Miracle-dz/UniFAR-FTUs huggingface dataset:
Chronic adenosine A2A receptor blockade induces locomotor sensitization and potentiates striatal LTD IN GPR37‐deficient mice

Adenosine A2A receptors (A2AR) play a key role in modulating dopamine‐dependent locomotor activity, as heralded by the sensitization of locomotor activity upon chronic A2AR blockade, which is associated with elevated dopamine levels and altered corticostriatal synaptic plasticity. Since the orphan receptor GPR37 has been shown to modulate A2AR function in vivo, we aimed to test whether the A2AR‐mediated sensitization of locomotor activity is GPR37‐dependent and involves adaptations of synaptic plasticity. To this end, we administered a selective A2AR antagonist, SCH58261 (1 mg/kg, i.p.), daily for 14 days, and the locomotor sensitization, striatum‐dependent cued learning, and corticostriatal synaptic plasticity (i.e., long‐term depression) were compared in wild‐type and GPR37−/− mice. Notably, GPR37 deletion promoted A2AR‐associated locomotor sensitization but not striatum‐dependent cued learning revealed upon chronic SCH58261 treatment of mice. Furthermore, chronic A2AR blockade potentiated striatal long‐term depression in corticostriatal synapses of GPR37−/− but not of wild‐type mice, thus correlating well with neurochemical alterations of the adenosinergic system. Overall, these results revealed the importance of GPR37 regulating A2AR‐dependent locomotor sensitization and synaptic plasticity in the basal ganglia circuitry.
Deubiquitylase USP9X maintains centriolar satellite integrity by stabilizing pericentriolar material 1 protein

ABSTRACT Centriolar satellites are small cytoplasmic granules that play important roles in regulating the formation of centrosomes and primary cilia. Ubiquitylation of satellite proteins, including the core satellite scaffold protein pericentriolar material 1 (PCM1), regulates centriolar satellite integrity. Currently, deubiquitylases that control centriolar satellite integrity have not been identified. In this study, we find that the deubiquitylase USP9X binds PCM1, and antagonizes PCM1 ubiquitylation to protect it from proteasomal degradation. Knockdown of USP9X in human cell lines reduces PCM1 protein levels, disrupts centriolar satellite particles and causes localization of satellite proteins, such as CEP290, to centrosomes. Interestingly, knockdown of mindbomb 1 (MIB1), a ubiquitin ligase that promotes PCM1 ubiquitylation and degradation, in USP9X-depleted cells largely restores PCM1 protein levels and corrects defects caused by the loss of USP9X. Overall, our study reveals that USP9X is a constituent of centriolar satellites and functions to maintain centriolar satellite integrity by stabilizing PCM1. Summary: Our study reveals that deubiquitylase USP9X is a constituent of centriolar satellites, and functions to maintain centriolar satellite integrity by preventing proteasomal degradation of the core satellite scaffold protein PCM1.
A review of aromatic l‐amino acid decarboxylase (AADC) deficiency in Taiwan

Aromatic l‐amino acid decarboxylase deficiency (AADCD) is a rare inherited disease prevalent in South East Asia. This disease is due to the founder mutation IVS 6 + 4A > T (c.714 + 4A > T), which accounts for most alleles. Patients with this mutation have severe phenotypes. About 90 % of these patients in South East Asia do not have head control and cannot sit, stand, or speak from birth to the time of observation. In 2012, a gene study to treat these patients with intraputamen injection of adeno‐associated virus2‐human AADC showed prominent motor improvement and an increased PDMS‐2 score 12 months after treatment. In addition, systemic gene therapy in a mouse model of AADCD achieved widespread correction of the Ddc gene. In this article, we review the natural history, clinical course, and treatment effects seen in these clinical and mouse studies. Future studies focusing on noninvasive viral vector delivery or alternative emerging treatments may also benefit patients with AADCD.
Breast mass classification in sonography with transfer learning using a deep convolutional neural network and color conversion

