The autophagic machinery is necessary for removal of cell corpses from the developing retinal neuroepithelium

12 páginas, 8 figuras -- PAGS nros. 1279-1290Autophagy is a homoeostatic process necessary for the clearance of damaged or superfluous proteins and organelles. The recycling of intracellular constituents also provides energy during periods of metabolic stress, thereby contributing to cell viability. In addition, disruption of autophagic machinery interferes with embryonic development in several species, although the underlying cellular processes affected remain unclear. Here, we investigate the role of autophagy during the early stages of chick retina development, when the retinal neuroepithelium proliferates and starts to generate the first neurons, the retinal ganglion cells. These two developmental processes are accompanied by programmed cell death. Upon treatment with the autophagic inhibitor 3-methyladenine, retinas accumulated numerous TdT-mediated dUTP nick-end labelling-positive cells that correlated with a lack of the ‘eat-me’ signal phosphatidylserine (PS). In consequence, neighbouring cells did not engulf apoptotic bodies and they persisted as individual cell corpses, a phenotype that was also observed after blockade of phagocytosis with phospho-L-Serine. Supplying the retinas with methylpyruvate, a cell-permeable substrate for ATP production, restored ATP levels and the presentation of PS at the cell surface. Hence, engulfment and lysosomal degradation of apoptotic bodies were also re-established. Together, these data point to a novel role for the autophagic machinery during the development of the central nervous systemThis research was supported by grants from the Spanish Ministerio de Educación y Ciencia (BFU2006-00508 to PB and SAF2007-66175 to EJdlR) and Comunidad de Madrid (CCG06-CSIC/SAL-0821 to PB). MAM is a FPU Fellow and PB is a Ramón y Cajal Fellow (both Ministerio de Educación y Ciencia programs)Peer reviewe

Inhibitors of \u3cem\u3eN\u3csup\u3eα\u3c/sup\u3e\u3c/em\u3e-acetyl-l-ornithine Deacetylase: Synthesis, Characterization and Analysis of their Inhibitory Potency

A series of N α-acyl (alkyl)- and N α-alkoxycarbonyl-derivatives of l- and d-ornithine were prepared, characterized, and analyzed for their potency toward the bacterial enzyme N α-acetyl-l-ornithine deacetylase (ArgE). ArgE catalyzes the conversion of N α-acetyl-l-ornithine to l-ornithine in the fifth step of the biosynthetic pathway for arginine, a necessary step for bacterial growth. Most of the compounds tested provided IC50 values in the μM range toward ArgE, indicating that they are moderately strong inhibitors. N α-chloroacetyl-l-ornithine (1g) was the best inhibitor tested toward ArgE providing an IC50 value of 85 μM while N α-trifluoroacetyl-l-ornithine (1f), N α-ethoxycarbonyl-l-ornithine (2b), and N α-acetyl-d-ornithine (1a) weakly inhibited ArgE activity providing IC50 values between 200 and 410 μM. Weak inhibitory potency toward Bacillus subtilis-168 for N α-acetyl-d-ornithine (1a) and N α-fluoro- (1f), N α-chloro- (1g), N α-dichloro- (1h), and N α-trichloroacetyl-ornithine (1i) was also observed. These data correlate well with the IC50 values determined for ArgE, suggesting that these compounds might be capable of getting across the cell membrane and that ArgE is likely the bacterial enzymatic target

Lysine Biosynthesis in Bacteria: A Metallodesuccinylase as a Potential Antimicrobial Target

In this review, we summarize the recent literature on dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) enzymes, with an emphasis on structure–function studies that provide insight into the catalytic mechanism. Crystallographic data have also provided insight into residues that might be involved in substrate and hence inhibitor recognition and binding. These data have led to the design and synthesis of several new DapE inhibitors, which are described along with what is known about how inhibitors interact with the active site of DapE enzymes, including the efficacy of a moderately strong DapE inhibitor

Patienten mit schizophrenen Störungen im psychiatrischen Maßregelvollzug: Ergeben sich Konsequenzen für die Allgemeinpsychiatrie?

Zusammenfassung: Es wurde eine Erhebung zu soziodemographischen, kriminologischen und psychiatrischen Merkmalen der 2007 gemäß §63 StGB und §126a StPO in Mecklenburg-Vorpommern untergebrachten Patienten mit Erkrankungen aus dem schizophrenen Formenkreis durchgeführt. Dabei konnten Daten zu allen im Untersuchungszeitraum untergebrachten 45Probanden erhoben werden. Diese stellen einen Anteil von 22% an der Gesamtzahl der 202 im Erhebungszeitraum untergebrachten Patienten. Dieser Wert liegt deutlich unter den Daten westlicher und auch eher städtisch geprägter Bundesländer. Ähnlich wie in anderen Untersuchungen aus Deutschland und Österreich zeigt sich eine hohe Rate von Vorbehandlungen in der Allgemeinpsychiatrie. Es bleibt eine wichtige Aufgabe, adäquate Interventionsstrategien für fremdaggressive Patienten mit kombinierten psychischen Störungen (z.B. Schizophrenie und Sucht), strafrechtlicher Vorgeschichte und fehlenden sozialen Perspektiven zu entwickel

