Molecular function of α7 nicotinic receptors as drug targets

Abstract

Nicotinic acetylcholine receptors (nAChR) are pentameric ligand-gated ion channels involved in many physiological and pathological processes. In vertebrates, there are seventeen different nAChR subunits that combine to yield a variety of receptors with different pharmacology, function, and localization. The homomeric α7 receptor is one of the most abundant nAChRs in the nervous system and it is also present in non-neuronal cells. It plays important roles in cognition, memory, pain, neuroprotection, and inflammation. Its diverse physiological actions and associated disorders have made of α7 an attractive novel target for drug modulation. Potentiation of the α7 receptor has emerged as a novel therapeutic strategy for several neurological diseases, such as Alzheimer's and Parkinson's diseases, and inflammatory disorders. In contrast, increased α7 activity has been associated to cancer cell proliferation. The presence of different drug target sites offers a great potential for α7 modulation in different pathological contexts. In particular, compounds that target allosteric sites offer significant advantages over orthosteric agonists due to higher selectivity and a broader spectrum of degrees and mechanisms of modulation. Heterologous expression of α7, together with chaperone proteins, combined with patch clamp recordings have provided important advances in our knowledge of the molecular basis of α7 responses and their potential modulation for pathological processes. This review gives a synthetic view of α7 and its molecular function, focusing on how its unique activation and desensitization features can be modified by pharmacological agents. This fundamental information offers insights into therapeutic strategies.

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Statistical and integrative system-level analysis of DNA methylation data

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Transcription: Putting R loops firmly on the map

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Functional genomics: Shining a light on genetic screen strategies

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Towards a genomics-informed, real-time, global pathogen surveillance system

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Strain-volume loops in severe aortic valve disease

Abstract

We read with interest the article by Hulshof et al. In their paper the Authors propose a new analysis based on simultaneous strain-load (volume or area) calculation to better describe patients with aortic valve disease.

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Ultrasound with neurostimulation compared with ultrasound guidance alone for lumbar plexus block: A randomised single blinded equivalence trial

BACKGROUND Ultrasound-guided lumbar plexus blocks usually require confirmatory neurostimulation. A simpler alternative is to inject local anaesthetic inside the posteromedial quadrant of the psoas muscle under ultrasound guidance. OBJECTIVE We hypothesised that both techniques would result in similar total anaesthesia time, defined as the sum of performance and onset time. DESIGN A randomised, observer-blinded, equivalence trial (equivalence margin = 7.4 min). SETTING Ramathibodi Hospital and Maharaj Nakorn Chiang Mai Hospital (Thailand) from 12 May 2016 to 10 January 2017. PATIENTS A total of 110 patients undergoing total hip or knee arthroplasty, who required lumbar plexus block for postoperative analgesia. INTERVENTION In the combined ultrasonography-neurostimulation group, quadriceps-evoked motor response was sought at a current between 0.2 and 0.8 mA prior to local anaesthetic injection (30 ml of lidocaine 1% and levobupivacaine 0.25% with epinephrine 5 μg ml−1 and 5 mg of dexamethasone). In the ultrasound guidance alone group, local anaesthetic was simply injected inside the posteromedial quadrant of the psoas muscle. MAIN OUTCOMES MEASURES We measured the total anaesthesia time, the success rate (at 30 min), the number of needle passes, block-related pain, cumulative opioid consumption (at 24 h) and adverse events (vascular puncture, paraesthesia, local anaesthetic spread to the epidural space). RESULTS Compared with ultrasound guidance alone, combined ultrasonography-neurostimulation resulted in decreased mean (±SD) total anaesthesia time [15.3 (±6.5) vs. 20.1 (±9.0) min; mean difference, −4.8; 95% confidence interval, −8.1 to −1.9; P = 0.005] and mean (±SD) onset time [10.2 (±5.6) vs. 15.5 (±9.0) min; P = 0.004). No inter-group differences were observed in terms of success rate, performance time, number of needle passes, block-related pain, opioid consumption or adverse events. CONCLUSION Although the ultrasonography-neurostimulation technique results in a shorter total anaesthesia time compared with ultrasound guidance alone, this difference falls within our accepted equivalence margin (±7.4 min). TRIAL REGISTRATION www.clinicaltrials in the (Study ID: TCTR20160427003). Correspondence to De Q. Tran, MD, FRCPC, Professor, Department of Anaesthesia, Montreal General Hospital, McGill University, 1650 Ave Cedar, Montreal, QC, Canada H3G-1A4 Tel: +1 514 934 1934x43261; fax: +1 514 934 8249; e-mail: de_tran@hotmail.com © 2017 European Society of Anaesthesiology

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Issue Information

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Functional Outcomes of Acute Inpatient Rehabilitation In Patients With Chronic Graft-Versus Host Disease

Growing numbers of allogeneic stem cell transplants (HSCT) and improved post-transplant care have led to an increase of individuals with chronic graft versus host disease (cGVHD). Although cGVHD leads to functional impairment for many, there is limited literature regarding the benefits of acute inpatient rehabilitation for cGVHD patients.