PURPOSE We propose a deep learning-based approach to breast mass classification in sonography and compare it with the assessment of four experienced radiologists employing breast imaging reporting and data system 4th edition lexicon and assessment protocol. METHODS Several transfer learning techniques are employed to develop classifiers based on a set of 882 ultrasound images of breast masses. Additionally, we introduce the concept of a matching layer. The aim of this layer is to rescale pixel intensities of the grayscale ultrasound images and convert those images to red, green, blue (RGB) to more efficiently utilize the discriminative power of the convolutional neural network pretrained on the ImageNet dataset. We present how this conversion can be determined during fine-tuning using back-propagation. Next, we compare the performance of the transfer learning techniques with and without the color conversion. To show the usefulness of our approach, we additionally evaluate it using two publicly available datasets. RESULTS Color conversion increased the areas under the receiver operating curve for each transfer learning method. For the better-performing approach utilizing the fine-tuning and the matching layer, the area under the curve was equal to 0.936 on a test set of 150 cases. The areas under the curves for the radiologists reading the same set of cases ranged from 0.806 to 0.882. In the case of the two separate datasets, utilizing the proposed approach we achieved areas under the curve of around 0.890. CONCLUSIONS The concept of the matching layer is generalizable and can be used to improve the overall performance of the transfer learning techniques using deep convolutional neural networks. When fully developed as a clinical tool, the methods proposed in this paper have the potential to help radiologists with breast mass classification in ultrasound.
HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

Significance The potential of protein therapeutics is limited because most proteins cannot reach the cytosol. Like many cell-penetrating peptides (CPPs), cell-permeant miniature proteins (CPMPs) that embody a penta-Arg motif are endocytosed; the difference is that CPMPs are released efficiently from endosomes while other CPPs are not. Here, we report that the trafficking of CPMPs into the cytosol requires the homotypic fusion and protein-sorting (HOPS) complex, a membrane-tethering complex that fuses Rab7+ endosomes. CPMPs neither inhibit nor activate HOPS function; instead, HOPS allows CPMPs to traffic into Lamp1+ endosomes as a prerequisite for endosomal escape. The identification of Lamp1+ late endosomes and lysosomes as portals for passing proteins into the cytosol will aid the development of next-generation biologics that overcome the limitations imposed by cellular membranes. Protein therapeutics represent a significant and growing component of the modern pharmacopeia, but their potential to treat human disease is limited because most proteins fail to traffic across biological membranes. Recently, we discovered a class of cell-permeant miniature proteins (CPMPs) containing a precisely defined, penta-arginine (penta-Arg) motif that traffics readily to the cytosol and nucleus of mammalian cells with efficiencies that rival those of hydrocarbon-stapled peptides active in animals and man. Like many cell-penetrating peptides (CPPs), CPMPs enter the endocytic pathway; the difference is that CPMPs containing a penta-Arg motif are released efficiently from endosomes, while other CPPs are not. Here, we seek to understand how CPMPs traffic from endosomes into the cytosol and what factors contribute to the efficiency of endosomal release. First, using two complementary cell-based assays, we exclude endosomal rupture as the primary means of endosomal escape. Next, using an RNA interference screen, fluorescence correlation spectroscopy, and confocal imaging, we identify VPS39—a gene encoding a subunit of the homotypic fusion and protein-sorting (HOPS) complex—as a critical determinant in the trafficking of CPMPs and hydrocarbon-stapled peptides to the cytosol. Although CPMPs neither inhibit nor activate HOPS function, HOPS activity is essential to efficiently deliver CPMPs to the cytosol. CPMPs localize within the lumen of Rab7+ and Lamp1+ endosomes and their transport requires HOPS activity. Overall, our results identify Lamp1+ late endosomes and lysosomes as portals for passing proteins into the cytosol and suggest that this environment is prerequisite for endosomal escape.
The role of the paraventricular nucleus of the thalamus in the augmentation of heroin seeking induced by chronic food restriction

