Miracle-dz/UniFAR-FTUs huggingface dataset:
Ca2+ transients in astrocyte fine processes occur via Ca2+ influx in the adult mouse hippocampus

Astrocytes display complex morphologies with an array of fine extensions extending from the soma and the primary thick processes. Until the use of genetically encoded calcium indicators (GECIs) selectively expressed in astrocytes, Ca2+ signaling was only examined in soma and thick primary processes of astrocytes where Ca2+‐sensitive fluorescent dyes could be imaged. GECI imaging in astrocytes revealed a previously unsuspected pattern of spontaneous Ca2+ transients in fine processes that has not been observed without chronic expression of GECIs, raising potential concerns about the effects of GECI expression. Here, we perform two‐photon imaging of Ca2+ transients in adult CA1 hippocampal astrocytes using a new single‐cell patch‐loading strategy to image Ca2+‐sensitive fluorescent dyes in the cytoplasm of fine processes. We observed that astrocyte fine processes exhibited a high frequency of spontaneous Ca2+ transients whereas astrocyte soma rarely showed spontaneous Ca2+ oscillations similar to previous reports using GECIs. We exploited this new approach to show these signals were independent of neuronal spiking, metabotropic glutamate receptor (mGluR) activity, TRPA1 channels, and L‐ or T‐type voltage‐gated calcium channels. Removal of extracellular Ca2+ almost completely and reversibly abolished the spontaneous signals while IP3R2 KO mice also exhibited spontaneous and compartmentalized signals, suggesting they rely on influx of extracellular Ca2+. The Ca2+ influx dependency of the spontaneous signals in patch‐loaded astrocytes was also observed in astrocytes expressing GCaMP3, further highlighting the presence of Ca2+ influx pathways in astrocytes. The mechanisms underlying these localized Ca2+ signals are critical for understanding how astrocytes regulate important functions in the adult brain. GLIA 2016;64:2093–2103
The Birth and Demise of the ISApl1-mcr-1-ISApl1 Composite Transposon: the Vehicle for Transferable Colistin Resistance

ABSTRACT The origin and mobilization of the ~2,609-bp DNA segment containing the mobile colistin resistance gene mcr-1 continue to be sources of uncertainty, but recent evidence suggests that the gene originated in Moraxella species. Moreover mcr-1 can be mobilized as an ISApl1-flanked composite transposon (Tn6330), but many sequences have been identified without ISApl1 or with just a single copy (single ended). To further clarify the origins and mobilization of mcr-1, we employed the Geneious R8 software suite to comprehensively analyze the genetic environment of every complete mcr-1 structure deposited in GenBank as of this writing (September 2017) both with and without associated ISApl1 (n = 273). This revealed that the 2,609-bp mcr-1 structure was likely mobilized from a close relative of a novel species of Moraxella containing a chromosomal region sharing >96% nucleotide identity with the canonical sequence. This chromosomal region is bounded by AT and CG dinucleotides, which have been described on the inside ends (IE) of all intact Tn6330 described to date and represent the ancestral 2-bp target site duplications (TSDs) generated by ISApl1 transposition. We further demonstrate that all mcr-1 structures with just one ISApl1 copy or with no ISApl1 copies were formed by deletion of ISApl1 from the ancestral Tn6330, likely by a process related to the “copy-out–paste-in” transposition mechanism. Finally, we show that only the rare examples of single-ended structures that have retained a portion of the excised downstream ISApl1 including the entire inverted right repeat might be capable of mobilization. IMPORTANCE A comprehensive analysis of all intact mcr-1 sequences in GenBank was used to identify a region on the chromosome of a novel Moraxella species with remarkable homology to the canonical mcr-1 structure and that likely represents the origin of this important gene. These data also demonstrate that all mcr-1 structures lacking one or both flanking ISApl1 were formed from ancestral composite transposons that subsequently lost the insertion sequences by a process of abortive transposition. This observation conclusively shows that mobilization of mcr-1 occurs as part of a composite transposon and that structures lacking the downstream ISApl1 are not capable of mobilization. A comprehensive analysis of all intact mcr-1 sequences in GenBank was used to identify a region on the chromosome of a novel Moraxella species with remarkable homology to the canonical mcr-1 structure and that likely represents the origin of this important gene. These data also demonstrate that all mcr-1 structures lacking one or both flanking ISApl1 were formed from ancestral composite transposons that subsequently lost the insertion sequences by a process of abortive transposition. This observation conclusively shows that mobilization of mcr-1 occurs as part of a composite transposon and that structures lacking the downstream ISApl1 are not capable of mobilization.
Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metastasis

