bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Ramadan Fasting on Tear Proteins
Authors: Sariri Reyhaneh , Varasteh Abdolali , Sajedi Reza Hassan
Published: September 2016

Muslims abstain from eating, drinking and smoking from dawn to sunset during the holy month of Ramadan. Prolonged fasting is thought to be among risk factors for many diseases, e.g., cardiovascular, gastrointestinal and various infectious diseases. It could also play a part in several eye diseases, including dry eye syndrome, glaucoma, and cataract. Toxic and oxidative effects due to increased concentrations of some biochemicals as a result of reduction in tear volume thought to play an important role in damaging ocular tissue. Human tear is an important biological fluid similar to blood in many aspects. Tear film is composed of three basic layers i.e. lipid, aqueous and mucin. The tear film covering the ocular surface presents a mechanical and antimicrobial barrier, and endures an optical refractive surface. The aim of this study was to analyze and compare tear protein of volunteers during fasting. Using two reliable analytical methods, i.e. electrophoresis and high performance liquid chromatography (HPLC), we compared tear protein content of sixty volunteers (35 males and 25 females, 23–27 years old) during fasting in holly month of Ramadan (FAST:n=62) and one month before Ramadan (CTRL:n=60). The results showed that some identified tear proteins decreased during fasting. On the other hand, the activity of some enzymes such as lysozyme, lactoferrin and alpha amylase also decreased in fasting samples. Electrophoresis results showed that tear protein patterns in FAST (P<0.05) were different from those of CTRL. There were a few more protein peaks in the FAST group (P<0.005) than in CTRL.
Neutrophilic Dermatosis of the Dorsal Hands Associated with a “Myeloproliferative Neoplasm, Unclassifiable“ and a Simultaneous Cancer of Colon
Authors: Fernández-Fernández Francisco José , Álvarez – Fernández Juan Carlos , Romero – Picos Esperanza , Garrido Juan Antonio , Sesma Pascual
Published: September 2016

Neutrophilic dermatosis of the dorsal hands is a variant of Sweet's syndrome. We herein describe an 83-year old woman with a neutrophilic dermatosis of the dorsal hands associated with a "myeloproliferative neoplasm, unclassifiable" and a simultaneous cancer of colon. To our knowledge, and after a search in PubMed, the association of Sweet's syndrome with a "myeloproliferative neoplasm, unclassifiable" and a simultaneous cancer of colon has not previously been reported.
Plasmapheresis-induced Clinical Improvement in a Patient with Steroid-Resistant Nephrotic Syndrome Due to Podocin (NPHS2) Gene Station
Authors: Skálová Sylva , Podhola Miroslav , Vondrák Karel , Chernin Gil
Published: September 2016

Podocin mutations (NPHS2gene) are mostly responsible for steroid-resistant nephrotic syndrome (SRNS) of childhood onset. Patients withNPHS2gene mutations do not respond to corticoids and other immunosuppressive agents; partial remission can be rarely induced by cyclosporin A. We present a boy, where SRNS was diagnosed within first year of life. By the age of 15 years, proteinuria reached 9000 mg/24 h, cholesterolemia 15 mmol/L, albuminemia 19.6 g/L, in spite of combined therapy with cyclosporine A, methylprednisolone, enalapril and losartan. At that time a combined heterozygous form of twoNPHS2gene mutations (p.R138Q and p.V290M) was diagnosed, methylprednisolone was discontinued and patient underwent ten plasmapheresis procedures. This resulted in clinical improvement (proteinuria 3000 mg/24 h, S-cholesterol 6 mmol/L, albumin 30g/L) lasting for three years. In conclusion, plasmapheresis can result in clinical improvement and stabilization of SRNS caused by podocine mutation, before renal replacement therapy is initiated.
The Impact of Implementing an "Incredible Years" Group Within a Family Living Unit in a Transitional Living Shelter: The Case of "Cathy"
Authors: Rogers Karen C. , Bobich Michelle , Heppell Patrick
Published: September 2016