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Sarcopenia in Peripheral Arterial Disease: Prevalence and Impact on Functional Status

Publication date: Available online 11 November 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Odessa Addison, Steven J. Prior, Rishi Kundi, Monica C. Serra, Leslie I. Katzel, Andrew W. Gardner, Alice S. Ryan
ObjectivesTo determine the prevalence of sarcopenia in older men with peripheral arterial disease (PAD) and to compare to a subset of the group to age, race, sex, and body mass index (BMI)-matched non-PAD control counterparts. We also sought to compare the functional status of those with PAD with and without sarcopenia.DesignCohort study.SettingA Veterans Affairs medical center.ParticipantsSedentary, community dwelling men age 50+ years with a confirmed diagnosis of PAD (N=108; 44% black; BMI 27.8 ± 0.4 kg/m²; ABI:0.62 ± 0.01; mean ±SEM).InterventionsNot applicable.Main OutcomesDual-energy x-ray absorptiometry scans were used to assess appendicular lean mass (ALM) and determine the prevalence of sarcopenia by ALM/height² (ALM/ht²). Treadmill tests were used to determine claudication onset time (COT), peak walking time (PWT), and claudication recovery time (CRT). Six-minute walk distance (6MWD) was also measured.ResultsSarcopenia prevalence in our PAD cohort was 25%. The PAD subset (N=42) matched with control counterparts for race, sex, age, and BMI had higher prevalence rates compared with their non-PAD counter parts (23.8% vs 2.4%, P<0.05). Individuals with sarcopenia (N=28) had lower 6MWD (p<0.05; 326± 18.8 vs 380 ± 9.7 meters) and higher CRT (p<0.05; 592 ± 98 vs 395 ± 29 seconds) compared to individuals with PAD but without sarcopenia (N=80). There was no difference in COT or PWT between the PAD groups.ConclusionsMen with PAD demonstrate a high prevalence of sarcopenia. Those with sarcopenia and PAD demonstrate decreased mobility function.



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Pain Neurophysiology Education and Therapeutic Exercise for Patients With Chronic Low Back Pain: A Single-Blind Randomized Controlled Trial.

Publication date: Available online 11 November 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Bodes Pardo Gema., Lluch Girbés Enrique., Roussel Nathalie A., Gallego Izquierdo Tomás., Jiménez Penick Virginia., Pecos Martín Daniel.
AimTo assess the effect of a pain neurophysiology education program plus therapeutic exercise for patients with chronic low back pain (CLBP).DesignSingle-blind randomized controlled trial.SettingPrivate clinic (Clínica Bonn) and Alcalá de Henares University, Madrid, Spain.Participants56 patients with CLBP for 6 months or more.InterventionParticipants were randomized to receive either a therapeutic exercise (TE) program consisting of motor control, stretching, and aerobic exercises (TE group, n=28) or the same therapeutic exercise program in addition to a pain neurophysiology education program (PNE+TE group, n=28), conducted in two 30 to 50 minute sessions in groups of 4 to 6 participants.Main outcomes measuresThe primary outcome was pain intensity rated on the Numeric Pain Rating Scale which was completed immediately following treatment and at a 1-month and 3-month follow-up. Secondary outcome measures were pressure pain threshold, finger-to-floor distance, Roland-Morris Disability Questionnaire, Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, and the Patient Global Impression of Change.ResultsAt the 3-month follow-up, a large change in pain intensity (-2.2 (-2.93,-1.28), p<0.001; d=1.37) was observed for the PNE+TE group, and a moderate effect size was observed for the secondary outcome measures.ConclusionCombining pain neurophysiology education plus therapeutic exercise resulted in significantly better results for participants with CLBP, with a large effect size, compared to therapeutic exercise alone.