Drug addiction is a chronic disorder that is characterized by compulsive drug seeking and involves cycling between periods of compulsive drug use, abstinence, and relapse. In both human addicts and animal models of addiction, chronic food restriction has been shown to increase rates of relapse. Previously, our laboratory has demonstrated a robust increase in drug seeking following a period of withdrawal in chronically food‐restricted rats compared with sated rats. To date, the neural mechanisms that mediate the effect of chronic food restriction on drug seeking have not been elucidated. However, the paraventricular nucleus of the thalamus (PVT) appears to be a promising target to investigate. The objective of the current study was to examine the role of the PVT in the augmentation of heroin seeking induced by chronic food restriction. Male Long‐Evans rats were trained to self‐administer heroin for 10 days. Rats were then removed from the training chambers and experienced a 14‐day withdrawal period with either unrestricted (sated) or mildly restricted (FDR) access to food. On day 14, rats underwent a 1‐hour heroin‐seeking test under extinction conditions, during which neural activity in the PVT was either inhibited or increased using pharmacological or chemogenetic approaches. Unexpectedly, inhibition of the PVT did not alter heroin seeking in food‐restricted or sated rats, while enhancing neural activity in the PVT‐attenuated heroin seeking in food‐restricted rats. These results indicate that PVT activity can modulate heroin seeking induced by chronic food restriction.
Summary of a Topical Forum FAQ Based on the Chinese Composition Structure

An automatic multiple-document summarization system for producing frequently asked questions (FAQ) of a topical forum can save forum Webmasters a great deal of time in theory. This work will address summary composition issue of a previous work by proposing a structured presentation based on a four-part pattern of traditional Chinese articles. The result of the experiment shows that the enhanced system with both domain-terminology corpus methods produced a significantly better summary presentation than the original system. Recall rate and precision rate performance indices and user evaluations are also presented and discussed to show their practical implications.
Évaluation de G-LexAr pour la traduction automatique statistique (Evaluation of G-Lexar for statistical machine translation)

G-LexAr est un analyseur morphologique de l’arabe qui a récemment reçu des améliorations substantielles. Cet article propose une évaluation de cet analyseur en tant qu’outil de pré-traitement pour la traduction automatique statistique, ce dont il n’a encore jamais fait l’objet. Nous étudions l’impact des différentes formes proposées par son analyse (voyellation, lemmatisation et segmentation) sur un système de traduction arabe-anglais, ainsi que l’impact de la combinaison de ces formes. Nos expériences montrent que l’utilisation séparée de chacune de ces formes n’a que peu d’influence sur la qualité des traductions obtenues, tandis que leur combinaison y contribue de façon très bénéfique.
How to Evaluate the Helpfulness of Product Review

In recent years, online product reviews have become important both for online consumers as well as online retailers. However, bad comments on product quality can often cause incomprehension of comments (the customers) to readers. The purpose of this article is to automatically predict the usefulness of reviews. This paper analyzes the features embedded in product assessments in nine different product types and explores their effects on the utility of assessments. In addition, the researcher used the RapidMiner application to analyze the data. Four data mining methods were examined to determine the one that best predicts the utility of the evaluation for each product type using, nine evaluation data bases obtained from Amazon.com. The results show that the evaluations for different types of products have linguistic characteristics and the disposition of the characters is the hierarchy of the data. The results also indicate that the method used to collect users' opinions before putting products on the market gives a progressive result not only for the companies through their profit but also for online customers who can directly obtain the products they are looking for. The study helps to improve the effective use of online reviews.
Calcium activation of cortical neurons by continuous electrical stimulation: Frequency dependence, temporal fidelity, and activation density