Young children who experience homelessness have a markedly increased risk of behavior disorders.  This case study illustrates the impact of the "Incredible Years" (IY) program, an evidence-supported group psychotherapy intervention, on "Cathy," a 4-year-old Latina girl with externalizing behaviors who was living in a transitional program for homeless women and children.  Adaptations of the model to address the child and family’s trauma history and to allow for its implementation in a residential program are delineated. Qualitative and quantitative data support that the IY group had a positive impact on Cathy and her family and led to significant symptom decreases in externalizing behaviors and PTSD symptoms, as well as an improvement in the quality of child and parent interactions. Additionally, recommendations for future studies and treatment considerations and adaptations for this underserved population are addressed.
上海市常住人口的语言选择和语言使用度研究
Authors: 三 端木 , 瀛月 张 , 岩 董 , 逸雯 周
Published: September 2016

近年来，随着中国社会产生的一系列巨大变化，语言使用也产生了相应的变化，其中城市的变化最大。以上海为例，二十多年前，上海话具有 “权威性”，是上海市区的主要使用语，而在一代人之后的今天，普通话已经取而代之。如此快速而大规模的变化为语言学家提供一个极好而难得的研究题目。本文介绍我们对上海常住人口的语言选择和使用度进行的研究。结果显示，普通话的总体使用度为 55%，上海话为 30%，英语为 7%，其他为 8%。这个结果从量化的角度证实了一些媒体和学者们的观察，即上海话的 “权威性” 已不再有，它已不再是上海市的主要交流工具。语言的选择和使用也跟年龄有关，即年龄越小，上海话用的越少。最后，本文试图从人口成分变化以及上海话的地位变化来探讨上海的语言选择和使用现状。
Change in Microwave-Absorbing Characteristics during the Oxidation Processes of an Ilmenite Concentrate
Authors: Li Wei , Meng Binfang , Wang Xinying , Liu Yuqi , Zhang Libo
Published: September 2016

Microwave-absorbing characteristics of the oxidized ilmenite concentrate were measured by the method of microwave cavity perturbation. The effects of particle size, oxidation temperature and oxidation time on the microwave-absorbing characteristics were investigated. The particle size, oxidation temperature and oxidation time have substantial impact on the microwave-absorbing characteristics of the sample and therefore the microwave heating performance during the oxidation processes of the ilmenite concentrate. Results indicated that at the same oxidation time, the microwave absorbing characteristics decreased as the oxidation temperature increased, and at a constant temperature, the microwave absorbing characteristics of the sample decreased as the oxidation time increased. The microwave absorbing characteristics of the ilmenite concentrate with 80–120 mesh particle size was stronger than that of 200 mesh particle size. The microwave absorbing characteristics of products oxidized at 900 °C for 30 min were slightly weaker than those treated at 800 °C for 30 min and 900 °C for 20 min. The sample becomes less efficient in absorbing microwave energy as the oxidation proceeds. It is therefore recommended strong microwave absorbing materials or conventional heating be applied at the late stage of oxidation to aid microwave heating.
The Inviscid Limit of the Fractional Complex Ginzburg–Landau Equation
Authors: Wang Lijun , Li Jingna , Xia Li
Published: September 2016

In this paper, the inviscid limit behavior of solution of the fractional complex Ginzburg–Landau (FCGL) equation$${\partial _t}u + (a + i\nu){\Lambda ^{2\alpha}}u + (b + i\mu){\left| u \right|^{2\sigma}}u = 0, \quad (x, t) \in {{\Cal T}^n} \times (0, \infty)$$is considered. It is shown that the solution of the FCGL equation converges to the solution of nonlinear fractional complex Schrödinger equation, while the initial data${u_0}$is taken in${L^2}, $${H^\alpha}$, and${L^{2\sigma + 2}}$as$a,\, b$tends to zero, and the convergence rate is also obtained.
Phonological patterning for English as a lingua franca in Asia: Implications for norms and practice in multilingual Asia
Authors: Low Ee-Ling
Published: September 2016

With the rapid economic development and the increasing activities in trade, education, cultural events, and tourism in Asia, more and more people are using English as a lingua franca (ELF). The Asian Corpus of English (ACE) project has, as one of its defining goals, the collection of a million-word corpus of naturally occurring speech in order to analyse and describe the distinctive linguistic features of Asian ELF and to identify shared features if any. However, little research has been done hitherto on the features of ELF in the Asian context. This paper, therefore, presents a description of the phonological patterns found in ELF. Specifically, the paper focuses, inter alia, on the monophthong vowels and rhythmic patterning in the spoken interactions of ELF speakers from the data as well as the implications for policy and practice of ELF in multilingual Asia. The study is based on the Asian Corpus of English (ACE) data collected in Singapore by the National Institute of Education (NIE) team. Participants in the study include speakers from China, Singapore, the Philippines, Indonesia and India. The paper aims to deepen the boundaries of thinking about shared pronunciation patternings of ELF speakers in Asia and considers the implications of such shared patternings and norms on practice in multilingual Asia.
Heuristic theory in corpus compilation
Authors: Patkin John
Published: September 2016