The invasion-promoting MT1-MMP is a cell surface-associated collagenase with a plethora of critical cellular functions. There is a consensus that MT1-MMP is a key protease in aberrant pericellular proteolysis in migrating cancer cells and, accordingly, a promising drug target. Because of high homology in the MMP family and a limited success in the design of selective small-molecule inhibitors, it became evident that the inhibitor specificity is required for selective and successful MT1-MMP therapies. Using the human Fab antibody library (over 1.25×109 individual variants) that exhibited the extended, 23-27 residue long, VH CDR-H3 segments, we isolated a panel of the inhibitory antibody fragments, from which the 3A2 Fab outperformed others as a specific and potent, low nanomolar range, inhibitor of MT1-MMP. Here, we report the in-depth characterization of the 3A2 antibody. Our multiple in vitro and cell-based tests and assays, and extensive structural modeling of the antibody/protease interactions suggest that the antibody epitope involves the residues proximal to the protease catalytic site and that, in contrast with tissue inhibitor-2 of MMPs (TIMP-2), the 3A2 Fab inactivates the protease functionality by binding to the catalytic domain outside the active site cavity. In agreement with the studies in metastasis by others, our animal studies in acute pulmonary melanoma metastasis support a key role of MT1-MMP in metastatic process. Conversely, the selective anti-MT1-MMP monotherapy significantly alleviated melanoma metastatic burden. It is likely that further affinity maturation of the 3A2 Fab will result in the lead inhibitor and a proof-of-concept for MT1-MMP targeting in metastatic cancers.
Weight- and race-based bullying: Health associations among urban adolescents

Stigma-based bullying is associated with negative mental and physical health outcomes. In a longitudinal study, surveys and physical assessments were conducted with mostly Black and Latino, socioeconomically disadvantaged, urban students. As hypothesized, greater weight- and race-based bullying each was significantly indirectly associated with increased blood pressure and body mass index, as well as decreased overall self-rated health across 2 years, through the mechanism of more negative emotional symptoms. Results support important avenues for future research on mechanisms and longitudinal associations of stigma-based bullying with health. Interventions are needed to reduce stigma-based bullying and buffer adolescents from adverse health effects.
A class of versatile circuits, made up of standard electrical components, are memristors

In this paper, we propose a whole class of memristor circuits. Each element from the class consists of the cascade connection between a static nonlinear two‐port and a dynamic one‐port. The class may be divided into two subclasses depending on the input variable (voltage or current). Within each of these subclasses, two further sets of memristor circuits may be distinguished according to which output voltage and current of the two‐port represents one of the system states. The simplest memristor circuits make only use of purely passive elementary components from circuit theory, an absolute novelty in this field of research. Thus they are suitable circuit primers for the introduction of the topic of memristors to undergraduate students. A sample circuit is built using discrete devices and its memristive nature is validated experimentally. In case the one‐port is purely passive, the proposed circuits feature volatile memristive behavior. Allowing active devices into the dynamic one‐port, non‐volatile dynamics may also emerge, as proved through concepts from the theory of nonlinear dynamics. Given the generality of the proposed class, the topology of the emulators may be adjusted so as to induce a large variety of dynamical behaviors, which may be exploited to accomplish new signal processing tasks, which conventional circuits are unable to perform. Copyright © 2015 John Wiley & Sons, Ltd.
Accountable internet protocol (aip)

