Resorufin Enters the Photodynamic Therapy Arena: A Monoamine Oxidase Activatable Agent for Selective Cytotoxicity

A red-absorbing, water-soluble, and iodinated resorufin derivative (R1) that can be selectively activated with a monoamine oxidase (MAO) enzyme was synthesized, and its potential as a photodynamic therapy (PDT) agent was evaluated. R1 showed high ¹O₂ generation yields in aqueous solutions upon addition of MAO isoforms, and it was further tested in cell culture studies. R1 induced photocytotoxicity after being triggered by endogenous MAO enzyme in cancer cells with a much higher efficiency in SH-SY5Y neuroblastoma cells with high MAO-A expression. Additionally, R1 displayed differential cytotoxicity between cancer and normal cells, without any considerable dark toxicity. To the best of our knowledge, R1 marks the first example of a resorufin-based photosensitizer (PS) as well as the first anticancer drug that is activated by a MAO enzyme. Remarkably, the target PDT agent was obtained only in three steps as a result of versatile resorufin chemistry.     

Neural properties of fundamental function encoding of sound selectivity in the female avian auditory cortex

Zebra finches (Taeniopygia guttata) use their voices for communication. Song structures in the songs of individual males are important for sound recognition in females. The caudomedial mesopallium (CMM) and nidopallium (NCM) are known to be essential higher auditory regions for sound recognition. These two regions have also been discussed with respect to their fundamental functions and song selectivity. To clarify their functions and selectivity, we investigated latencies and spiking patterns and also developed a novel correlation analysis to evaluate the relationship between neural activity and the characteristics of acoustic factors. We found that the latencies and spiking patterns in response to song stimuli differed between the CMM and NCM. In addition, our correlation analysis revealed that amplitude and frequency structures were important temporal acoustic factors for both regions. Although the CMM and NCM have different fundamental functions, they share similar encoding systems for acoustic factors.     

A Model for the Origin of Motion Direction Selectivity in Visual Cortex

Motion perception is a vital part of our sensory repertoire in that it contributes to navigation, awareness of moving objects, and communication. Motion sense in carnivores and primates originates with primary visual cortical neurons selective for motion direction. More than 60 years after the discovery of these neurons, there is still no consensus on the mechanism underlying direction selectivity. This paper describes a model of the cat''s visual system in which direction selectivity results from the well-documented orientation selectivity of inhibitory neurons: inhomogeneities in the orientation preference map for inhibitory neurons leads to spatially asymmetric inhibition, and thus to direction selectivity. Stimulation of the model with a drifting grating shows that direction selectivity results from the relative timing of excitatory and inhibitory inputs to a neuron. Using a stationary contrast-reversing grating reveals that the inhibitory input is spatially displaced in the preferred direction relative to the excitatory input, and that this asymmetry leads to the timing difference. More generally, the model yields physiologically realistic estimates of the direction selectivity index, and it reproduces the critical finding with contrast-reversing gratings that response phase advances with grating spatial phase. It is concluded that a model based on intracortical inhibition can account well for the known properties of direction selectivity in carnivores and primates.SIGNIFICANCE STATEMENT Motion perception is vital for navigation, communication, and the awareness of moving objects. Motion sense depends on cortical neurons that are selective for motion direction, and this paper describes a model for the physiological mechanism underlying cortical direction selectivity. The essence of the model is that intracortical inhibition of a direction-selective cell is spatially inhomogeneous and therefore depends on whether a stimulus generates inhibition before or after reaching the cell''s receptive field: the response is weaker in the former than in the latter case. If the model is correct, it will contribute to the understanding of motion processing in carnivores and primates.     