Использование аналитики при создании бренда территории

Рассматриваются компоненты брендинга и бренда территории, раскрываются возможности использования аналитики при его создании и продвижении. Под аналитикой понимается обширное использование данных, статистического и количественного анализа, описательных и прогнозных моделей для принятия решений и действий, на основе реальных фактов. Делается вывод о том, что аналитика является наиболее эффективным механизмом при создании и продвижении бренда территории

Быстродействующая система стабилизации переменного напряжения

Рассматривается система стабилизации переменного напряжения на основе магнитно-полупроводникового регулятора без подмагничивания постоянным током и быстродействующей обратной связи. По описанному принципу могут быть построены быстродействующие однофазные и трехфазные стабилизаторы напряжения на встречно-параллельных управляемых вентилях при их естественной или принудительной коммутации

Mono-\u3cem\u3eN\u3c/em\u3e-acyl-2,6-diaminopimelic Acid Derivatives: Analysis by Electromigration and Spectroscopic Methods and Examination of Enzyme Inhibitory Activity

Thirteen mono-N-acyl derivatives of 2,6-diaminopimelic acid (DAP)—new potential inhibitors of the dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18)—were analyzed and characterized by infrared (IR) and nuclear magnetic resonance (NMR) spectroscopies and two capillary electromigration methods: capillary zone electrophoresis (CZE) and micellar electrokinetic chromatography (MEKC). Structural features of DAP derivatives were characterized by IR and NMR spectroscopies, whereas CZE and MEKC were applied to evaluate their purity and to investigate their electromigration properties. Effective electrophoretic mobilities of these compounds were determined by CZE in acidic and alkaline background electrolytes (BGEs) and by MEKC in acidic and alkaline BGEs containing a pseudostationary phase of anionic detergent sodium dodecyl sulfate (SDS) or cationic detergent cetyltrimethylammonium bromide (CTAB). The best separation of DAP derivatives, including diastereomers of some of them, was achieved by MEKC in an acidic BGE (500 mM acetic acid [pH 2.54] and 60 mM SDS). All DAP derivatives were examined for their ability to inhibit catalytic activity of DapE from Haemophilus influenzae (HiDapE) and ArgE from Escherichia coli (EcArgE). None of these DAP derivatives worked as an effective inhibitor of HiDapE, but one derivative—N-fumaryl, Me-ester-DAP—was found to be a moderate inhibitor of EcArgE, thereby providing a promising lead structure for further studies on ArgE inhibitors

Inhibition of the \u3cem\u3edapE\u3c/em\u3e-Encoded \u3cem\u3eN\u3c/em\u3e-Succinyl- ʟ, ʟ-diaminopimelic Acid Desuccinylase from \u3cem\u3eNeisseria meningitidis\u3c/em\u3e by ʟ-Captopril

Binding of the competitive inhibitor ʟ-captopril to the dapE-encoded N-succinyl-ʟ, ʟ-diaminopimelic acid desuccinylase from Neisseria meningitidis (NmDapE) was examined by kinetic, spectroscopic, and crystallographic methods. ʟ-Captopril, an angiotensin-converting enzyme (ACE) inhibitor, was previously shown to be a potent inhibitor of the DapE from Haemophilus influenzae (HiDapE) with an IC50 of 3.3 μM and a measured Ki of 1.8 μM and displayed a dose-responsive antibiotic activity toward Escherichia coli. ʟ-Captopril is also a competitive inhibitor of NmDapE with a Ki of 2.8 μM. To examine the nature of the interaction of ʟ-captopril with the dinuclear active site of DapE, we have obtained electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) data for the enzymatically hyperactive Co(II)-substituted forms of both HiDapE and NmDapE. EPR and MCD data indicate that the two Co(II) ions in DapE are antiferromagnetically coupled, yielding an S = 0 ground state, and suggest a thiolate bridge between the two metal ions. Verification of a thiolate-bridged dinuclear complex was obtained by determining the three-dimensional X-ray crystal structure of NmDapE in complex with ʟ-captopril at 1.8 Å resolution. Combination of these data provides new insights into binding of ʟ-captopril to the active site of DapE enzymes as well as important inhibitor–active site residue interaction’s. Such information is critical for the design of new, potent inhibitors of DapE enzymes

An Authoring Tool for Building Mobile Phone AR Applications

This thesis describes the research on developing an authoring tool for mobile phone Augmented Reality (AR) applications. This work is based on earlier work at the HIT Lab NZ on ComposAR, a tool for authoring PC based AR applications. We describe modifications to ComposAR that allows end-users to prototype mobile AR applications on a PC, and player software that allows prototype AR applications to be delivered on a mobile phone. In this way, end-users with little programming experience can develop simple mobile AR applications. To prove the applicability of this authoring tool, a user evaluation was conducted with some users and performance compared between programmers and non-programmers and across different authoring tools

Разработка двухпозиционной системы управления уровнем жидкости

Micro-hairs are profound elements widely used in nature. A great variety of animals use them as sensors to gather information about their surroundings. To artificially fabricate these kinds of sensors, we present a method to produce micro-hairs made of polydimethylsiloxane (PDMS). We investigated the laser micro-drilling of wax and polycarbonate (PC) substrates with a 193-nm ArF laser to produce molds suitable for casting micro-hairs. Especially PC molds lead to high-quality micro-hairs. Thus, laser ablation of PC was intensively studied. In order to obtain micro-hair arrays, experiments where performed to optimize the casting techniques of PDMS in PC molds. The possibilities and limitations of the investigated method of micro-hair production are presented