a previously unrecognized structural similarity, consistent with a common mechanism of action. Gene expression and biochemical studies revealed that they both activate HNF4α. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path towards the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4α activators.
doi:10.1021/cb4000986
PMCID: PMC3922238  PMID: 23675775
22.  Development and implementation of Baltimore Healthy Eating Zones: a youth-targeted intervention to improve the urban food environment 
Health Education Research  2013;28(4):732-744.
Poor accessibility to affordable healthy foods is associated with higher rates of obesity and diet-related chronic diseases. We present our process evaluation of a youth-targeted environmental intervention (Baltimore Healthy Eating Zones) that aimed to increase the availability of healthy foods and promote these foods through signage, taste tests and other interactive activities in low-income Baltimore City. Trained peer educators reinforced program messages. Dose, fidelity and reach—as measured by food stocking, posting of print materials, distribution of giveaways and number of interactions with community members—were collected in six recreation centers and 21 nearby corner stores and carryouts. Participating stores stocked promoted foods and promotional print materials with moderate fidelity. Interactive sessions were implemented with high reach and dose among both adults and youth aged 10–14 years, with more than 4000 interactions. Recreation centers appear to be a promising location to interact with low-income youth and reinforce exposure to messages.
doi:10.1093/her/cyt066
PMCID: PMC3888143  PMID: 23766452
24.  MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signaling 
Nature communications  2013;4:2354.
Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is a ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme UBE2H. Molecular manipulations that disrupt the E3 ligase function of MG53 abolishes IRS-1 ubiquitination and enhances skeletal myogenesis. Skeletal muscles derived from the MG53−/− mice show an elevated IRS-1 level with enhanced insulin signaling, which protects the MG53−/− mice from developing insulin resistance when challenged with a high fat/high sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance.
doi:10.1038/ncomms3354
PMCID: PMC3941707  PMID: 23965929
25.  Creation of an Anatomic Femoral Tunnel With Minimal Damage to the Remnant Bundle in Remnant-Preserving Anterior Cruciate Ligament Reconstruction Using an Outside-In Technique 
Arthroscopy Techniques  2014;3(1):e175-e179.
We established a method for creation of an anatomic femoral tunnel with minimal damage to the remnant bundle in remnant-preserving anterior cruciate ligament (ACL) reconstruction. The goals of this surgical technique were to preserve the remnant bundle as much as possible, especially at the femoral insertion, and to make the tunnel at the anatomic position. The critical points are that the posterior side of the femoral footprint of the ACL is observed through the posterolateral portal using a 70° arthroscope and a femoral tunnel is made by use of an outside-in technique with remnant preservation. This technique allows for easy viewing of the posterior side of the ACL and enables performance of an anatomic ACL reconstruction.
doi:10.1016/j.eats.2013.09.012
PMCID: PMC3986658  PMID: 24749041

Results 1-25 (47)