Building the Asian Corpus of English (ACE, 2014) involved complex interactions between researchers, participants, transcription conventions, software and hardware. The gathering and transcribing of naturally occurring conversations of English among Asian multilinguals was undertaken by a team of more than twenty researchers in nine locations across Asia. Modelled on the Vienna Oxford Corpus of English (VOICE), ACE faced unique challenges due to linguistic, cultural and geographical differences. These problems were solved through procedures and tools known as heuristics which were built on prior experience and also trial and error. The process of developing and categorising these skills are presented with experiences shared by ACE researchers and the author along with examples from the corpus.
Review of Microwave Photonics Technique to Generate the Microwave Signal by Using Photonics Technology
Authors: Raghuwanshi Sanjeev Kumar , Srivastav Akash
Published: September 2016

Microwave photonics system provides high bandwidth capabilities of fiber optic systems and also contains the ability to provide interconnect transmission properties, which are virtually independent of length. The low-loss wide bandwidth capability of optoelectronic systems makes them attractive for the transmission and processing of microwave signals, while the development of high-capacity optical communication systems has required the use of microwave techniques in optical transmitters and receivers. These two strands have led to the development of the research area of microwave photonics. So, we can considered microwave photonics as the field that studies the interaction between microwave and optical waves for applications such as communications, radars, sensors and instrumentations. In this paper we have thoroughly reviewed the microwave generation techniques by using photonics technology.
Transmitter Spatial Diversity for FSO Uplink in Presence of Atmospheric Turbulence and Weather Conditions for Different IM Schemes
Authors: Viswanath Anjitha , Kumar Jain Virander , Kar Subrat
Published: September 2016

We investigate the error performance of an earth-to-satellite free space optical uplink using transmitter spatial diversity in presence of turbulence and weather conditions, using gamma–gamma distribution and Beer–Lambert law, respectively, for on–off keying (OOK),
Channel Model Optimization with Reflection Residual Component for Indoor MIMO-VLC System
Authors: Chen Yong , Li Tengfei , Liu Huanlin , Li Yichao
Published: September 2016

A fast channel modeling method is studied to solve the problem of reflection channel gain for multiple input multiple output-visible light communications (MIMO-VLC) in the paper. For reducing the computational complexity when associating with the reflection times, no more than 3 reflections are taken into consideration in VLC. We think that higher order reflection link consists of corresponding many times line of sight link and firstly present reflection residual component to characterize higher reflection (more than 2 reflections). We perform computer simulation results for point-to-point channel impulse response, receiving optical power and receiving signal to noise ratio. Based on theoretical analysis and simulation results, the proposed method can effectively reduce the computational complexity of higher order reflection in channel modeling.
The Effect of Warming Oceans at a Tide Gauge
Station
Authors: Bâki Iz H.
Published: September 2016

This study proposes a new paradigm for assessing
thermosteric effects of warming oceans at a tide gauge
station. For demonstration, the trend due to the global
thermosteric sea level at the Key West, FL tide gauge station
was estimated using the tide gauge measurements
and the global sea surface temperature anomalies that
were represented by yearly distributed lags. A comparison
of the estimate with the trend estimate from a descriptive
model revealed that 0.7±0.1 mm/yr, (p<0.01), of the total
trend 2.2±0.1 mm/yr (p<0.01) estimated using the descriptive
model can be attributed to the global warming of the
oceans during the last century at this station. The remaining
1.5±0.1 mm/yr, 70 percent of the total trend, is the lump
sum estimate of the secular changes due to the eustatic,
halosteric, and various local isostatic contributions.
Corrosion of reinforced steel in the environment of blast furnace slag and steelmaking slag
Authors: Rodziňák D. , Halama M. , Čerňan J. , Kovalčíková M.
Published: September 2016

