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1.  Retinal Circuitry Balances Contrast Tuning of Excitation and Inhibition to Enable Reliable Computation of Direction Selectivity 
The Journal of Neuroscience  2016;36(21):5861-5876.
Feedforward (FF) inhibition is a common motif in many neural networks. Typically, excitatory inputs drive both principal neurons and interneurons; the interneurons then inhibit the principal neurons, thereby regulating the strength and timing of the FF signal. The interneurons introduce a likely nonlinear processing step that could distort the excitation/inhibition (E/I) ratio in the principal neuron, potentially degrading the reliability of computation in the circuit. In the retina, FF inhibition is an essential feature of the circuitry underlying direction selectivity (DS): glutamatergic bipolar cells (BCs) provide excitatory input to direction-selective ganglion cells (DSGCs) and GABAergic starburst amacrine cells (SACs), and the SACs then provide FF inhibition onto DSGCs. Robust DS computation requires a consistent synaptic E/I ratio in the DSGC in various visual conditions. Here, we show in mouse retina that the E/I ratio is maintained in DSGCs over a wide stimulus contrast range due to compensatory mechanisms in the diverse population of presynaptic BCs. BC inputs to SACs exhibit higher contrast sensitivity, so that the subsequent nonlinear transformation in SACs reduces the contrast sensitivity of FF inhibition to match the sensitivity of direct excitatory inputs onto DSGCs. Measurements of light-evoked responses from individual BC synaptic terminals suggest that the distinct sensitivity of BC inputs reflects different contrast sensitivity between BC subtypes. Numerical simulations suggest that this network arrangement is crucial for reliable DS computation.
SIGNIFICANCE STATEMENT Properly balanced excitation and inhibition are essential for many neuronal computations across brain regions. Feedforward inhibition circuitry, in which a common excitatory source drives both the principal cell and an interneuron, is a typical mechanism by which neural networks maintain this balance. Feedforward circuits may become imbalanced at low stimulation levels, however, if the excitatory drive is too weak to overcome the activation threshold in the interneuron. Here we reveal how excitation and inhibition remain balanced in direction selective ganglion cells in the mouse retina over a wide visual stimulus range.
PMCID: PMC4879202  PMID: 27225774
calcium imaging; direction selectivity; feedforward; iGluSnFR; starburst amacrine; synaptic balance
2.  Antibody-antigen kinetics constrain intracellular humoral immunity 
Scientific Reports  2016;6:37457.
During infection with non-enveloped viruses, antibodies stimulate immunity from inside cells by activating the cytosolic Fc receptor TRIM21. This intracellular humoral response relies on opsonized viral particles reaching the cytosol intact but the antigenic and kinetic constraints involved are unknown. We have solved the structure of a potent TRIM21-dependent neutralizing antibody in complex with human adenovirus 5 hexon and show how these properties influence immune activity. Structure-guided mutagenesis was used to generate antibodies with 20,000-fold variation in affinity, on-rates that differ by ~50-fold and off-rates by >175-fold. Characterization of these variants during infection revealed that TRIM21-dependent neutralization and NFκB activation was largely unaffected by on-rate kinetics. In contrast, TRIM21 antiviral activity was exquisitely dependent upon off-rate, with sub-μM affinity antibodies nevertheless unable to stimulate signaling because of fast dissociation kinetics. These results define the antibody properties required to elicit an efficient intracellular immune response during viral infection.
PMCID: PMC5121590  PMID: 27881870
3.  Paclitaxel suppresses collagen-induced arthritis: a reevaluation 
Objective: To reevaluate the suppressive effect of paclitaxel (PTX) liposome on collagen-induced arthritis (CIA) in rats and explore its mechanisms. Methods: Female Lewis rats were immunized with bovine type II collagen (CII) to induce arthritis. The rats with CIA were randomly divided into three groups: 5% GS control group, 2.5 mg/kg PTX treatment group and 1 mg/kg methotrexate (MTX) positive control group. The drugs were administered by intraperitoneal injection on the second day after arthritis onset. The body weights, arthritis scores and paw volumes were observed consecutively. The ankle joints of rats were collected for X-ray examination and histological evaluation. Serum samples were collected to test the levels of anti-CII antibodies and cytokines. Results: Body weights were not significantly affected after PTX or MTX treatments (p>0.05). Compared with 5% GS control or MTX treatment groups, PTX group showed significant decrease of arthritis scores and paw volumes (p<0.05). Radiographic and histologic evaluation provided evidence that rats with PTX treatment had less synovial proliferation and bone erosion. In addition, the levels of anti-CII antibodies as well as serum tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) levels were remarkably lower in PTX group than those in 5% GS controls (p<0.05). Conclusions: PTX inhibits the progression of CIA in rats and prevents the destruction of joints. The mechanism might be related to its inhibition on the levels of serum anti-CII antibodies, TNF-α and VEGF.
