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Abstract The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that the zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to the promoter region of the planar cell polarity gene Fuzzy to regulate its transcription. We show that YY1 interacts with GGGGCC repeat RNA via its ZF and that this interaction compromises the binding of YY1 to the Fuzzy YY1 promoter sites, resulting in the downregulation of Fuzzy transcription. The decrease in Fuzzy protein expression in turn activates the canonical Wnt/β-catenin pathway and induces synaptic deficits in C9ALS/FTD neurons. Our findings demonstrate a C9orf72 GGGGCC RNA-initiated perturbation of YY1–Fuzzy transcriptional control that implicates aberrant Wnt/β-catenin signalling in C9ALS/FTD-associated neurodegeneration. This pathogenic cascade provides a potential new target for disease-modifying therapy.

Introduction: We present a unique case of iris chafing syndrome in a patient with a complex ophthalmologic history after successful placement of a single-piece in-the-bag intraocular lens (IOL) in an eye with healthy zonular support. Case Presentation: A patient with a previous history of multiple retinal surgeries presented with pain and elevated intraocular pressure (IOP) secondary to retained viscoelastic material in the anterior chamber. Following removal of the viscoelastic material in clinic, the patient underwent a combined cataract and glaucoma surgery. Subsequently, the patient developed signs and symptoms of iris chafing syndrome. Anterior segment imaging revealed the cause to be iridociliary adhesion causing an elimination of the sulcus space. Iris chafing syndrome was suspected when the patient presented post-operatively with changes in vision and anterior chamber inflammation. New iris transillumination defects present at the edge of the optic and haptic of the 1-piece lens helped confirm the diagnosis of UGH. Upon further investigation with gonioscopy, ultrasound biomicroscopy and anterior segment optical coherence tomography, it was determined that the patient had iridociliary adhesions. These adhesions eliminated the sulcus space, which resulted in iris chafing. The patient opted for conservative medical management. Best-corrected distance visual acuity remained stable at 20/100 and IOP remained well controlled. Conclusion: A complex ocular history of multiple retinal surgeries and retained viscoelastic material in the anterior chamber resulted in adhesions of the ciliary processes to the iris, leading to UGH syndrome in a patient with an otherwise unremarkable placement of a single-piece in-the-bag IOL.

The authors wrestle effectively with the inherent issues of music industry research through a cultural/arts administration lens, particularly the lack of an accepted definition of popular music and differing national understandings of what - and who - are part of the music industry. It is worth nothing that the authors have defined popular music as, "the forms and genres of music that are most accessible to, meaningful to, and enjoyed by large numbers of people" (Chen et al. [1]). This reality demands a new understanding of the economic and cultural impacts of the music industry and the roles of national economic and cultural policy in a global music marketplace. [Extracted from the article]

Polyglutamine (polyQ) diseases, including spinocerebellar ataxias and Huntington’s disease, are progressive neurodegenerative disorders caused by CAG triplet-repeat expansion in the coding regions of disease-associated genes. In this study, we found that neurotoxic small CAG (sCAG) RNA species, microscopic Ataxin-2 CAG RNA foci, and protein aggregates exist as independent entities in cells. Synaptic defects and neurite outgrowth abnormalities were observed in mutant Ataxin-2-expressing mouse primary cortical neurons. We examined the suppression effects of the CAG RNA-binding peptide beta-structured inhibitor for neurodegenerative diseases (BIND) in mutant Ataxin-2-expressing mouse primary cortical neurons and found that both impaired synaptic phenotypes and neurite outgrowth defects were rescued. We further demonstrated that BIND rescued cell death through inhibiting sCAG RNA production, Ataxin-2 CAG RNA foci formation, and mutant Ataxin-2 protein translation. Interestingly, when the expanded CAG repeats in the mutant Ataxin-2 transcript was interrupted with the alternative glutamine codon CAA, BIND’s inhibitory effect on mutant protein aggregation was lost. We previously demonstrated that BIND interacts physically and directly with expanded CAG RNA sequences. Our data provide evidence that the BIND peptide associates with transcribed mutant CAG RNA to inhibit the formation of toxic species, including sCAG RNA, RNA foci, and polyQ protein translation and aggregation.

A multi-modal search space can be defined as having multiple attraction basins – each basin has a single local optimum which is reached from all points in that basin when greedy local search is used. Optimization in multi-modal search spaces can then be viewed as a two-phase process. The first phase is exploration in which the most promising attraction basin is identified. The second phase is exploitation in which the best solution (i.e. the local optimum) within the previously identified attraction basin is attained. The goal of thresheld convergence is to improve the performance of search techniques during the first phase of exploration. The effectiveness of thresheld convergence has been demonstrated through applications to existing metaheuristics such as particle swarm optimization and differential evolution, and through the development of novel metaheuristics such as minimum population search and leaders and followers.