Synthesis and Structure–Activity Relationships of N-Benzyl Phenethylamines as 5-HT2A/2C Agonists

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A repulsion mechanism explains magnesium permeation and selectivity in CorA

Magnesium (Mg²⁺) plays a central role in biology, regulating the activity of many enzymes and stabilizing the structure of key macromolecules. In bacteria, CorA is the primary source of Mg²⁺ uptake and is self-regulated by intracellular Mg²⁺. Using a gating mutant at the divalent ion binding site, we were able to characterize CorA selectivity and permeation properties to both monovalent and divalent cations under perfused two-electrode voltage clamp. The present data demonstrate that under physiological conditions, CorA is a multioccupancy Mg²⁺-selective channel, fully excluding monovalent cations, and Ca²⁺, whereas in absence of Mg²⁺, CorA is essentially nonselective, displaying only mild preference against other divalents (Ca²⁺ > Mn²⁺ > Co²⁺ > Mg²⁺ > Ni²⁺). Selectivity against monovalent cations takes place via Mg²⁺ binding at a high-affinity site, formed by the Gly-Met-Asn signature sequence (Gly312 and Asn314) at the extracellular side of the pore. This mechanism is reminiscent of repulsion models proposed for Ca²⁺ channel selectivity despite differences in sequence and overall structure.Among biological divalent cations, Mg²⁺ is not only the most abundant, but also plays an essential role in a wealth of cellular processes, including enzymatic reactions, and the stability of nucleic acids and biological membranes (1). Although the biological importance of Mg²⁺ is well established, the molecular entities and mechanisms that govern its cellular homeostasis are not well understood. In bacteria, Mg²⁺ influx is primarily catalyzed by members of the CorA family of divalent ion transport systems (2, 3). The X-ray structure of CorA has provided an excellent template toward a molecular understanding of the mechanisms underlying Mg²⁺ influx (4–7). However, although CorA has been crystallized in a wide range of conditions, so far all available CorA structures seem to correspond to nonconductive conformations, which obviously limits the basic mechanistic insights regarding Mg²⁺ selectivity and translocation that can be derived from these high-resolution structures. Computational analyses, together with NMR, X-ray absorption, and Raman spectroscopy studies, have established that Mg²⁺ holds to its first hydration shell much more tightly than any other physiological cation (8–11); this implies that any Mg²⁺-selective transport system must either compensate for the high hydration energy (and accommodate the invariable octahedral geometry of this hexacoordinated ion) or establish a selectivity mechanism able to discriminate a hydrated or partially hydrated Mg²⁺ ion from monovalent and other divalent cations.Several hypotheses have been postulated to explain CorA’s function, including its role as a Mg²⁺ -selective channel (12), a Co²⁺ transporter (13), and even as an exporter of divalent cations (14). However, detailed mechanistic evaluation of CorA’s functional properties has been limited by the resolution of existing functional assays (15). Mg²⁺ transport through CorA depends on the combination of three parameters: (i) number of open gates, (ii) the electrical potential across the membrane, and (iii) the Mg²⁺ driving force, none of which can be properly controlled with sufficient time-resolution in in vivo experiments. Although a prokaryotic membrane protein, we have been able to heterologously express CorA in Xenopus oocytes, which, in combination with standard electrophysiological approaches, allowed us to measure CorA-catalyzed divalent macroscopic currents under a variety of ionic conditions. Crystallographic studies have suggested that intracellular Mg²⁺ act as the main regulator of CorA gating under physiological conditions (6). That Mg²⁺ acts as both a gating ligand and charge carrier ultimately complicates functional studies of CorA permeation and selectivity properties. To circumvent this issue we used a mutation at the divalent cation sensor that abolishes CorA Mg²⁺-dependent gating (Fig. 1A). This construct is ideally suited to evaluate ion permeation because it stabilizes steady-state currents by inhibiting the divalent ion-driven negative-feedback loop that defines CorA gating. Our results demonstrate that CorA is a bona fide multioccupancy ion channel, and that its divalent cation permeation and tight selectivity against monovalent cations can be explained on the basis of a block and repulsion mechanism, where the canonical “signature sequence” Gly-Met-Asn (GMN) plays a central role.Open in a separate windowFig. 1.CorA-driven Mg²⁺ currents recorded from TEVC. (A) The divalent cation sensor is highlighted on a cartoon representation of CorA crystal structure. Residues Asp89 and Asp253 are shown as purple sticks (B). The membrane potential (Vm) is clamped and held at −60 mV. The external solution is exchanged between two isosmotic buffers: one containing no monovalent or divalent cation (colored in gray on the horizontal bar), and one containing 20 mM Mg²⁺ (noted Mg²⁺). A representative trace recorded on a CorA–WT-expressing oocyte is shown in teal, and control oocyte trace is shown in gray and D253K in purple. The horizontal dotted line indicates the 0 A current level. (C) Representative traces of CorA D253K mutant in TEVC. The voltage pulse protocol is shown on top of the current traces. The dotted line represents the 0 current levels. (D) The corresponding I/V relationships recorded at different external Mg²⁺ concentrations are shown. The GHK-flux equation fits are displayed as solid lines, and experimental values are dots. (E) Mg²⁺ current recorded at −60 mV under external solution perfusion. The external solution is changed stepwise and the corresponding solution exchange protocol is superimposed to the trace. (F) Mean values (±SD) of several traces (n ≥ 5) were recorded and normalized to the maximum current. The values were plotted against the external [Mg²⁺] and fitted with a single-site binding curve.     