PMCID: PMC5126347  PMID: 27904705
Paclitaxel; therapy; collagen-induced arthritis; rheumatoid arthritis
4.  Index-Based Dietary Patterns and Colorectal Cancer Risk: A Systematic Review123 
Advances in Nutrition  2015;6(6):763-773.
Colorectal cancer (CRC) is the third most common cancer in both men and women in the United States. Various a priori dietary patterns that take into account diet complexity have been associated with CRC risk. This systematic review augments the evidence for an association between CRC risk and the Mediterranean Diet Score (MDS) and the Healthy Eating Index (HEI), and provides new evidence for a novel Dietary Inflammatory Index (DII). Human studies published in English after 31 December 2008 were reviewed. Five case-control studies and 7 prospective cohort studies conducted in the United States and Europe were identified. Five of the studies examined the MDS, 4 examined the HEI, and 4 examined the DII. Comparing highest to lowest score groups, higher MDSs were associated with an 8–54% lower CRC risk, and higher HEI scores were associated with a 20–56% lower CRC risk. More proinflammatory diet scores were associated with a 12–65% higher CRC risk compared with more anti-inflammatory diets in studies that used the DII. The results reported by sex suggested similar associations for men and women. This review builds upon the evidence supporting the association between higher overall diet quality and lower risk of CRC. Increasing scores of MDS and HEI and anti-inflammatory DII scores are characterized by high intake of plant-based foods and low intake of animal products. Future studies in more diverse populations and with consistent scoring calculations are recommended.
PMCID: PMC4642428  PMID: 26567200
colorectal cancer; dietary patterns; Mediterranean diet; Healthy Eating Index; Dietary Inflammatory Index; epidemiology; systematic review
5.  Multilayered Magnetic Gelatin Membrane Scaffolds 
ACS applied materials & interfaces  2015;7(41):23098-23109.
A versatile approach for the design and fabrication of multilayer magnetic scaffolds with tunable magnetic gradients is described. Multilayer magnetic gelatin membrane scaffolds with intrinsic magnetic gradients were designed to encapsulate magnetized bioagents under an externally applied magnetic field for use in magnetic-field-assisted tissue engineering. The temperature of the individual membranes increased up to 43.7 °C under an applied oscillating magnetic field for 70 s by magnetic hyperthermia, enabling the possibility of inducing a thermal gradient inside the final 3D multilayer magnetic scaffolds. On the basis of finite element method simulations, magnetic gelatin membranes with different concentrations of magnetic nanoparticles were assembled into 3D multilayered scaffolds. A magnetic-gradient-controlled distribution of magnetically labeled stem cells was demonstrated in vitro. This magnetic biomaterial–magnetic cell strategy can be expanded to a number of different magnetic biomaterials for various tissue engineering applications.
PMCID: PMC4867029  PMID: 26451743
magnetic; nanoparticles; gelatin; scaffold; biomaterials; gradient; tissue engineering
6.  Predicting survival of patients with idiopathic pulmonary fibrosis using GAP score: a nationwide cohort study 
Respiratory Research  2016;17:131.
The clinical course of idiopathic pulmonary fibrosis (IPF) varies widely. Although the GAP model is useful for predicting mortality, survivals have not yet been validated for each GAP score. We aimed to elucidate how prognosis is related to GAP score and GAP stage in IPF patients.
The Korean Interstitial Lung Disease Study Group conducted a national survey to evaluate various characteristics in IPF patients from 2003 to 2007. Patients were diagnosed according to the 2002 criteria of the ATS/ERS. We enrolled 1,685 patients with IPF; 1,262 had undergone DLCO measurement. Patients were stratified based on GAP score (0–7): GAP score Group 0 (n = 26), Group 1 (n = 150), Group 2 (n = 208), Group 3 (n = 376), Group 4 (n = 317), Group 5 (n = 138), Group 6 (n = 39), and Group 7 (n = 8).