Computer modeling of protein ligand interactions is one of the most important phases in a drug design process. Part of the process involves the optimization of highly multi-modal objective (scoring) functions. This research presents the Minimum Population Search heuristic as an alternative for solving these global unconstrained optimization problems. To determine the effectiveness of Minimum Population Search, a comparison with seven state-of-the-art search heuristics is performed. Being specifically designed for the optimization of large scale multi modal problems, Minimum Population Search achieves excellent results on all of the tested complexes, especially when the amount of available function evaluations is strongly reduced. A first step is also made toward the design of hybrid algorithms based on the exploratory power of Minimum Population Search. Computational results show that hybridization leads to a further improvement in performance.

El cómputo de alto rendimiento es una necesidad para el desarrollo de investigaciones con grandes volúmenes de datos. La creciente demanda de este tipo de resultados ha impulsado a varios centros de investigación a poner en funcionamiento recursos de cómputo de alto rendimiento. En Cuba no existe una solución definitiva que permita a todos los centros de investigación disponer de los recursos de cómputo necesarios para desarrollar sus proyectos. Este trabajo propone el empleo de un clúster de computadoras de la Universidad de Griffith a través de una interfaz basada en el correo electrónico. Esta solución permite disponer de recursos de cómputo de alto rendimiento sin necesidad de una alta conectividad. Como caso de estudio se analizan los resultados obtenidos en un proyecto de optimización global en grandes dimensiones desarrollado en la Universidad de La Habana. Para experimentos con un mes de duración (en una computadora estándar) los resultados muestran que al utilizar el recurso de alto rendimiento es posible alcanzar un incremento en el rendimiento relativo superior al 1300%.

Category: Midfoot/Forefoot; Hindfoot Introduction/Purpose: Accurate characterization of foot type can facilitate identification of patients at risk for different foot disorders and direct operative treatment. Foot type can be determined qualitatively with visual assessment and quantitatively using arch index (AI), calcaneal pitch (CP), Meary's angle (MA), and foot posture index (FPI). Agreement between various foot typing measures is unclear. The purpose of this study was to assess the agreement between different measurements of foot type. We hypothesized that quantitative measures would have better interrater reliability than qualitative measures, and that visual assessment of foot type would be strongly correlated with radiographic assessment. Methods: Bilateral foot photographs were acquired from 92 asymptomatic participants (50 men, 42 women, mean age of 43.3+- 18.6 years) to assess photographic arch type (PAT) and photographic foot posture (PFP). Hindfoot alignment and lateral radiographs were acquired of each foot to assess calcaneal pitch (CP), Meary's angle (MA), x-ray foot posture (XFP), and x-ray arch type (XAT). Photographs and radiographs were assessed by five reviewers in random order. Foot Posture Index (FPI) was determined through manual exam. Arch Index (AI) was measured on lightbox images. Interrater reliability was assessed using Intraclass Correlation Coefficient (ICC) for continuous variables and Kendall's W for categorical variables. Correlations between measures and sensitivity/specificity were assessed using calcaneal pitch as the reference standard with cavus feet >= 26 degrees and planus feet measuring

Imaging of the ocular vasculature can provide new insights into the pathophysiology of ocular diseases. This study proposes a novel high-frequency super-resolution ultrasound localization microscopy (SRULM) technique and evaluates its ability to measure in vivo perfusion changes in the rat eye at elevated intraocular pressure (IOP). A 38.4 MHz center frequency linear array transducer on a VisualSonics Vevo F2 imaging platform was used to collect high frame rate (1 kHz) radiofrequency data of the posterior rat eye following systemic microbubble contrast injection. Following clutter and spatiotemporal non-local means filtering, individual microbubbles were localized and tracked. The microbubble tracks were accumulated over 10,000 frames to generate vascular images quantifying perfusion velocity and direction. Experiments were performed using physiologic relevant controlled flow states for algorithm validation and subsequently performed in vivo on the rat eye at 10 mm Hg IOP increments from 10 to 60 mm Hg. The posterior vasculature of the rat eye, including the ophthalmic artery, long posterior ciliary arteries and their branches, central retinal artery and retinal arterioles and venules were successfully visualized, and velocities quantified at each IOP level. Significant reductions in arterial flow were measured as IOP was elevated. High-frequency SRULM can be used to visualize and quantify the perfusion velocity of the rat eye in both the retrobulbar and intraocular vasculature simultaneously. The ability to detect ocular perfusion changes throughout the depth of the eye may help elucidate the role ischemia has in the pathophysiology of ocular diseases such as glaucoma.