This paper presents AIP (Accountable Internet Protocol), a network architecture that provides accountability as a first-order property. AIP uses a hierarchy of self-certifying addresses, in which each component is derived from the public key of the corresponding entity. We discuss how AIP enables simple solutions to source spoofing, denial-of-service, route hijacking, and route forgery. We also discuss how AIP's design meets the challenges of scaling, key management, and traffic engineering.
Metabolically Healthy Obesity and Ischemic Heart Disease: A 10-Year Follow-Up of the Inter99 Study

Context Recent studies have suggested that a subgroup of obese individuals is not at increased risk of obesity-related complications. This subgroup has been referred to as metabolically healthy obese. Objective To investigate whether obesity is a risk factor for development of ischemic heart disease (IHD) irrespective of metabolic health. Design In all, 6238 men and women from the Danish prospective Inter99 study were followed during 10.6 (standard deviation = 1.7) years. Setting General community. Participants Participants were classified according to body mass index and four metabolic risk factors (low high-density lipoprotein cholesterol, elevated blood pressure, triglycerides, and fasting plasma glucose). Metabolically healthy individuals were defined as having no metabolic risk factors, and metabolically unhealthy individuals were defined as having a minimum of one. Main Outcome Measures IHD. Results During follow-up, 323 participants developed IHD. Metabolically healthy obese men had increased risk of IHD compared with metabolically healthy normal-weight men [hazard ratio (HR), 3.1; 95% confidence interval (CI), 1.1 to 8.2)]. The corresponding results for women were less pronounced (HR, 1.8; 95% CI, 0.7 to 4.8). Being metabolically healthy but overweight was not associated with higher risk of IHD in men (HR, 1.1; 95% CI, 0.5 to 2.4), and in women the risk was only slightly increased and insignificant (HR, 1.5; 95% CI, 0.8 to 3.0). A substantial proportion of metabolically healthy individuals became metabolically unhealthy after 5 years of follow-up. When these changes in exposure status were taken into account, slightly higher risk estimates were found. Conclusions Being obese is associated with higher incidence of IHD irrespective of metabolic status, and we question the feasibility of denoting a subgroup of obese individuals as metabolically healthy.
Semantic Annotation of Software Requirements with Language Frame

An end user generally writes down software requirements in ambiguous expressions using natural language; hence, a software developer attuned to programming language finds it difficult to understand th meaning of the requirements. To solve this problem we define semantic categories for disambiguation and classify/annotate the requirement into the categories by using machine-learning models. We extensively use a language frame closely related to such categories for designing features to overcome the problem of insufficient training data compare to the large number of classes. Our proposed model obtained a micro-average F1-score of 0.75, outperforming the previous model, REaCT.
Using Tn-seq To Identify Pigmentation-Related Genes of Porphyromonas gingivalis: Characterization of the Role of a Putative Glycosyltransferase