Higher GAP score and GAP stage were associated with a poorer prognosis (p < 0.001, respectively). Survival time in Group 3 was lower than those in Groups 1 and 2 (p = 0.043 and p = 0.039, respectively), and higher than those in groups 4, 5, and 6 (p = 0.043, p = 0.032, and p = 0.003, respectively). Gender, age, and DLCO (%) differed significantly between Groups 2 and 3. All four variables in the GAP model differed significantly between Groups 3 and 4.
The GAP system showed significant predictive ability for mortality in IPF patients. However, prognosis in IPF patients with a GAP score of 3 were significantly different from those in the other stage I groups and stage II groups of Asian patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-016-0454-0) contains supplementary material, which is available to authorized users.
PMCID: PMC5069824  PMID: 27756398
Idiopathic pulmonary fibrosis; GAP stage; Prognosis
7.  IL-10 plays an important role in the control of inflammation but not in the bacterial burden in S. epidermidis CNS catheter infection 
Shunt infection is a frequent and serious complication in the surgical treatment in hydrocephalus. Previous studies have shown an attenuated immune response to these biofilm-mediated infections. We proposed that IL-10 reduces the inflammatory response to Staphylococcus epidermidis (S. epidermidis) CNS catheter infection.
In this study, a murine model of catheter-associated S. epidermidis biofilm infection in the CNS was generated based on a well-established similar model for S. aureus. The catheters were pre-coated with a clinically derived biofilm-forming strain of S. epidermidis (strain 1457) which were then stereotactically implanted into the lateral left ventricle of 8-week-old C57BL/6 and IL-10 knockout (IL-10 knockout) mice. Bacterial titers as well as cytokine and chemokine levels were measured at days 3, 5, 7, and 10 in mice implanted with sterile and S. epidermidis-coated catheters.
Cultures demonstrated a catheter-associated and parenchymal infection that persisted through 10 days following infection. Cytokine analysis of the tissue surrounding the catheters revealed greater levels of IL-10, an anti-inflammatory cytokine, in the infected group compared to the sterile. In IL-10 KO mice, we noted no change in bacterial burdens, showing that IL-10 is not needed to control the infection in a CNS catheter infection model. However, IL-10 KO mice had increased levels of pro-inflammatory mediators in the tissues immediately adjacent to the infected catheter, as well as an increase in weight loss.
Together our results indicate that IL-10 plays a key role in regulating the inflammatory response to CNS catheter infection but not in control of bacterial burdens. Therefore, IL-10 may be a useful therapeutic target for immune modulation in CNS catheter infection but this should be used in conjunction with antibiotic therapy for bacterial eradication.
PMCID: PMC5064787  PMID: 27737696
S. epidermidis; IL-10; Central nervous system; Cytokines; Chemokines; Biofilm; Catheter; Shunt
8.  Ophthalmologists' practice patterns and challenges in achieving optimal management for glaucoma in Nigeria: results from a nationwide survey 
BMJ Open  2016;6(10):e012230.
Purpose of the study
Glaucoma, a chronic non-communicable disease, and leading cause of irreversible blindness worldwide is a public health problem in Nigeria, with a prevalence of 5.02% in people aged ≥40 years. The purpose of this nationwide survey was to assess Nigerian ophthalmologists’ practice patterns and their constraints in managing glaucoma.
Study design
Ophthalmologists were sent a semistructured questionnaire on how they manage glaucoma, their training in glaucoma care, where they practice, their access to equipment for diagnosis and treatment, whether they use protocols and the challenges they face in managing patients with glaucoma.
153/250 ophthalmologists in 80 centres completed questionnaires. Although 79% felt their training was excellent or good, 46% needed more training in glaucoma diagnosis and surgery. All had ophthalmoscopes, 93% had access to applanation tonometers, 81% to visual field analysers and 29% to laser machines (in 19 centres). 3 ophthalmologists had only ophthalmoscopes and schiøtz tonometers. For 85%, a glaucomatous optic disc was the most important feature that would prompt glaucoma work-up. Only 56% routinely performed gonioscopy and 61% used slit-lamp stereoscopic biomicroscopy for disc assessment. Trabeculectomy (with/without antimetabolites) was the only glaucoma surgery performed with one mention of canaloplasty. Poor compliance with medical treatment (78%) and low acceptance of surgery (71%) were their greatest challenges.
