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  • 1
    Publication Date: 2012-06-16
    Description: Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Won, Hyejung -- Lee, Hye-Ryeon -- Gee, Heon Yung -- Mah, Won -- Kim, Jae-Ick -- Lee, Jiseok -- Ha, Seungmin -- Chung, Changuk -- Jung, Eun Suk -- Cho, Yi Sul -- Park, Sae-Geun -- Lee, Jung-Soo -- Lee, Kyungmin -- Kim, Daesoo -- Bae, Yong Chul -- Kaang, Bong-Kiun -- Lee, Min Goo -- Kim, Eunjoon -- England -- Nature. 2012 Jun 13;486(7402):261-5. doi: 10.1038/nature11208.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, KAIST, Daejeon 305-701, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699620" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/*genetics ; Animals ; Antimetabolites/pharmacology ; *Autistic Disorder/genetics/metabolism ; Behavior, Animal/*drug effects/physiology ; Benzamides/*pharmacology ; Cycloserine/*pharmacology ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/*genetics ; Pyrazoles/*pharmacology ; Receptors, N-Methyl-D-Aspartate/*agonists/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-01-19
    Description: Many procedures in modern clinical medicine rely on the use of electronic implants in treating conditions that range from acute coronary events to traumatic injury. However, standard permanent electronic hardware acts as a nidus for infection: bacteria form biofilms along percutaneous wires, or seed haematogenously, with the potential to migrate within the body and to provoke immune-mediated pathological tissue reactions. The associated surgical retrieval procedures, meanwhile, subject patients to the distress associated with re-operation and expose them to additional complications. Here, we report materials, device architectures, integration strategies, and in vivo demonstrations in rats of implantable, multifunctional silicon sensors for the brain, for which all of the constituent materials naturally resorb via hydrolysis and/or metabolic action, eliminating the need for extraction. Continuous monitoring of intracranial pressure and temperature illustrates functionality essential to the treatment of traumatic brain injury; the measurement performance of our resorbable devices compares favourably with that of non-resorbable clinical standards. In our experiments, insulated percutaneous wires connect to an externally mounted, miniaturized wireless potentiostat for data transmission. In a separate set-up, we connect a sensor to an implanted (but only partially resorbable) data-communication system, proving the principle that there is no need for any percutaneous wiring. The devices can be adapted to sense fluid flow, motion, pH or thermal characteristics, in formats that are compatible with the body's abdomen and extremities, as well as the deep brain, suggesting that the sensors might meet many needs in clinical medicine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Seung-Kyun -- Murphy, Rory K J -- Hwang, Suk-Won -- Lee, Seung Min -- Harburg, Daniel V -- Krueger, Neil A -- Shin, Jiho -- Gamble, Paul -- Cheng, Huanyu -- Yu, Sooyoun -- Liu, Zhuangjian -- McCall, Jordan G -- Stephen, Manu -- Ying, Hanze -- Kim, Jeonghyun -- Park, Gayoung -- Webb, R Chad -- Lee, Chi Hwan -- Chung, Sangjin -- Wie, Dae Seung -- Gujar, Amit D -- Vemulapalli, Bharat -- Kim, Albert H -- Lee, Kyung-Mi -- Cheng, Jianjun -- Huang, Younggang -- Lee, Sang Hoon -- Braun, Paul V -- Ray, Wilson Z -- Rogers, John A -- F31MH101956/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Feb 4;530(7588):71-6. doi: 10.1038/nature16492. Epub 2016 Jan 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, Republic of Korea. ; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Engineering Science and Mechanics, Materials Research Institute, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Institute of High Performance Computing, Singapore 138632, Singapore. ; Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Biomicrosystem Technology, Korea University, Seoul 136-701, South Korea. ; Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-713, South Korea. ; Weldon School of Biomedical Engineering, School of Mechanical Engineering, The Center for Implantable Devices, Birck Nanotechnology Center, Purdue University, West Lafayette, Indiana 47907, USA. ; School of Mechanical Engineering, Purdue University, West Lafayette, Indiana 47907, USA. ; Department of Mechanical Engineering, Civil and Environmental Engineering, Materials Science and Engineering, and Skin Disease Research Center, Northwestern University, Evanston, Illinois 60208, USA. ; Department of Biomedical Engineering, College of Health Science, Korea University, Seoul 136-703, South Korea. ; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26779949" target="_blank"〉PubMed〈/a〉
    Keywords: *Absorbable Implants/adverse effects ; Administration, Cutaneous ; Animals ; Body Temperature ; Brain/*metabolism/surgery ; Electronics/*instrumentation ; Equipment Design ; Hydrolysis ; Male ; Monitoring, Physiologic/adverse effects/*instrumentation ; Organ Specificity ; Pressure ; *Prostheses and Implants/adverse effects ; Rats ; Rats, Inbred Lew ; *Silicon ; Telemetry/instrumentation ; Wireless Technology/instrumentation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The kinetics of reactions between 2-phenylethyl benzenesulphonates (2-PEB) and benzylamines in acetonitrile at 65·0°C have been studied; the mechanism was examined on the basis of the sign and magnitude of cross-interaction constants ρij and βij. In contrast to the reactions of 2-PEB with anilines in methanol, participation of the aryl-assisted pathway was negligible, with a strong indication that the reaction proceeds largely by an intermolecular SNi mechanism with a four-centre transition state (TS). The effect of substituents on the TS variation was in accord with the predictions of the quantum mechanical model.