Electrical stimulation of the brain has become a mainstay of fundamental neuroscience research and an increasingly prevalent clinical therapy. Despite decades of use in basic neuroscience research and the growing prevalence of neuromodulation therapies, gaps in knowledge regarding activation or inactivation of neural elements over time have limited its ability to adequately interpret evoked downstream responses or fine‐tune stimulation parameters to focus on desired responses. In this work, in vivo two‐photon microscopy was used to image neuronal calcium activity in layer 2/3 neurons of somatosensory cortex (S1) in male C57BL/6J‐Tg(Thy1‐GCaMP6s)GP4.3Dkim/J mice during 30 s of continuous electrical stimulation at varying frequencies. We show frequency–dependent differences in spatial and temporal somatic responses during continuous stimulation. Our results elucidate conflicting results from prior studies reporting either dense spherical activation of somas biased toward those near the electrode, or sparse activation of somas at a distance via axons near the electrode. These findings indicate that the neural element specific temporal response local to the stimulating electrode changes as a function of applied charge density and frequency. These temporal responses need to be considered to properly interpret downstream circuit responses or determining mechanisms of action in basic science experiments or clinical therapeutic applications.
Quantifying the Vasculogenic Potential of Induced Pluripotent Stem Cell-Derived Endothelial Progenitors in Collagen Hydrogels.

IMPACT STATEMENT Our work reinforces the role of extracellular matrix (ECM) density and matrix metalloprotease activity on the formation of microvasculature from induced pluripotent stem cell (iPSC)-derived vascular cells. The cell-matrix interactions discussed in this study underscore the importance of understanding the role of mechanoregulation and matrix degradation on vasculogenesis and can potentially drive the development of ECM-mimicking angiogenic biomaterials. Furthermore, our work has broader implications concerning the response of iPSC-derived cells to the mechanics of engineered microenvironments. An understanding of these interactions will be critical to creating physiologically relevant transplantable tissue replacements.
Finite element analysis of titanium alloy-graphene based mandible plate

Abstract Titanium alloy based maxillofacial plates and implants are widely used in fracture treatment and reconstructions. Filler materials Graphene Nanoplatlets(GNPs) were used in a Titanium alloy maxillofacial plate and a Finite Element Model (FEM) was designed to reconstruct a fractured human mandible. Both 50N and 500N bite forces were applied on the mandible and stress distribution using Von mises failure theory across the plate sections was analyzed. A pure plate was critically stressed at a section near the mandible fracture region for a Von mises stress of nearly 27.5GPa while this stress reduced by nearly 10–22% with the presence of minor composition of GNPs in the plate. GNPs orientation in parallel (21.1 GPa) to the plate axis were more effective in comparison to other orientations(90°, 45° and 135°) and the location variation of these GNPs along the plate had no significant effect on the stress distribution. The fatigue analyses showed that, under these stresses and forces the plate with GNP was able to endure for nearly 7000 days, while the pure Titanium plate could fail by fatigue in approximately 70 days. Hence, presence of minor compositions of GNPs could enhance endurance life of the Titanium plate by reducing stress concentrations at critical sections of the plate.
Perspectives of participants with rotator cuff-related pain to a neuroscience-informed pain education session: an exploratory mixed method study

Abstract Purpose: To explore perceptions and initial outcomes of patients with rotator cuff-related pain to a pain education session. Materials and Methods: Ten individuals with persistent rotator cuff-related pain (≥3 months duration) attended an individual pain education session. They completed patient-reported outcomes measures on a weekly basis, three weeks prior and three weeks following the session. Individual semi-structured interviews were conducted three weeks following the pain education. Interviews were recorded, transcribed verbatim, and analyzed using the General Inductive Approach. Results: There were two over-arching key themes: firstly, ‘Participants’ Perspectives’ of the session generated four themes: Improved understanding of ‘the whole’; Mindful self-awareness; Taking charge; “The pain is still there”. Their understanding of pain was reconceptualised, evident by their ability to describe the role of neurophysiological mechanisms, stress and general well-being towards their pain. The second over-arching key theme, ‘Participants’ Recommendations’, had two themes: Integrating neuroscience with pathoanatomical knowledge and Educating other health professionals. Pain levels decreased post-pain education compared to pre-pain education. Conclusions: Following the pain education session, participants had greater understanding of factors influencing their shoulder pain. Pain education, in addition to pathoanatomical information may be useful as part of treatment for persistent rotator cuff-related pain.
Mechanism of Siponimod: Anti-Inflammatory and Neuroprotective Mode of Action