This study indicates that a systems-oriented approach is required to enhance ophthalmologist's capability for glaucoma care. Strategies to improve glaucoma management include strengthening poorly equipped centres including provision of lasers and training, and improving patients’ awareness and education on glaucoma.
PMCID: PMC5073544  PMID: 27729348
9.  Reversible Posterior Leukoencephalopathy Syndrome Developing After Restart of Sunitinib Therapy for Metastatic Renal Cell Carcinoma 
Case Reports in Medicine  2016;2016:6852951.
A 64-year-old Japanese man had started molecular-targeted therapy with sunitinib for lymph node metastasis 5 years after nephrectomy for left renal cell carcinoma (clear cell carcinoma, G2, pT2N0M0). He was transported to our emergency department because of generalized tonic-clonic seizure, vision loss, and impaired consciousness with acute hypertension after 8 cycles of treatment (2 years after the initiation of sunitinib therapy, including a drug withdrawal period for one year). MRI of the brain (FLAIR images) showed multiple high-intensity lesions in the white matter of the occipital and cerebellar lobes, dorsal brain stem, and left thalamus. Reversible posterior leukoencephalopathy syndrome caused by sunitinib was suspected. In addition to the immediate discontinuation of sunitinib therapy, the administration of antihypertensive agents and anticonvulsants improved the clinical symptoms without neurological damage. Physicians should be aware that sunitinib causes reversible posterior leukoencephalopathy syndrome. The early recognition of reversible posterior leukoencephalopathy syndrome is critical to avoid irreversible neurological damage.
PMCID: PMC5067324  PMID: 27795711
10.  Selective looking at natural scenes: Hedonic content and gender☆ 
Choice viewing behavior when looking at affective scenes was assessed to examine differences due to hedonic content and gender by monitoring eye movements in a selective looking paradigm. On each trial, participants viewed a pair of pictures that included a neutral picture together with an affective scene depicting either contamination, mutilation, threat, food, nude males, or nude females. The duration of time that gaze was directed to each picture in the pair was determined from eye fixations. Results indicated that viewing choices varied with both hedonic content and gender. Initially, gaze duration for both men and women was heightened when viewing all affective contents, but was subsequently followed by significant avoidance of scenes depicting contamination or nude males. Gender differences were most pronounced when viewing pictures of nude females, with men continuing to devote longer gaze time to pictures of nude females throughout viewing, whereas women avoided scenes of nude people, whether male or female, later in the viewing interval. For women, reported disgust of sexual activity was also inversely related to gaze duration for nude scenes. Taken together, selective looking as indexed by eye movements reveals differential perceptual intake as a function of specific content, gender, and individual differences.
PMCID: PMC4578996  PMID: 26156939
Emotion; Scene; Eye movements; Selective looking; Pupil
11.  Current understanding in source control management in septic shock patients: a review 
Sepsis and septic shock is one of the leading causes of death worldwide. Antibiotics, fluid resuscitation support of vital organ function and source control are the cornerstones for the treatment of these patients. Source control measures include all those actions taken in the process of care to control the foci of infection and to restore optimal function of the site of infection. Source control represents the multidisciplinary team required in order to optimize critical care for septic shock patients. In the last decade an increase interest on fluids, vasopressors, antibiotics, and organ support techniques in all aspects whether time, dose and type of any of those have been described. However information of source control measures involving minimal invasion and new techniques, time of action and outcome without it, is scarce. In this review the authors resumes new information, recommendations and future directions on this matter when facing the more common types of infections.
PMCID: PMC5050189  PMID: 27713888
Source control; sepsis; septic shock; intra-abdominal sepsis; skin; soft tissue infection; empyema
12.  Nuclear vacuolization: Giant Lochkern-like cells 
PMCID: PMC5051277  PMID: 27721594
13.  Aging is Associated With an Earlier Arrival of Reflected Waves Without a Distal Shift in Reflection Sites 
Despite pronounced increases in central pulse wave velocity (PWV) with aging, reflected wave transit time (RWTT), traditionally defined as the timing of the inflection point (TINF) in the central pressure waveform, does not appreciably decrease, leading to the controversial proposition of a “distal‐shift” of reflection sites. TINF, however, is exceptionally prone to measurement error and is also affected by ejection pattern and not only by wave reflection. We assessed whether RWTT, assessed by advanced pressure‐flow analysis, demonstrates the expected decline with aging.