    Additional Material: 6 Tab.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Nucleophilic substitution reactions of benzoic anhydrides, in which one of the rings is substituted, with anilines were investigated in methanol. The product-formation step coincides with the rate-limiting step so that the two rate constants, kXZ and kXZ, for the competitive reaction pathways can be dissected. The two cross-interaction constants, ρXY and ρXY, especially an unusually large magnitude of the latter, indicate that the reaction proceeds by a frontside SN2 attack on either one of the caronyl carbon with a strong interaction between the nucleophile (X) and the leaving group (Z). The mechanism is also supposed by the trends in the activation parameters.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The base-promoted nitrile-forming elimination reactions of YCH=CHCβH=NOCH=CHZ (Y=OCH3, H or Cl and Z=H or NO2) were studied by the AM1 MO theoretical method with Cl- as a base. The reaction is found to proceed by an E1cB-like E2 mechanism in which Cβ - H bond cleavage is more advanced than N - O bond breaking. The syn-elimination has a more E1cB-like transition state (TS) than the anti elimination, which is attributed to the structurally favourable nN - ó * (Cβ - H) charge-transfer interaction. An electron-withdrawing Y substituent lowers the activation barrier by stabilizing negative charge developed on Cβ in the TS. An electron-withdrawing substituent in the leaving group (Z = NO2) tends to enhance the anti relative to the syn elimination process by depressing the δ*(N - O) level, which in turn makes the nć - δ*(N - O) interaction more effective. The YCH=CH -  and  - CβH=N fragments are perpendicular in the TS, which is stabilized by delocalization of negative charge developed on the Cβ atom.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Rate constants (k2) were determined for the reduction of 1-benzyl-3-cyanoquinolinium ion by phosphonate dianion in mixed solvents consisting of propan-2-ol and water. The reduction product was mostly 1-benzyl-3-cyano-1,4-dihydroquinoline with a trace of the 1,2-isomer. The solvent properties were varied by increasing the fraction of water in the mixed solvent, which increases the polarity of the solvent. Increasing the proportion of alcohol makes the solvent a better electron pair donor. The higher fraction of propan-2-ol in the mixed solvent gives rise to a substantial increase in k2. A quantitative comparison of the solvent effect on this reaction with the solvent effects on related reactions suggests a solvent Brønsted α value of 0·45. This suggests that the PO3- unit of the transition state interacts only weakly with the solvent although the final oxidized product is phosphate.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The negative slope (ΔρY+ 〈 0) of the Hammett-type plot using kinetic solvent isotope effect, log kSOH/kSOD versus σ+, for methanolysis of 1-(Y-phenyl)ethyl chlorides is rationalized by an ion-pair mechanism in which a solvent molecule attacks the relatively stable carbocation formed in the pre-equilibrium.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The kinetics and mechanisms of the reactions between 1-phenylethyl benzenesulfonates (1-PEB) with N,N-dimethylanilines are investigated in methanol at 35·0°C. Reactivity and selectivity trends were found to be similar to those for the reactions of 1-PEB with anilines, but the magnitudes of cross interaction constants, ρXZ, between substituents X in the nucleophile and Z in the leaving group were substantially smaller indicating no hydrogen-bond bypass bridge formation in the transition state. However, the magnitude of ρXZ suggested a direct electrostatic interaction between the reaction centers in the nucleophile and leaving group in the frontside nucleophilic attack with a loose transition state structure.
    Additional Material: 6 Tab.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The magnitude ρx(ρnuc) is shown to decrease with increase in the extent of bond making estimated by the kinetic isotope effect for the reactions of Y-benzoyl chlorides with anilines, XC6H4NH2, in acetonitrile at 25·0°C.
    Additional Material: 2 Tab.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The gas-phase thermal decomposition of diacetyl compounds, (CH3CO)2X with X = O and S, was investigated theoretically using the semiempirical MO methods MNDO and AM1. The initial decomposition of the diacetyl compounds proceeded through a six-membered ring transition state involving the keto form with a slightly lower activation enthalpy for diacetyl sulphide (X = S); the process via an enolic form of the transition state was kinetically unfavourable. In the initial decomposition of the diacetyl compounds and in the subsequent pyrolysis of acetic and thioacetic acid, ketene formation was found to be the most preferred path, where the ease of Cα—X bond cleavage is relatively more important than nucleophilic attack on the β-hydrogen in determining the overall reactivity. In the methane formation process, the reactivity was entirely dependent on the X—H bond strength in CH3COXH where X = S, NH and O.
    Additional Material: 6 Tab.
    Type of Medium: Electronic Resource
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