Interrelation of food selectivity,oral sensory sensitivity,and nutrient intake in children with autism spectrum disorder: A scoping review

BackgroundFood selectivity is an emerging health concern among children with autism spectrum disorder (ASD). Food selectivity is used to describe food refusal, limited food choices, and/or food fussiness.MethodWe used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-Scoping Review Guidelines to systematically identify the relationship between food selectivity and oral sensory sensitivity and the possible consequences of food selectivity on nutrient intake in children with ASD.Thirty studies were included in the review based on search terms from three online databases.ResultsAssessment of food selectivity, oral sensory sensitivity, and nutrient intake was found to be focused primarily on the parent-report technique. Only a handful of studies have used Cronbach’s alpha to measure the psychometric properties. Twenty-one of the included studies reported a higher rate of food selectivity in children with ASD than typically developing (TD) children. Notably, several studies (n =7) have identified oral hypersensitivity (e.g., taste/smell) as a significant risk factor for food aversion and/or limited variety in children with ASD. Compared with TD children, the ASD group significantly consumed significantly fewer fruits/vegetables (n = 8). The intake of micronutrients, including vitamin A, vitamin B6, folate, vitamin B12, vitamin C, vitamin D, calcium, iron, and zinc that associates with food selectivity, was also low (n=13).ConclusionImplementation of screening and assessment protocols using valid and reliable instruments to identify food selectivity and oral sensory sensitivity is crucial for the medical evaluations of children with ASD.     

Enantioselectivity in environmental safety of current chiral insecticides

Chiral pesticides currently constitute about 25% of all pesticides used, and this ratio is increasing as more complex structures are introduced. Chirality occurs widely in synthetic pyrethroids and organophosphates, which are the mainstay of modern insecticides. Despite the great public concerns associated with the use of insecticides, the environmental significance of chirality in currently used insecticides is poorly understood. In this study, we resolved enantiomers of a number of synthetic pyrethroid and organophosphate insecticides on chiral selective columns and evaluated the occurrence of enantioselectivity in aquatic toxicity and biodegradation. Dramatic differences between enantiomers were observed in their acute toxicity to the freshwater invertebrates Ceriodaphnia dubia and Daphnia magna, suggesting that the aquatic toxicity is primarily attributable to a specific enantiomer in the racemate. In field sediments, the (-)enantiomer of cis-bifenthrin or cis-permethrin was preferentially degraded, resulting in relative enrichment of the (+)enantiomer. Enantioselective degradation was also observed during incubation of sediments under laboratory conditions. Enantioselectivity in these processes is expected to result in ecotoxicological effects that cannot be predicted from our existing knowledge and must be considered in future risk assessment and regulatory decisions.