Methods and Results
We studied a sample of unselected adults without cardiovascular disease (n=48; median age 48 years) and a clinical population of older adults with suspected/established cardiovascular disease (n=164; 61 years). We measured central pressure and flow with carotid tonometry and phase‐contrast MRI, respectively. We assessed RWTT using wave‐separation analysis (RWTTWSA) and partially distributed tube‐load (TL) modeling (RWTTTL). Consistent with previous reports, TINF did not appreciably decrease with age despite pronounced increases in PWV in both populations. However, aging was associated with pronounced decreases in RWTTWSA (general population −15.0 ms/decade, P<0.001; clinical population −9.07 ms/decade, P=0.003) and RWTTTL (general −15.8 ms/decade, P<0.001; clinical −11.8 ms/decade, P<0.001). There was no evidence of an increased effective reflecting distance by either method. TINF was shown to reliably represent RWTT only under highly unrealistic assumptions about input impedance.
RWTT declines with age in parallel with increased PWV, with earlier effects of wave reflections and without a distal shift in reflecting sites. These findings have important implications for our understanding of the role of wave reflections with aging.
PMCID: PMC5079032  PMID: 27572821
aging; effective reflective distance; pulse wave velocity; reflection timing; wave reflections; Hypertension; Hemodynamics; Aging; Mechanisms; High Blood Pressure
14.  New evidence for grain specific C4 photosynthesis in wheat 
Scientific Reports  2016;6:31721.
The C4 photosynthetic pathway evolved to allow efficient CO2 capture by plants where effective carbon supply may be limiting as in hot or dry environments, explaining the high growth rates of C4 plants such as maize. Important crops such as wheat and rice are C3 plants resulting in efforts to engineer them to use the C4 pathway. Here we show the presence of a C4 photosynthetic pathway in the developing wheat grain that is absent in the leaves. Genes specific for C4 photosynthesis were identified in the wheat genome and found to be preferentially expressed in the photosynthetic pericarp tissue (cross- and tube-cell layers) of the wheat caryopsis. The chloroplasts exhibit dimorphism that corresponds to chloroplasts of mesophyll- and bundle sheath-cells in leaves of classical C4 plants. Breeding to optimize the relative contributions of C3 and C4 photosynthesis may adapt wheat to climate change, contributing to wheat food security.
PMCID: PMC4987656  PMID: 27530078
15.  A Rare Association of Hepatitis A Virus Infection with Type-1 Diabetes 
Clinics and Practice  2016;6(2):844.
Patients with type-1 diabetes are predisposed to develop a spectrum of liver diseases, which includes fatty liver, steatohepatitis and cirrhosis. The association of hepatitis A infection with type-1 diabetes is extremely rare. To the best of our knowledge, our case is the first case report in children. We described a nine year-old girl who had type-1 diabetes and developed hepatitis A virus infection without complications. A review of the literature is also provided.
PMCID: PMC4943102  PMID: 27478582
Hepatitis A virus; type-1 diabetes
16.  Evaluation of medical devices in thoracic radiograms in intensive care unit - time to pay attention! 
To identify and evaluate the correct positioning of the most commonly used medical devices as visualized in thoracic radiograms of patients in the intensive care unit of our center.
A literature search was conducted for the criteria used to evaluate the correct positioning of medical devices on thoracic radiograms. All the thoracic radiograms performed in the intensive care unit of our center over an 18-month period were analyzed. All admissions in which at least one thoracic radiogram was performed in the intensive care unit and in which at least one medical device was identifiable in the thoracic radiogram were included. One radiogram per admission was selected for analysis. The radiograms were evaluated by an independent observer.
Out of the 2,312 thoracic radiograms analyzed, 568 were included in this study. Several medical devices were identified, including monitoring leads, endotracheal and tracheostomy tubes, central venous catheters, pacemakers and prosthetic cardiac valves. Of the central venous catheters that were identified, 33.6% of the subclavian and 23.8% of the jugular were malpositioned. Of the endotracheal tubes, 19.9% were malpositioned, while all the tracheostomy tubes were correctly positioned.