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A systematic review on the effect of serious games and wearable technology used in rehabilitation of patients with traumatic bone and soft tissue injuries

Publication date: Available online 11 November 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Henriëtte A.W. Meijer, Maurits Graafland, J. Carel Goslings, Marlies P. Schijven
ObjectiveTo determine the effects on functional outcomes and treatment adherence of wearable technology and serious games (i.e., interactive computer applications with specific purposes useful in the 'real world') currently applied in physical rehabilitation of patients after traumatic bone and soft tissue injuries.Data SourcesPubMed, Embase, the Cochrane Library and CINAHL were searched without publication date restrictions for the terms 'wearable', 'serious game', 'videogame' or 'mobile application', and 'rehabilitation', 'exercise therapy' or 'physiotherapy'.Study SelectionThe search yielded 2704 eligible articles, which were screened by two independent reviewers. Studies comparing a serious game to standard therapy were included.Data ExtractionMethodology and results of the studies were critically appraised in conformity with PRISMA guidelines.Data SynthesisTwelve articles were included, all of which tested 'off-the-shelf' games. No studies on 'wearable-controlled' games, or games specifically developed for rehabilitation could be included. Medical conditions included post-operative rehabilitation and acute traumatic injuries. All studies were of low to moderate quality. Only two studies found beneficial effects of serious games over conventional therapy. One of three studies reporting pain scores found beneficial effects of a serious game compared to physiotherapy. One out of five trials reporting treatment adherence found a statistically significant advantage in the game-group compared to conventional physiotherapy. Due to heterogeneity in study design and outcome measures, pooling of data was not possible.ConclusionsSerious games seem a safe alternative or addition to conventional physiotherapy after traumatic bone and soft tissue injury. Future research should determine their validity and effectiveness in rehabilitation therapy, next to their cost-effectiveness and effect on treatment adherence.



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Monitoring of uranium concentrations in water samples collected near potentially hazardous objects in North-West Tajikistan

Publication date: January 2018
Source:Journal of Environmental Radioactivity, Volume 181
Author(s): P. Zoriy, M. Schläger, K. Murtazaev, J. Pillath, M. Zoriy, B. Heuel-Fabianek
The water contamination near ecologically problematic objects was investigated between 2009 and 2014 in North-West Tajikistan as a part of a joint project between Forschungszentrum Jülich and Khujand State University. The main part of this work was the determination of uranium in water samples collected near the Degmay tailings dump, the Taboshar pit lake and the Syr Darya river. More than 130 water samples were collected and analyzed to monitor the uranium concentration near the investigated areas. Two different mass spectrometers and an ion chromatograph were used for element concentration measurements. Based on the results obtained, the uranium influence of the Degmay tailings on the rivers Khoja-Bakyrgan-Say and Syr Darya and surrounding water was not found. The uranium concentration in water samples was monitored for a lengthy period at seven locations Great differences in the uranium concentration in waters collected in 2010, 2011, 2012, 2013 for each location were not observed. Drinking water samples from the region of North-West Tajikistan were analyzed and compared with the World Health Organization's guidelines. Seven out of nine drinking water samples near Taboshar exceeded the WHO guideline value for uranium concentrations (30 μg/L). The average uranium concentration of water samples from Syr Darya for the period from 2009 to 2014 was determined to be 20.1 (±5.2) μg/L. The uranium contamination of the Syr Darya was determined from the western border to the eastern border and the results are shown in this paper.



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Familial choreoathetosis due to novel heterozygous mutation in PDE10A

PDE10A encodes a dual cAMP-cGMP phosphodiesterase that is enriched in the medium spiny neurons of the corpus striatum in the brain and plays an important role in basal ganglia circuitry. Three unrelated patients with childhood onset chorea and striatal abnormalities on MRI brain with heterozygous de novo variants in PDE10A have been described previously. Two families with eight affected individuals with biallelic mutations in PDE10A have also been described previously. We report a family with multiple affected individuals with childhood onset chorea, striatal abnormalities, and a novel heterozygous mutation, c.1001T>G(p.F334C) in PDE10A which was identified by exome sequencing.

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DOCK3-related neurodevelopmental syndrome: Biallelic intragenic deletion of DOCK3 in a boy with developmental delay and hypotonia

Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6–12 of the DOCK3 gene at 3p21.2. Symptoms of our proband resembles a phenotype of Dock3 knockout mice exhibiting sensorimotor impairments. Furthermore, our proband has clinical similarities with two siblings with compound heterozygous loss-of-function mutations of DOCK3 reported in [Helbig, Mroske, Moorthy, Sajan, and Velinov (); http://ift.tt/2AyB7SX]. Biallelic DOCK3 mutations cause a neurodevelopmental disorder characterized by unsteady gait, hypotonia, and developmental delay.