Multiple sclerosis (MS) is a neuroinflammatory disorder of the central nervous system (CNS), and represents one of the main causes of disability in young adults. On the histopathological level, the disease is characterized by inflammatory demyelination and diffuse neurodegeneration. Although on the surface the development of new inflammatory CNS lesions in MS may appear consistent with a primary recruitment of peripheral immune cells, questions have been raised as to whether lymphocyte and/or monocyte invasion into the brain are really at the root of inflammatory lesion development. In this review article, we discuss a less appreciated inflammation-neurodegeneration interplay, that is: Neurodegeneration can trigger the formation of new, focal inflammatory lesions. We summarize old and recent findings suggesting that new inflammatory lesions develop at sites of focal or diffuse degenerative processes within the CNS. Such a concept is discussed in the context of the EXPAND trial, showing that siponimod exerts anti-inflammatory and neuroprotective activities in secondary progressive MS patients. The verification or rejection of such a concept is vital for the development of new therapeutic strategies for progressive MS.
Being a dad to a child with Down’s syndrome: Overcoming the challenges to adjustment

Abstract Background Historically, research exploring the impact of having a child with an Intellectual Disability (ID), has focussed exclusively on mothers. The present study aimed to investigate fathers’ experiences of parenting a child with Down's syndrome (DS), their contributions, influences on family functioning and inclusion in their child's support provision. Method Semi‐structured interviews were conducted with 15 fathers. Interviews were analysed using Grounded Theory (GT). Results Fathers’ adjustment appeared to be on a fluid trajectory with three key categories influencing this: “Accommodating the Child,” “Adapting the Parental/Spousal Role” and “Adapting Society. ” Conclusions The accounts uncovered fathers’ adjustment trajectory to parenting a child with DS, concluding that despite practical and emotional challenges, fathers employed strategies to achieve positive adjustment. Fathers identified the need for services to recognize their role and involve them in their child's support provision. Implications for clinical practice and future research are discussed.
Caregiving Experience of Dementia among Korean American Family Caregivers

Abstract Dementia is a major public health problem affecting 5.5 million people in USA. This qualitative study explored the caregiving experience of Korean American (KA) families of persons with dementia (PWD). Adult KA caregivers of PWD (n = 18) were recruited for semi-structured interviews. Thematic analysis yielded four themes: challenges in finding resources, struggling with mental health issues, traveling the path of acceptance, and finding ways to survive. Due to the language barrier, most KA caregivers reported using Korean Internet for information on dementia and caregiving. Some traveled to South Korea seeking medical assistance for dementia (medical tourism). Importantly, some KA caregivers expressed suicidal thoughts and depression. Unexpectedly, familism prevented help seeking and possible relief from their difficulties. There is an urgent need to improve access to dementia care services and education for the KA community. Building a trusting relationship with healthcare providers is even more important for KA caregivers to address their mental health concerns.
The Identification and Interpretation of cis-Regulatory Noncoding Mutations in Cancer

In the need to characterise the genomic landscape of cancers and to establish novel biomarkers and therapeutic targets, studies have largely focused on the identification of driver mutations within the protein-coding gene regions, where the most pathogenic alterations are known to occur. However, the noncoding genome is significantly larger than its protein-coding counterpart, and evidence reveals that regulatory sequences also harbour functional mutations that significantly affect the regulation of genes and pathways implicated in cancer. Due to the sheer number of noncoding mutations (NCMs) and the limited knowledge of regulatory element functionality in cancer genomes, differentiating pathogenic mutations from background passenger noise is particularly challenging technically and computationally. Here we review various up-to-date high-throughput sequencing data/studies and in silico methods that can be employed to interrogate the noncoding genome. We aim to provide an overview of available data resources as well as computational and molecular techniques that can help and guide the search for functional NCMs in cancer genomes.