Malpositioning of central venous catheters and endotracheal tubes is frequently identified in radiograms of patients in an intensive care unit. This is relevant because malpositioned devices may be related to adverse events. In future studies, an association between malpositioning and adverse events should be investigated.
PMCID: PMC5051193  PMID: 27737432
Radiography, thoracic; Central venous catheters/utilization; Intubation, intratracheal/instrumentation; Equipment and supplies; Intensive care units
17.  A molecular study of the genus Spelaeomyia (Diptera: Phlebotominae) with description of the male of Spelaeomyia moucheti 
Parasites & Vectors  2016;9:367.
The genus Spelaeomyia includes four African species considered as being cavernicolous: Spelaeomyia darlingi, Spelaeomyia mirabilis, Spelaeomyia emilii and Spelaeomyia moucheti. Despite a potential role in Leishmania major leishmaniasis transmission in Mali, no molecular studies and only few morphological studies have addressed relationships between species of Spelaeomyia.
Specimens of Sa. moucheti were collected in two different sites in Gabon. Spelaeomyia emilii and Sa. darlingi specimens came from Gabon and Mali. Specimens of Sa. mirabilis were collected in the Democratic Republic of Congo and Gabon. All specimens were caught using CDC miniature light traps, then dissected, both heads and genitalia were kept for morphological analysis and the rest of the bodies were kept for molecular processing and analyses.
Some unidentified males are associated to Sa. moucheti females using molecular tools and are described for the first time. A new morphological feature is observed on the spermathecae of the female and new drawings are provided. For the first time a phylogenetic analysis is carried out on rDNA and mtDNA markers and it shows that Sa. moucheti is the sister species of Sa. mirabilis.
Spelaeomyia moucheti is the sister species of Sa. mirabilis. This result is in agreement with the sharing of morphological characters between these closely related species. Moreover, these two species are not as cavernicolous as literature previously indicated. They were caught in open rainforest in Gabon.
PMCID: PMC4928309  PMID: 27357585
Sand fly; Spelaeomyia; Morphology; Phylogeny; Africa
18.  Critical Role of COI1-Dependent Jasmonate Pathway in AAL toxin induced PCD in Tomato Revealed by Comparative Proteomics 
Scientific Reports  2016;6:28451.
Alternaria alternata f.sp. Lycopersici (AAL) toxin induces programmed cell death (PCD) in susceptible tomato (Solanum lycopersicum) leaves. Jasmonate (JA) promotes AAL toxin induced PCD in a COI1 (coronatine insensitive 1, JA receptor)-dependent manner by enhancement of reactive oxygen species (ROS) production. To further elucidate the underlying mechanisms of this process, we performed a comparative proteomic analysis using tomato jasmonic acid insensitive1 ( jai1), the receptor mutant of JA, and its wild type (WT) after AAL toxin treatment with or without JA treatment. A total of 10367 proteins were identified in tomato leaves using isobaric tags for relative and absolute quantitation (iTRAQ) quantitative proteomics approach. 2670 proteins were determined to be differentially expressed in response to AAL toxin and JA. Comparison between AAL toxin treated jai1 and its WT revealed the COI1-dependent JA pathway regulated proteins, including pathways related to redox response, ceramide synthesis, JA, ethylene (ET), salicylic acid (SA) and abscisic acid (ABA) signaling. Autophagy, PCD and DNA damage related proteins were also identified. Our data suggest that COI1-dependent JA pathway enhances AAL toxin induced PCD through regulating the redox status of the leaves, other phytohormone pathways and/or important PCD components.
PMCID: PMC4914994  PMID: 27324416
19.  Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors 
Nature Communications  2016;7:11915.
Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer's disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients.
Hippocampal synaptic dysfunctions are an early symptom of Alzheimer's disease. Here, the authors find adenosine A2A receptors are up-regulated in APP/PS1 model mice and that deleting or blocking receptor activity helps alleviate plasticity and memory impairments.
PMCID: PMC4915032  PMID: 27312972
20.  Peer-engagement and its role in reducing the risky behavior among crack and methamphetamine smokers of the Downtown Eastside community of Vancouver, Canada 
The role of peers (former or current drug users) in reducing risky behavior within methamphetamine and crack smokers has not been well described or researched. The current study not only explores the role of peers in reducing risk factors for morbidity within the illicit drug smoking population in the Downtown Eastside (DTES) community of Vancouver but it also investigates the changes in the nature of drug use after the closure of an unsanctioned smoking facility.