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In reply to “Mast Cell Disorders in Ehlers–Danlos Syndrome”

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Expanding the phenotypic spectrum of TP63-related disorders including the first set of monozygotic twins

Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay–Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T-cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63-related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63-related disorders, as it was reported in one prior individual and two of the individuals in our case series.

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How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome

A congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3.

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Co-occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines

Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. The United States Preventive Service Task Force (USPSTF) has developed criteria for prioritizing conditions of public health importance with the potential for providing screening recommendations to improve clinical care. The quality of existing evidence needed to inform clinical guidelines has not been previously reviewed. Using the National Library of Medicine (NLM) database PubMed, we first identified 18 peer reviewed articles that addressed co-occurring medical conditions in adults with DS. Those conditions discussed in over half of the articles were prioritized for further review. Second, we performed detailed literature searches on these specific conditions. To inform the search strategy and review process a series of key questions were formulated a priori. The quality of available evidence was then graded and knowledge gaps were identified. The number of participating adults and the design of clinical studies varied by condition and were often inadequate for answering all of our key questions. We provide data on thyroid disease, cervical spine disease, hearing impairment, overweight-obesity, sleep apnea, congenital heart disease, and osteopenia-osteoporosis. Minimal evidence demonstrates massive gaps in our clinical knowledge that compromises clinical decision-making and management of these medically complex individuals. The development of evidence-based clinical guidance will require an expanded clinical knowledge-base in order to move forward.

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A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness

The primary cilium is a key organelle in numerous physiological and developmental processes. Genetic defects in the formation of this non-motile structure, in its maintenance and function, underlie a wide array of ciliopathies in human, including craniofacial, brain and heart malformations, and retinal and hearing defects. We used exome sequencing to study the molecular basis of disease in an 11-year-old female patient who suffered from growth retardation, global developmental delay with absent speech acquisition, agenesis of corpus callosum and paucity of white matter, sensorineural deafness, retinitis pigmentosa, vertebral anomalies, patent ductus arteriosus, and facial dysmorphism reminiscent of STAR syndrome, a suspected ciliopathy. A homozygous variant, c.870_871del, was identified in the CDK10 gene, predicted to cause a frameshift, p.Trp291Alafs*18, in the cyclin-dependent kinase 10 protein. CDK10 mRNAs were detected in patient cells and do not seem to undergo non-sense mediated decay. CDK10 is the binding partner of Cyclin M (CycM) and CDK10/CycM protein kinase regulates ciliogenesis and primary cilium elongation. Notably, CycM gene is mutated in patients with STAR syndrome. Following incubation, the patient cells appeared less elongated and more densely populated than the control cells suggesting that the CDK10 mutation affects the cytoskeleton. Upon starvation and staining with acetylated-tubulin, γ-tubulin, and Arl13b, the patient cells exhibited fewer and shorter cilia than control cells. These findings underscore the importance of CDK10 for the regulation of ciliogenesis. CDK10 defect is likely associated with a new form of ciliopathy phenotype; additional patients may further validate this association.

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Short rib syndrome Beemer–Langer type, a short history

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Calvarial mass as a presenting feature of neurofibromatosis type 2 in a pediatric patient

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Further delineation of the GDF6 related multiple synostoses syndrome

A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome.

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Interstitial microdeletion of 17q11.2 is associated with hypotonia, fatigue, intellectual disability, and a subtle facial phenotype in three unrelated patients

Over the past decade chromosomal microarray analysis (array CGH) has allowed the discovery of many novel disease-causing recurrent microdeletion and microduplication syndromes. Here we present three unrelated patients (2F; 1M) from three different countries, with developmental delay, intellectual disability, hypotonia, fatigue, and highly similar dysmorphic facial features. Shared facial features are a broad and wide forehead, similar shape of the eyes with long palpebral fissures, a bulbous tip of the nose and thick lips. Intellectual disabilities range from mild to severe. One female patient and the male patient were investigated in childhood for significant hypotonia thought to be suggestive of a neuromuscular disorder. The two female patients also show excessive fatigue with daytime somnolence. The patients carry overlapping, de novo microdeletions of chromosome 17q11.2, with sizes ranging from 0.97 to 1.18 Mb. The smallest region of overlap (SRO) between the three patients is 863 kb, and contains seven genes, five of which are predicted to exhibit haploinsufficiency (CDK5R1, PSMD11, RHOT1, SUZ12, ZNF207) although none has yet been associated with genetic syndromes. Of these five genes, the brain expressed CDK5R1 gene constitutes a good candidate for the developmental delay, while the RHOT1 gene, involved in mitochondrial trafficking, might underlie the hypotonia and the excessive fatigue.

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