This article focuses on corrosion of the steel reinforcement in the concrete where the blast or demetalized steelmaking slag as one of the components for fabrication was used. The slag from iron and steel production from U.S. Steel Kosice was used in the experiment. Steel reinforcement type S 235 (STN 11 375) were made by cold drawing. Chemical composition of slag in form of powder and slag leachates was analysed using X-ray fl uorescence spectrometry. Corrosion tests were carried out by measuring the polarization curves based on potentiodynamic polarization of steel samples exposed in leachate and also by polarization resistance method directly on the steel embedded in concrete and exposed in atmospheric precipitation. The results revealed differences in the corrosion rate, depending on chemical composition of the slag, which is closely related to its metallic and sulphur content.
A New Housing Concept for the Karl Friedrich Schinkel Collection: Chemical and Mechanical Aspects
Authors: Meyer Fabienne , Volland Gerhard
Published: September 2016

This paper describes the measures taken to rehouse the collection of drawings and prints by Karl Friedrich Schinkel in the Kupferstichkabinett Berlin. Previously, the collection had been exposed to high concentrations of volatile organic compounds (VOCs). Housing the artworks in piles inside portfolios had caused mechanical damage. The VOC concentration in the object’s environment was reduced by replacing the main emission sources with low-emissive materials, by increasing the air exchange rate of the cabinets, and by sealing emission sources that could not be removed from the cabinets. It was decided to dispense with the application of any chemisorbents since they proved to be ineffective for the given storage situation. To avoid further mechanical damage, the objects were inserted into folders made either from cardboard or, depending on the characteristics and sensitivity of the object, from a combination of cardboard and polyester film. Groups of artworks were stored in new, lightweight enclosures that combine the advantages of the Solander box, the corrugated cardboard box, and the four-flap portfolio. Crosswise bonding of the corrugated boards provides sufficient stability. The joints that are particularly subjected to stress were reinforced with fabric. These new enclosures protect the objects from slipping and lateral impact. The historic portfolios were preserved as documentary material and are now stored in a separate place.
Optimization of biogas generation using anaerobic digestion models and computational intelligence approaches
Authors: Enitan Abimbola M. , Adeyemo Josiah , Swalaha Feroz M. , Kumari Sheena , Bux Faizal
Published: September 2016

Anaerobic digestion (AD) technology has become popular and is widely used due to its ability to produce renewable energy from wastes. The bioenergy produced in anaerobic digesters could be directly used as fuel, thereby reducing the release of biogas to the atmosphere. Due to the limited knowledge on the different process disturbances and microbial composition that are vital for the efficient operation of AD systems, models and control strategies with respect to external influences are needed without wasting time and resources. Different simple and complex mechanistic and data-driven modeling approaches have been developed to describe the processes taking place in the AD system. Microbial activities have been incorporated in some of these models to serve as a predictive tool in biological processes. The flexibility and power of computational intelligence of evolutionary algorithms (EAs) as direct search algorithms to solve multiobjective problems and generate Pareto-optimal solutions have also been exploited. Thus, this paper reviews state-of-the-art models based on the computational optimization methods for renewable and sustainable energy optimization. This paper discusses the different types of model approaches to enhance AD processes for bioenergy generation. The optimization and control strategies using EAs for advanced reactor performance and biogas production are highlighted. This information would be of interest to a dynamic group of researchers, including microbiologists and process engineers, thereby offering the latest research advances and importance of AD technology in the production of renewable energy.
Examining Fundamental Movement Competency and Closed-Chain Upper-Extremity Dynamic Balance in Swimmers
Authors: Bullock Garrett S. , Brookreson Nate , Knab Amy M. , Butler Robert J.
Published: September 2016

