抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Driven by the high demand for sensitive and specific tools for optical sensing and imaging, bioprobes with various working mechanisms and advanced functionalities are flourishing at an incredible speed. Conventional fluorescent probes suffer from the notorious effect of aggregation-caused quenching that imposes limitation on their labelling efficiency or concentration to achieve desired sensitivity. The recently emerged fluorogens with an aggregation-induced emission (AIE) feature offer a timely remedy to tackle the challenge. Utilizing the unique properties of AIE fluorogens (AIEgens), specific light-up probes have been constructed through functionalization with recognition elements, showing advantages such as low background interference, a high signal to noise ratio and superior photostability with activatable therapeutic effects. In this tutorial review, we summarize the recent progress in the development of specific AIEgen-based light-up bioprobes. Through illustration of their operation mechanisms and application examples, we hope to provide guidelines for the design of more advanced AIE sensing and imaging platforms with high selectivity, great sensitivity and wide adaptability to a broad range of biomedical applications.

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Specific light-up bioprobes based on AIEgen conjugates

In vitro pharmacological profiling is increasingly being used earlier in the drug discovery process to identify undesirable off-target activity profiles that could hinder or halt the development of candidate drugs or even lead to market withdrawal if discovered after a drug is approved Here, for the first time, the rationale, strategies and methodologies for in vitro pharmacological profiling at four major pharmaceutical companies (AstraZeneca, GlaxoSmithKline, Novartis and Pfizer) are presented and illustrated with examples of their impact on the drug discovery process We hope that this will enable other companies and academic institutions to benefit from this knowledge and consider joining us in our collaborative knowledge sharing

Reducing safety-related drug attrition: the use of in vitro pharmacological profiling

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.

Fragile X syndrome

Many studies have reported abnormal gut microbiota in individuals with Autism Spectrum Disorders (ASD), suggesting a link between gut microbiome and autism-like behaviors. Modifying the gut microbiome is a potential route to improve gastrointestinal (GI) and behavioral symptoms in children with ASD, and fecal microbiota transplant could transform the dysbiotic gut microbiome toward a healthy one by delivering a large number of commensal microbes from a healthy donor. We previously performed an open-label trial of Microbiota Transfer Therapy (MTT) that combined antibiotics, a bowel cleanse, a stomach-acid suppressant, and fecal microbiota transplant, and observed significant improvements in GI symptoms, autism-related symptoms, and gut microbiota. Here, we report on a follow-up with the same 18 participants two years after treatment was completed. Notably, most improvements in GI symptoms were maintained, and autism-related symptoms improved even more after the end of treatment. Important changes in gut microbiota at the end of treatment remained at follow-up, including significant increases in bacterial diversity and relative abundances of Bifidobacteria and Prevotella. Our observations demonstrate the long-term safety and efficacy of MTT as a potential therapy to treat children with ASD who have GI problems, and warrant a double-blind, placebo-controlled trial in the future.

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Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota

Currently, the lack of a selective dopamine D3 PET (positron emission tomography) radioligand for in vivo brain occupancy studies is problematic. Several requirements are necessary for a potential PET radioligand for visualization of a receptor into the brain: i) high affinity and selectivity for the target receptor; ii) suitable lipophilicity for both blood-brain barrier permeation and low nonspecific binding to proteins and lipids; iii) structural features that allow labelling with a positron emission isotope. In this study the synthesis and binding affinities for dopamine D3 and D2 receptors of several N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides are reported. These compounds were designed by the structural modification of the formerly reported D3 receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2benzofurancarboxamide (1), with the aim to obtain a suitable lipophilicity and the structural features for labelling. In particular, both the 2,3-dichlorophenyl group and the 7-methoxy-2benzofurancarboxamide moiety were replaced by less lipophilic fragments. Among the studied compounds, derivatives N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(4morpholinyl)benzamide (20), N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(1Himidazol-1-yl)benzamide (21), and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]5-(2-furanyl)-1H-pyrazole-3-carboxamide (22) displayed good D3 receptor affinities (Ki values 38, 22.6, and 21.3 nM, respectively) and were found to be inactive at D2 receptor. Moreover, on the basis of their experimental log P values and their ability to cross the Caco-2 monolayer, compounds 20-22 are likely to permeate the blood-brain barrier, differently from compound 1.

http://www.arkat-usa.org/get-file.php?fileid=19965

Synthesis and biological evaluation of potential positron emission tomography (PET) ligands for brain visualization of dopamine D3 receptors

Serotonin receptor 7 stimulation rescues fear generalization in a male mouse model of post-traumatic stress disorder

The impact of novel synthetic FPR2 ligands on the prenatal stress-induced activity of primary microglial cells

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1 A (5-HT1A) demonstrates a unique ability to inhibit β-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT1A receptor. The compounds were prepared by conjugating the scaffold of the 5-HT1A receptor agonist 8-OH-DPAT with two fluorophores suitable for live-cell imaging. Compound 5a {5-(dimethylamino)-N-[5-[(8hydroxy-1,2,3,4-tetrahydronaphthalen-2yl)(propyl)amino]pentyl]naphtalen-1-sulfonammide} showed high affinity for the 5-HT1A receptor (Ki =1.8 nM). Fluoroprobe 5a was able to label the 5-HT1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co-administration of the 5-HT1A receptor antagonist WAY-100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor‘s role.

Design, Synthesis, and Characterization of a Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5-HT1A Receptor

Introduction Autism spectrum disorder (ASD) is a persistent neurodevelopmental condition characterized by two core behavioral symptoms: impaired social communication and interaction, as well as stereotypic, repetitive behavior. No distinct cause of ASD is known so far; however, excitatory/inhibitory imbalance and a disturbed serotoninergic transmission have been identified as prominent candidates responsible for ASD etiology. Methods The GABAB receptor agonist R-Baclofen and the selective agonist for the 5HT7 serotonin receptor LP-211 have been reported to correct social deficits and repetitive behaviors in mouse models of ASD. To evaluate the efficacy of these compounds in more details, we treated BTBR T+ Itpr3tf/J and B6.129P2-Fmr1tm1Cgr/J mice acutely with R-Baclofen or LP-211 and evaluated the behavior of animals in a series of tests. Results BTBR mice showed motor deficits, elevated anxiety, and highly repetitive behavior of self-grooming. Fmr1-KO mice exhibited decreased anxiety and hyperactivity. Additionally, Fmr1-KO mice’s ultrasonic vocalizations were impaired suggesting a reduced social interest and communication of this strain. Acute LP-211 administration did not affect the behavioral abnormalities observed in BTBR mice but improved repetitive behavior in Fmr1-KO mice and showed a trend to change anxiety of this strain. Acute R-Baclofen treatment improved repetitive behavior only in Fmr1-KO mice. Conclusion Our results add value to the current available data on these mouse models and the respective compounds. Yet, additional studies are needed to further test R-Baclofen and LP-211 as potential treatments for ASD therapy.

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Enza Lacivita

Papers

Synthesis and biological evaluation of potential positron emission tomography (PET) ligands for brain visualization of dopamine D3 receptors

Serotonin receptor 7 stimulation rescues fear generalization in a male mouse model of post-traumatic stress disorder

The impact of novel synthetic FPR2 ligands on the prenatal stress-induced activity of primary microglial cells

Design, Synthesis, and Characterization of a Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5-HT1A Receptor

Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models