Abstract Polyglutamine (polyQ) diseases comprise Huntington’s disease and several subtypes of spinocerebellar ataxia, including spinocerebellar ataxia type 3 (SCA3). The genomic expansion of coding CAG trinucleotide sequence in disease genes leads to the production and accumulation of misfolded polyQ domain-containing disease proteins, which cause cellular dysfunction and neuronal death. As one of the principal cellular protein clearance pathways, the activity of the ubiquitin–proteasome system (UPS) is tightly regulated to ensure efficient clearance of damaged and toxic proteins. Emerging evidence demonstrates that UPS plays a crucial role in the pathogenesis of polyQ diseases. Ubiquitin (Ub) E3 ligases catalyze the transfer of a Ub tag to label proteins destined for proteasomal clearance. In this study, we identified an E3 ligase, pre-mRNA processing factor 19 (Prpf19/prp19), that modulates expanded ataxin-3 (ATXN3-polyQ), disease protein of SCA3, induced neurodegeneration in both mammalian and Drosophila disease models. We further showed that Prpf19/prp19 promotes poly-ubiquitination and degradation of mutant ATXN3-polyQ protein. Our data further demonstrated the nuclear localization of Prpf19/prp19 is essential for eliciting its modulatory function towards toxic ATXN3-polyQ protein. Intriguingly, we found that exocyst complex component 7 (Exoc7/exo70), a Prpf19/prp19 interacting partner, modulates expanded ATXN3-polyQ protein levels and toxicity in an opposite manner to Prpf19/prp19. Our data suggest that Exoc7/exo70 exerts its ATXN3-polyQ-modifying effect through regulating the E3 ligase function of Prpf19/prp19. In summary, this study allows us to better define the mechanistic role of Exoc7/exo70-regulated Prpf19/prp19-associated protein ubiquitination pathway in SCA3 pathogenesis.

Abstract Background CCDC88C is a ubiquitously expressed protein with multiple functions, including roles in cell polarity and the development of dendrites in the nervous system. Bi-allelic mutations in the CCDC88C gene cause autosomal recessive congenital hydrocephalus (OMIM #236600). Studies recently linked heterozygous mutations in CCDC88C to the development of the late-onset spinocerebellar ataxia type 40 (OMIM #616053). Case presentation A 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. Exome sequencing, in-silico analysis, and Sanger sequencing identified the heterozygous NM_001080414.4:c.1993G > A (p.E665K) variant in CCDC88C as a potential cause of her illness. To explore the pathogenicity of the NM_001080414.4:c.1993G > A (p.E665K) variant, we expressed it in human embryonic kidney 293 cells and assessed its effects on apoptosis. In our experiment, NM_001080414.4:c.1993G > A (p.E665K) induced JNK hyper-phosphorylation and enhanced apoptosis. In contrast to previous reports, our patient developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. Conclusion We, herein, heighlighted the possibility of extending the phenotype associated with variants in CCDC88C to include early-onset pure hereditary spastic paraplegia.

Purpose With advancing endovascular technology and increasing interest in minimally invasive intra-arterial therapies such as stem cell and chemotherapy for cerebral disease, the establishment of a translational model with cerebral circulation accessible to microcatheters is needed. We report our experience catheterizing canine cerebral circulation with microcatheters, present high-resolution angiographic images of the canine vascular anatomy, describe arterial branch flow patterns and provide measurements of canine arterial conduits. Materials and Methods Angiograms were performed on 10 intact purpose-bred hounds. Angiography, measurements of arterial conduits and catheterization information for intracranial arterial branches were obtained. Results Selective and superselective cerebral angiography was successful in all subjects. Relevant arterial mean diameters include the femoral (4.64 mm), aorta (9.38 mm), external carotid (3.65 mm), internal carotid arteries (1.6 mm), vertebrobasilar system and Circle of Willis branches. Catheterization of the Circle of Willis was achieved via the posterior circulation in all subjects tested (n=3) and the use of flow directed microcatheters resulted in reduced arterial tree deformation and improved superselection of intracranial vessels. Catheterization of the intracranial circulation was attempted but not achieved via the internal carotid artery (n=7) due to its tortuosity and subsequent catheter related vasospasm. Conclusion The canine cerebral vasculature is posterior circulation dominant. Anterior circulation angiography is achievable via the internal carotid artery, but direct cerebral arterial access is best achieved via the posterior circulation using flow-directed microcatheters. It is feasible to deliver intra-arterial therapies to selective vascular territories within the canine cerebral circulation, thus making it a viable animal model for testing novel intra-arterial cerebral treatments.

Biomass polyphenols are bio-active macromolecules with distinct chemical structures in a variety of biomass. In recent years, the study of biomass polyphenols and their application in food and medicine fields has become a research hotspot, which predominantly focuses on the preparation, purification, structural identifications, and measurements of biological activities. Many studies describe methodologies for extraction and application of polyphenols, but comprehensive work to review its physiological activities like drugs and health products are lacking. This paper comprehensively unlocks the bioactivities of antioxidant, antibacterial, antitumor, anticancer, neuroprotection, control of blood sugar, regulation of blood fat, and promotion of gastrointestinal health functions of polyphenols from different biomass sources. This review will serve as an illuminating resource for the global scientific community, especially for those who are actively working to promote the advances of the polyphenols research field.