Bullock, GS, Brookreson, N, Knab, AM, and Butler, RJ. Examining fundamental movement competency and closed-chain upper-extremity dynamic balance in swimmers. J Strength Cond Res 31(6): 1544–1551, 2017—Abnormal fundamental movement patterns and upper-quarter dynamic balance are proposed mechanisms affecting athletic performance and injury risk. There are few studies investigating functional movement and closed-chain upper-extremity dynamic stability in swimmers. The purpose of this study was to determine differences in fundamental movement competency and closed-chain upper-extremity dynamic balance, using the Functional Movement Screen (FMS) and Upper-Quarter Y Balance Test (YBT-UQ), of high school (HS; n = 70) and collegiate (COL; n = 70) swimmers. Variables included the individual movement tests on the FMS and the average normalized reach (percent limb length [%LL]) for each direction, with the YBT-UQ. Statistical analysis was completed using a chi square for the independent test scores on the FMS while independent samples t-test to examine performance on the YBT-UQ (p ≤ 0.05). HS swimmers exhibited a statistically significant greater percentage of below average performance (score of 0 or 1) on the following FMS tests: lunge (HS: 22.9%, COL: 4.3%), hurdle step (HS: 31.4%, COL: 7.1%), and push-up (HS: 61.4%, COL: 31.4%). Furthermore, COL males performed worse in the lunge (male: 9%, female: 0%), whereas COL females had poorer efficiency in the push-up (male: 17.6%, female: 44%). Significant effects of competition level and sex were observed in YBT-UQ medial reach (HS: female 92.06, male 101.63; COL: female 101.3, male 101.5% LL). Individual fundamental movement patterns that involved lumbopelvic neuromuscular control differed between HS and COL swimmers. General upper-extremity dynamic balance differed between competition levels. These data may be helpful in understanding injury and performance-based normative data for participation and return to swimming.
The Effects of Accentuated Eccentric Loading on the Drop Jump Exercise and the Subsequent Postactivation Potentiation Response
Authors: Bridgeman Lee A. , McGuigan Michael R. , Gill Nicholas D. , Dulson Deborah K.
Published: September 2016

Bridgeman, LA, McGuigan, MR, Gill, ND, and Dulson, DK. The effects of accentuated eccentric loading on the drop jump exercise and the subsequent postactivation potentiation response. J Strength Cond Res 31(6): 1620–1626, 2017—The aims of this study were (a) to investigate the acute effects of different drop jump (DJ) accentuated eccentric loading (AEL) protocols and (b) to investigate the effect of these AEL DJ protocols on subsequent countermovement jump (CMJ) performance. The subjects were 12 strength-trained athletes; initially, baseline CMJ performance was assessed and individual optimal DJ drop height identified. In subsequent weeks, subjects completed 1 set of 5 DJs with no additional load or an AEL of 10, 20, or 30% of their individual body mass (BM) using dumbbells to provide the extra load. After the AEL DJ protocols, 3 CMJs were completed after 2, 6, and 12 minutes rest. A generalized linear mixed model was used to investigate the effects of AEL load and time post-DJs on CMJ height, peak power, and ground reaction force. The 20% AEL condition resulted in greater CMJ height in comparison with all other conditions (p < 0.001). CMJ height was significantly greater after 2 and 6 minutes rest compared with 12 minutes (p < 0.001 and p ≤ 0.05 respectively). Greater peak power was also found during the CMJs after the 20% AEL condition compared with baseline, BM, and 10% AEL (p ≤ 0.05). In conclusion, 5 DJs with 20% AEL followed by a 2 minutes recovery period resulted in significant enhancement in CMJ height and peak power.
The Training Octagon: Training the Anterior and Posterior Serape
Authors: Santana Juan C. , Brown Lee E. , Ferrigno Vance A.
Published: September 2016

THE PURPOSE OF THIS ARTICLE IS TO EXPLAIN HOW THE ANTERIOR AND POSTERIOR SERAPE (APS) CAN BE SYSTEMATICALLY TRAINED USING A SIMPLE MOVEMENT MODEL; THE TRAINING OCTAGON (TO). THE DIRECTIONS OF THE MUSCLES ARE ASSOCIATED WITH THE DIRECTIONS OF THE TO, AND A SYSTEM OF FIVE BASIC CABLE/BAND EXERCISES IS PROVIDED FOR TRAINING. TABLES AND FIGURES ORGANIZING AND CLASSIFYING THE MUSCLES, MOVEMENTS, AND EXERCISES FURTHER ASSOCIATE THE TRAINING AND BIOMECHANICAL MODELS OF THE APS. THE MODEL PRESENTED IN THIS ARTICLE IS A TOOL FOR STRENGTH AND CONDITIONING PROFESSIONALS TO USE WHEN TRAINING THE CORE MUSCULATURE.
Ventral Tegmental Area Dopamine Cell Activation during Male Rat Sexual Behavior Regulates Neuroplasticity and d-Amphetamine Cross-Sensitization following Sex Abstinence
Authors: Beloate Lauren N. , Omrani Azar , Adan Roger A. , Webb Ian C. , Coolen Lique M.
Published: September 2016

Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA ofTH::Creadult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience.