The data pertain to qualitative interviews with 10 peers and 10 illicit drug smokers. The semi-structured interviews were conducted through community-based research, and the digital transcripts were analyzed via NVivo 10 software.
The results indicate that peers (former and current drug users who are employed as educators) are instrumental in transferring risk reduction knowledge within crack and methamphetamine smokers. For example, these peers have been able to teach users about the risk of sharing pipes, using brillo, and using public drug. Furthermore, the Vancouver Area Network of Drug Users provides employment for crack and methamphetamine users in Vancouver who tend to have scarce sources of employment. However, since the closure of the unsanctioned inhalation facility, there has been significantly more public drug use and pipe sharing in the vicinity of the facility, placing drug smokers at significant risk of arrest, violence, and blood-borne infections.
The current study recommends expanding the harm reduction peer network for people who smoke illicit drugs in the DTES community of Vancouver who have historically been underserved.
PMCID: PMC4898457  PMID: 27278459
Peers, the Downtown Eastside; Crack; Methamphetamine; VANDU; HIV; Hepatitis C; Advocacy; People who smoke drugs
21.  Findings of Research Misconduct 
Federal Register  2016;81(107):35785-35786.
PMCID: PMC5019512  PMID: 27737272
22.  Establishing the Lysine-rich Protein CEST Reporter Gene as a CEST MR Imaging Detector for Oncolytic Virotherapy 
Radiology  2015;275(3):746-754.
This study demonstrates the possibility of engineering an MR imaging reporter gene into oncolytic viruses that is detectable with chemical exchange saturation transfer MR imaging at acute stages of viral infection and does not interfere with viral replication or therapeutic effectiveness.
To (a) evaluate whether the lysine-rich protein (LRP) magnetic resonance (MR) imaging reporter gene can be engineered into G47Δ, a herpes simplex–derived oncolytic virus that is currently being tested in clinical trials, without disrupting its therapeutic effectiveness and (b) establish the ability of chemical exchange saturation transfer (CEST) MR imaging to demonstrate G47Δ-LRP.
Materials and Methods
The institutional subcommittee for research animal care approved all in vivo procedures. Oncolytic herpes simplex virus G47Δ, which carried the LRP gene, was constructed and tested for its capacity to replicate in cancer cells and express LRP in vitro. The LRP gene was detected through CEST imaging of lysates derived from cells infected with G47Δ-LRP or the control G47Δ–empty virus. G47Δ-LRP was then tested for its therapeutic effectiveness and detection with CEST MR imaging in vivo. Images of rat gliomas were acquired before and 8–10 hours after injection of G47Δ-LRP (n = 7) or G47Δ–empty virus (n = 6). Group comparisons were analyzed with a paired t test.
No significant differences were observed in viral replication or therapeutic effectiveness between G47Δ-LRP and G47Δ–empty virus. An increase in CEST image contrast was observed in cell lysates (mean ± standard deviation, 0.52% ± 0.06; P = .01) and in tumors (1.1% ± 0.3, P = .02) after infection with G47Δ-LRP but not G47Δ–empty viruses. No histopathologic differences were observed between tumors infected with G47Δ-LRP and G47Δ–empty virus.
This study has demonstrated the ability of CEST MR imaging to show G47Δ-LRP at acute stages of viral infection. The introduction of the LRP transgene had no effect on the viral replication or therapeutic effectiveness. This can aid in development of the LRP gene as a reporter for the real-time detection of viral spread.
© RSNA, 2015
Online supplemental material is available for this article.
PMCID: PMC4450912  PMID: 25686366
23.  Analysis of the Relationship between Hypertrophy of the Ligamentum Flavum and Lumbar Segmental Motion with Aging Process 
Asian Spine Journal  2016;10(3):528-535.
Study Design
Retrospective cross-sectional study.
To investigate the relationship between ligamentum flavum (LF) hypertrophy and lumbar segmental motion.
Overview of Literature
The pathogenesis of LF thickening is unclear and whether the thickening results from tissue hypertrophy or buckling remains controversial.