ABSTRACT Cellular pigmentation is an important virulence factor of the oral pathogen Porphyromonas gingivalis. Pigmentation has been associated with many bacterial functions, including but not limited to colonization, maintaining a local anaerobic environment by binding oxygen molecules, and defense against reactive oxygen species (ROS) produced by immune cells. Pigmentation-associated loci identified to date have involved lipopolysaccharide, fimbriae, and heme acquisition and processing. We utilized a transposon mutant library of P. gingivalis strain ATCC 33277 and screened for pigmentation-defective colonies using massively parallel sequencing of the transposon junctions (Tn-seq) to identify genes involved in pigmentation. Transposon insertions at 235 separate sites, located in 67 genes and 15 intergenic regions, resulted in altered pigmentation: 7 of the genes had previously been shown to be involved in pigmentation, while 75 genes and intergenic regions had not. To further confirm identification, we generated a smaller transposon mutant library in P. gingivalis strain W83 and identified pigment mutations in several of the same loci as those identified in the screen in ATCC 33277 but also eight that were not identified in the ATCC 33277 screen. PGN_0361/PG_0264, a putative glycosyltransferase gene located between two tRNA synthetase genes and adjacent to a miniature inverted-repeat transposable element, was identified in the Tn-seq screen and then verified through targeted deletion and complementation. Deletion mutations in PGN_0361/PG_0264 glycosyltransferase abolish pigmentation, modulate gingipain protease activity, and alter lipopolysaccharide. The mechanisms of involvement in pigmentation for other loci identified in this study remain to be determined, but our screen provides the most complete survey of genes involved in pigmentation to date. IMPORTANCE P. gingivalis has been implicated in the onset and progression of periodontal disease. One important virulence factor is the bacterium's ability to produce pigment. Using a transposon library, we were able to identify both known and novel genes involved in pigmentation of P. gingivalis. We identified a glycosyltransferase, previously not associated with pigmentation, that is required for pigmentation and determined its mechanism of involvement. A better understanding of the genes involved in pigmentation may lead to new insights into the complex mechanisms involved in this important virulence characteristic and could facilitate development of novel therapeutics.
Episodic Memory Impairments in Primary Brain Tumor Patients

Objective Cognitive investigations in brain tumor patients have mostly explored episodic memory without differentiating between encoding, storage, and retrieval deficits. The aim of this study is to offer insight into the memory sub-processes affected in primary brain tumor patients and propose an appropriate assessment method. Method We retrospectively reviewed the clinical and memory assessments of 158 patients with primary brain tumors who had presented to our departments with cognitive complaints and were investigated using the Free and Cued Selective Reminding Test. Results Retrieval was the process of episodic memory most frequently affected, with deficits in this domain detected in 92% of patients with episodic memory impairments. Storage and encoding deficits were less prevalent, with impairments, respectively, detected in 41% and 23% of memory-impaired patients. The pattern of episodic memory impairment was similar across different tumor histologies and treatment modalities. Conclusion Although all processes of episodic memory were found to be impaired, retrieval was by far the most widely affected function. A thorough assessment of all three components of episodic memory should be part of the regular neuropsychological evaluation in patients with primary brain tumors.
The Pathologic Classification of Neuroendocrine Tumors: A Review of Nomenclature, Grading, and Staging Systems

Neuroendocrine tumors (NETs) arise in most organs of the body and share many common pathologic features. However, a variety of different organ-specific systems have been developed for nomenclature, grading, and staging of NETs, causing much confusion. This review examines issues in the pathologic assessment of NETs that are common among primaries of different sites. The various systems of nomenclature are compared along with new proposal for grading and staging NETs. Although differences persist, there are many common themes, such as the distinction of well-differentiated (low and intermediate-grade) from poorly differentiated (high-grade) NETs and the significance of proliferative rate in prognostic assessment. A recently published minimum pathology data set is presented to help standardize the information in pathology reports. Although an ultimate goal of standardizing the pathologic classification of all NETs, irrespective of primary site, remains elusive, an understanding of the common themes among the different current systems will permit easier translation of information relevant to prognosis and treatment.
Set-Shifting Deficits: A Possible Neurocognitive Endophenotype for Tourette Syndrome Without ADHD

Objective: Tourette syndrome (TS) can be associated with cognitive dysfunction. We assessed a range of cognitive abilities in adults with TS without comorbid disorders. Method: Participants completed tests of sustained attention, verbal and non-verbal reasoning, comprehension, verbal fluency, working memory, inhibition, and set-shifting. We compared patients’ task performance with that of healthy controls, and evaluated relationships between cognitive abilities and symptoms of obsessive-compulsive disorder (OCD), ADHD, impulse control problems, and mood disorders. Results: Patients with TS exhibited impairments on four measures assessing response inhibition, fine motor control, set-shifting, and sustained attention. The Wisconsin Card Sorting Test (WCST) discriminated best between patients and controls. Patients’ deficits were not correlated with tic severity or symptoms related to OCD, ADHD, or mood disorders. Conclusion: Deficits on the WCST could constitute a neurocognitive endophenotype for TS, reflecting dysfunction within neural networks involving basal ganglia, pre-supplementary motor area, and inferior prefrontal regions.
Imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) infection from Oman to Thailand, June 2015