SIGNIFICANCE STATEMENTDrugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward.
The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats
Authors: Lindenbach David , Conti Melissa M. , Ostock Corinne Y. , George Jessica A. , Goldenberg Adam A. , Melikhov-Sosin Mitchell , Nuss Emily E. , Bishop Christopher
Published: September 2016

Long-term treatment of Parkinson's disease withl-DOPA almost always leads to the development of involuntary movements termedl-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterizein vivochanges in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed byl-DOPA. Among sham-lesioned rats,l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats,l-DOPA given acutely (1 d) or chronically (14–16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated thatl-DOPA-induced dyskinesia was reduced by M1 infusion of a D1antagonist, an AMPA antagonist, or a GABAAagonist. Overall, the present study demonstrates thatl-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy.

SIGNIFICANCE STATEMENTMost Parkinson's disease patients will receivel-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigatingin vivoneurotransmitter release in M1 during dyskinesia. In parkinsonian rats,l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAAreceptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.
Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas
Authors: Whitney Meredith Sorenson , Shemery Ashley M. , Yaw Alexandra M. , Donovan Lauren J. , Glass J. David , Deneris Evan S.
Published: September 2016

Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditionaltryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep–wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior.

SIGNIFICANCE STATEMENTSerotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep–wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder.
Reduced Efficacy of Anti-Aβ Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity
Authors: Weekman Erica M. , Sudduth Tiffany L. , Caverly Carly N. , Kopper Timothy J. , Phillips Oliver W. , Powell Dave K. , Wilcock Donna M.
Published: September 2016

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aβ levels, there was no cognitive benefit of the anti-Aβ immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PS1/control but further increased in an additive fashion when 3D6 was administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Aβ immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes.

SIGNIFICANCE STATEMENTDespite significant mouse model data demonstrating both pathological and cognitive efficacy of anti-Aβ immunotherapy for the treatment of Alzheimer's disease, clinical trial outcomes have been underwhelming, failing to meet any primary endpoints. We show here that vascular cognitive impairment and dementia (VCID) comorbidity eliminates cognitive efficacy of anti-Aβ immunotherapy, despite amyloid clearance. Further, cerebrovascular adverse events of the anti-Aβ immunotherapy are significantly exacerbated by the VCID comorbidity. These data suggest that VCID comorbidity with Alzheimer's disease may mute the response to anti-Aβ immunotherapy.
Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression
Authors: Saito Takashi , Matsuba Yukio , Yamazaki Naomi , Hashimoto Shoko , Saido Takaomi C.
Published: September 2016

Intraneuronal calcium stimulates the calpain-dependent conversion of p35 to p25, a CDK5 activator. It is widely believed that amyloid β peptide (Aβ) induces this conversion that, in turn, has an essential role in Alzheimer's disease pathogenesis. However,in vivostudies on p25 generation used transgenic mice overexpressing mutant amyloid precursor protein (APP) and presenilin (PS). Here, using singleAppknock-in mice, we show that p25 generation is an artifact caused by membrane protein overexpression. We show that massive Aβ42accumulation without overexpression of APP or presenilin does not produce p25, whereas p25 generation occurred with APP/PS overexpression and in postmortem mouse brain. We further support this finding using mice deficient for calpastatin, the sole calpain-specific inhibitor protein. Thus, the intracerebral environment of the APP/PS mouse brain and postmortem brain is an unphysiological state.

SIGNIFICANCE STATEMENTWe recently estimated using singleAppknock-in mice that accumulate amyloid β peptide without transgene overexpression that 60% of the phenotypes observed in Alzheimer's model mice overexpressing mutant amyloid precursor protein (APP) or APP and presenilin are artifacts (Saito et al., 2014). The current study further supports this estimate by invalidating key results from papers that were published inCell. These findings suggest that more than 3000 publications based on APP and APP/PS overexpression must be reevaluated.
Dysregulated NMDA-Receptor Signaling Inhibits Long-Term Depression in a Mouse Model of Fragile X Syndrome
Authors: Toft Anna Karina Hugger , Lundbye Camilla Johanne , Banke Tue G.
Published: September 2016