296 consecutive patients underwent assessment of the lumbar spine by radiographic and magnetic resonance imaging (MRI). Of these patients, 39 with normal L4–L5 disc height were selected to exclude LF buckling as one component of LF hypertrophy. The study group included 27 men and 12 women, with an average age of 61.2 years (range, 23–81 years). Disc degeneration and LF thickness were quantified on MRI. Lumbar segmental spine instability and presence of a vacuum phenomenon were identified on radiographic images.
The distribution of disc degeneration and LF thickness included grade II degeneration in 4 patients, with a mean LF thickness of 2.43±0.20 mm; grade III in 10 patients, 3.01±0.41 mm; and grade IV in 25 patients, 4.16±1.12 mm. LF thickness significantly increased with grade of disc degeneration and was significantly correlated with age (r=0.55, p<0.01). Logistic regression analysis identified predictive effects of segmental angulation (odds ratio [OR]=1.55, p=0.014) and age (OR=1.16, p=0.008).
Age-related increases in disc degeneration, combined with continuous lumbar segmental flexion-extension motion, leads to the development of LF hypertrophy.
PMCID: PMC4917773  PMID: 27340534
Disc degeneration; Ligamentum flavum; Lumbar spine; Spinal canal stenosis
24.  Piceatannol and Other Wine Stilbenes: A Pool of Inhibitors against α-Synuclein Aggregation and Cytotoxicity 
Nutrients  2016;8(6):367.
The aggregation of α-synuclein is one on the key pathogenic events in Parkinson’s disease. In the present study, we investigated the inhibitory capacities of stilbenes against α-synuclein aggregation and toxicity. Thioflavin T fluorescence, transmission electronic microscopy, and SDS-PAGE analysis were performed to investigate the inhibitory effects of three stilbenes against α-synuclein aggregation: piceatannol, ampelopsin A, and isohopeaphenol. Lipid vesicle permeabilization assays were performed to screen stilbenes for protection against membrane damage induced by aggregated α-synuclein. The viability of PC12 cells was examined using an MTT assay to assess the preventive effects of stilbenes against α-synuclein-induced toxicity. Piceatannol inhibited the formation of α synuclein fibrils and was able to destabilize preformed filaments. It seems to induce the formation of small soluble complexes protecting membranes against α-synuclein-induced damage. Finally, piceatannol protected cells against α-synuclein-induced toxicity. The oligomers tested (ampelopsin A and hopeaphenol) were less active.
PMCID: PMC4924208  PMID: 27314384
stilbene; piceatannol; Parkinson’s disease; α-synuclein
25.  Association of nineteen polymorphisms from seven DNA repair genes and the risk for bladder cancer in Gansu province of China 
Oncotarget  2016;7(21):31372-31383.
Balance of DNA damage and proper repair plays an important role in progression of bladder cancer. Here we aimed to assess the associations of nineteen polymorphisms from seven DNA repair–associated genes (PRAP1, OGG1, APEX1, MUTYH, XRCC1, XRCC2 and XRCC3) with bladder cancer and their interactions in the disease in a Han Chinese population.
Methodology/Principal Findings
A chip-based TaqMan genotyping for the candidate genes was performed on 227 bladder cancer patients and 260 healthy controls. APEX1 rs3136817, MUTYH rs3219493, three SNPs (rs3213356, rs25487 and rs1799782) in XRCC1, and three SNPs (rs1799794, rs861531 and rs861530) in XRCC3 showed significant associations with the risk of bladder cancer. In haplotype analysis, elevated risks of bladder cancer were observed in those with either haplotype GT (OR = 1.56, P = 0.003) of APEX1, or GGGTC (OR = 2.05, P = 0.002) of XRCC1, whereas decreased risks were in individuals with either GCGCC (OR = 0.40, P = 0.001), or GCGTT (OR = 0.60, = 0.005) of XRCC1, or CCC (OR = 0.65, P = 0.004) of MUTYH, or TTTAT (OR = 0.36, P = 0.009) of XRCC3. Interaction analysis showed that the two-loci model (rs1799794 and rs861530) was the best with the maximal testing accuracy of 0.701, and the maximal 100% cross-validation consistency (P = 0.001).
Polymorphisms and haplotypes of DNA repair genes are associated with the risk of bladder cancer, and of which the SNPs (rs1799794 and rs861530) in XRCC3 gene might be two major loci in relation to the susceptibility to bladder cancer in a northwest Chinese population.
PMCID: PMC5058763  PMID: 27153553
bladder cancer; polymorphisms; DNA repair; gene interaction

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