Thailand reported the first Middle East respiratory syndrome (MERS) case on 18 June 2015 (day 4) in an Omani patient with heart condition who was diagnosed with pneumonia on hospital admission on 15 June 2015 (day 1). Two false negative RT-PCR on upper respiratory tract samples on days 2 and 3 led to a 48-hour diagnosis delay and a decision to transfer the patient out of the negative pressure unit (NPU). Subsequent examination of sputum later on day 3 confirmed MERS coronavirus (MERS-CoV) infection. The patient was immediately moved back into the NPU and then transferred to Bamrasnaradura Infectious Disease Institute. Over 170 contacts were traced; 48 were quarantined and 122 self-monitored for symptoms. High-risk close contacts exhibiting no symptoms, and whose laboratory testing on the 12th day after exposure was negative, were released on the 14th day. The Omani Ministry of Health (MOH) was immediately notified using the International Health Regulation (IHR) mechanism. Outbreak investigation was conducted in Oman, and was both published on the World Health Organization (WHO) intranet and shared with Thailand’s IHR focal point. The key to successful infection control, with no secondary transmission, were the collaborative efforts among hospitals, laboratories and MOHs of both countries.
Physical activity participation and the association with work‐related upper quadrant disorders (WRUQDs): A systematic review

BACKGROUND Workers in various occupations often report work-related upper quadrant disorders (WRUQDs). Research has shown that associative factors for WRUQDs include psychosocial and environmental elements, gender and physical activity levels. To date, no review has investigated whether physical activity participation is associated with and/or predicts the development of WRUQDs, so the present study set out to determine this. METHODS A systematic review was conducted including searches of PubMed (MEDLINE), EMBASE and CINAHL from inception to 31 March 2017. Quantitative studies, including any outcome measure of physical activity participation and its association with and/or prediction of WRUQDs, were included. One reviewer conducted the search and two reviewers independently assessed eligibility and completed methodological quality assessment using a modified Downs and Black checklist. Data were analysed narratively. RESULTS Eight studies were eligible for inclusion in the final review. The quality of these ranged from moderate to high quality. Three studies reported no statistical difference between physical activity participation and the risk of developing WRUQD. Three studies reported a negative and one study a positive association between physical activity participation and WRUQDs. One study reported that little or no physical exercise participation was a risk factor for WRUQD. CONCLUSIONS There is limited evidence for a negative association between physical activity participation and the development of WRUQDs. However, this was not a consistent finding across all studies included. Further research is indicated in standardizing diagnostic criteria and the measurement of physical activity participation in this patient population.
Humanoids learn object properties from robust tactile feature descriptors via multi-modal artificial skin

This paper presents new methods for the recognition and categorization of object properties such as surface texture, weight, and compliance using a multi-modal artificial skin mounted on both arms of a humanoid. In addition, it introduces two novel feature descriptors, which are useful for providing high-level information to learning algorithms. The artificial skin has built-in 3-axis accelerometer, normal force, proximity, and temperature sensors. To explore different surface textures and weights, objects were left sliding between the NAO humanoid's arms. The caused vibration was detected by accelerometers. Surface texture and weight recognition models were learned from the extracted features of the vibration signals thanks to two learning algorithms, namely the support vector machine (SVM) and the Expectation Maximization (EM). In order to recognize objects having different compliances, SVM and EM took into account total amount of forces applied by the arms to hold the object firmly. The experimental results show that the humanoid can distinguish between different objects having different surface textures and weights with a recognition rate of 100%. Furthermore, it can categorize objects with hard and soft surfaces and classify objects having similar compliance with 100% and 70% accuracy rates respectively.