Fragile X syndrome (FXS) is a neurodevelopmental disease. It is one of the leading monogenic causes of intellectual disability among boys with most also displaying autism spectrum disorder traits. Here we investigated the role of NMDA receptors on mGluR-dependent long-term depression (mGluR-LTD), a key biomarker in the disease, at four different developmental stages. First, we applied the mGluR agonist 3,5-dihydroxyphenylglycine in the absence or presence of the NMDAR blocker, APV, hereby unmasking the NMDAR component in this process. As expected, in the presence of APV, we found more LTD in the mouse KO than in WT. This, however, was only observed in the p30–60 age group. At all other age groups tested, mGluR-LTD was almost identical between KO and WT. Interestingly, at p60, in the absence of APV, no or very little LTD was found in KO that was completely restored by application of APV. This suggests that the underlying cause of the enhanced mGluR-LTD in KO (at p30) is caused by dysregulated NMDAR signaling. To investigate this further, we next used NMDAR-subunit-specific antagonists. Inhibition of GluN2B, but not GluN2A, blocked mGluR-LTD only in WT. This was in contrast in the KO where blocking GluN2B rescued mGluR-LTD, suggesting GluN2B-containing NMDARs in the KO are hyperactive. Thus, these findings suggest strong involvement of GluN2B-containing-NMDARs in the pathophysiology of FXS and highlight a potential path for treatment for the disease.

SIGNIFICANCE STATEMENTThere is currently no cure for fragile X, although medications targeting specific FXS symptoms do exist. The FXS animal model, theFmr1knock-out mouse, has demonstrated an increased mGluR5-mediated long-term depression (LTD) leading to several clinical trials of mGluR5 inhibitors/modulators, yet all have failed. In addition, surprisingly little information exists about the possible role of other ion channels/receptors, including NMDA receptors (NMDAR), in mGluR-LTD. Here we focus on NMDARs and their regulation of mGluR-mediated LTD at different developmental stages using several different NMDAR blockers/antagonists. Our findings suggest dysregulated NMDARs in the pathophysiology of FXS leading to altered mGluR-mediated LTD. Together, these data will help to develop new drug candidates that could lead to reversal of the FXS phenotype.
Heteromodal Cortical Areas Encode Sensory-Motor Features of Word Meaning
Authors: Fernandino Leonardo , Humphries Colin J. , Conant Lisa L. , Seidenberg Mark S. , Binder Jeffrey R.
Published: September 2016

The capacity to process information in conceptual form is a fundamental aspect of human cognition, yet little is known about how this type of information is encoded in the brain. Although the role of sensory and motor cortical areas has been a focus of recent debate, neuroimaging studies of concept representation consistently implicate a network of heteromodal areas that seem to support concept retrieval in general rather than knowledge related to any particular sensory-motor content. We used predictive machine learning on fMRI data to investigate the hypothesis that cortical areas in this “general semantic network” (GSN) encode multimodal information derived from basic sensory-motor processes, possibly functioning as convergence–divergence zones for distributed concept representation. An encoding model based on five conceptual attributes directly related to sensory-motor experience (sound, color, shape, manipulability, and visual motion) was used to predict brain activation patterns associated with individual lexical concepts in a semantic decision task. When the analysis was restricted to voxels in the GSN, the model was able to identify the activation patterns corresponding to individual concrete concepts significantly above chance. In contrast, a model based on five perceptual attributes of the word form performed at chance level. This pattern was reversed when the analysis was restricted to areas involved in the perceptual analysis of written word forms. These results indicate that heteromodal areas involved in semantic processing encode information about the relative importance of different sensory-motor attributes of concepts, possibly by storing particular combinations of sensory and motor features.

SIGNIFICANCE STATEMENTThe present study used a predictive encoding model of word semantics to decode conceptual information from neural activity in heteromodal cortical areas. The model is based on five sensory-motor attributes of word meaning (color, shape, sound, visual motion, and manipulability) and encodes the relative importance of each attribute to the meaning of a word. This is the first demonstration that heteromodal areas involved in semantic processing can discriminate between different concepts based on sensory-motor information alone. This finding indicates that the brain represents concepts as multimodal combinations of sensory and motor representations.
T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly
Authors: Potorac Iulia , Petrossians Patrick , Daly Adrian F , Alexopoulou Orsalia , Borot Sophie , Sahnoun-Fathallah Mona , Castinetti Frederic , Devuyst France , Jaffrain-Rea Marie-Lise , Briet Claire , Luca Florina , Lapoirie Marion , Zoicas Flavius , Simoneau Isabelle , Diallo Alpha M , Muhammad Ammar , Kelestimur Fahrettin , Nazzari Elena , Centeno Rogelio Garcia , Webb Susan M , Nunes Marie-Laure , Hana Vaclav , Pascal-Vigneron Véronique , Ilovayskaya Irena , Nasybullina Farida , Achir Samia , Ferone Diego , Neggers Sebastian J C M M , Delemer Brigitte , Petit Jean-Michel , Schöfl Christof , Raverot Gerald , Goichot Bernard , Rodien Patrice , Corvilain Bernard , Brue Thierry , Schillo Franck , Tshibanda Luaba , Maiter Dominique , Bonneville Jean-François , Beckers Albert
Published: September 2016

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively;P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001,r = 0.22), IGF-1 (P < 0.0001,r = 0.14) and adenoma volume (P < 0.0001,r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.
Uterine focal adhesions are retained at implantation after rat ovarian hyperstimulation
Authors: Lindsay Laura A , Dowland Samson N , Murphy Christopher R
Published: September 2016

Controlled ovarian hyperstimulation is an essential component of IVF techniques to ensure proliferation and development of multiple ovarian follicles, but the effects of these hormones on the endometrium are largely unknown. During normal pregnancy in rats, there are significant changes in the basal plasma membrane of uterine epithelial cells (UECs) at the time of receptivity, including loss of focal adhesions. This enables the UECs to be removed from the implantation chamber surrounding the blastocyst, thus allowing invasion into the underlying stroma. This study investigated the influence of ovarian hyperstimulation (OH) on the basal plasma membrane of UECs during early pregnancy in the rat. Immunofluorescence results demonstrate the presence of paxillin, talin, integrin β1 and phosphorylated FAK (Y397FAK) in the basal portion of UECs at the time of implantation in OH pregnancy. TEM analysis demonstrated a flattened basal lamina and the presence of focal adhesions on the basal surface at this time in OH pregnancy. Significantly low full-length paxillin, high paxillin δ and integrin β1 were seen at the time of implantation in OH compared with those in normal pregnancy. The increase in paxillin δ suggests that these cells are less mobile, whereas the increase in integrin β1 and Y397FAK suggests the retention of a stable FA complex. Taken together with the increase in morphological focal adhesions, this represents a cell type that is stable and less easily removed for blastocyst implantation. This may be one mechanism explaining lower implantation rates after fresh embryo transfers compared with frozen cycles.
Sperm of patients with severe asthenozoospermia show biochemical, molecular and genomic alterations
Authors: Bonanno Oriana , Romeo Giulietta , Asero Paola , Pezzino Franca Maria , Castiglione Roberto , Burrello Nunziatina , Sidoti Giuseppe , Frajese Giovanni Vanni , Vicari Enzo , D’Agata Rosario
Published: September 2016

The multifactorial pathological condition, that is, severe low sperm motility is a frequent cause of infertility. However, mechanisms underlying the development of this condition are not completely understood. Single abnormalities have been reported in sperm of patients with asthenozoospermia. In this study, we characterized, in 22 normozoospermic men and in 37 patients with asthenozoospermia, biochemical, molecular and genomic abnormalities that frequently occur in sperm of patients with asthenozoospermia. We evaluated a panel of sperm biomarkers that may affect the motility and fertilizing ability of sperm of patients with severe asthenozoospermia. Since reactive oxygen species (ROS) production is involved in the pathogenesis of such sperm abnormalities, we determined the association between ROS production and sperm abnormalities. High percentage of patients with severe asthenozoospermia showed increased basal and stimulated ROS production. Moreover, these patients showed increased mitochondrial DNA (mtDNA) copy number but decreased mtDNA integrity and they were associated with elevated ROS levels. Furthermore, mitochondrial membrane potential was also significantly decreased and again associated with high ROS production in these patients. However, the rate of nuclear DNA fragmentation was increased only in less than one-fifth of these patients. An important cohort of these patients showed multiple identical biochemical, molecular and genomic abnormalities, which are typical manifestations of oxidative stress. The most frequent association was found in patients with high ROS levels, increased mtDNA copy number and decreased integrity, and low MMP. A smaller cohort of the aforementioned patients also showed nDNA fragmentation. Therefore, patients with asthezoospermia likely present reduced fertilizing potential because of such composed abnormalities.