Miracle-dz/UniFAR-FTUs huggingface dataset:
The HTLV-1 Virological Synapse

Human T-lymphotropic virus-1 (HTLV-1) spreads efficiently between T-cells via a tight and highly organized cell-cell contact known as the virological synapse. It is now thought that many retroviruses and other viruses spread via a virological synapse, which may be defined as a virus-induced, specialized area of cell-to-cell contact that promotes the directed transmission of the virus between cells. We summarize here the mechanisms leading to the formation of the HTLV-1 virological synapse and the role played by HTLV-1 Tax protein. We propose a model of HTLV-1 transmission between T-cells based on the three-dimensional ultrastructure of the virological synapse. Finally, in the light of recent advances, we discuss the possible routes of HTLV-1 spread across the virological synapse.
Genetic variation in androgen disposition: implications in clinical medicine including testosterone abuse

Background: Testosterone replacement therapy in hypogonadal men has been used for > 60 years. The use of testosterone substitution is continuously growing and is given to aging men to improve the quality of life. Because testosterone use is associated with muscle strength enhancing effects, it has become a popular drug to abuse. Doping with anabolic steroids, such as testosterone, is a severe challenge to the vision, moral and ethics in sports and has also become a significant and increasing problem in society. Objective: The primary aim of this review is to summarize and discuss the contribution of genetic components to inter-individual variation in androgen disposition. Conclusion: Genetic variation has a large impact on androgen disposition. This variation is of the utmost importance for the interpretation of doping test results and may modulate the effects of testosterone replacement therapy and testosterone doping.
Leaving tissue associated with infrequent intracranial EEG seizure onsets is compatible with post-operative seizure freedom

Abstract Identify seizure onset electrodes that need to be resected for seizure freedom in children undergoing intracranial electroencephalography recording for treatment of medically refractory epilepsy. All children undergoing intracranial electroencephalography subdural grid electrode placement at the Children’s Hospital of Philadelphia from 2002–2008 were asked to enroll. We utilized intraoperative pictures to determine the location of the electrodes and define the resection cavity. A total of 15 patients had surgical fields that allowed for complete identification of the electrodes over the area of resection. Eight of 15 patients were seizure free after a follow up of 1.7 to 8 yr. Only one seizure-free patient had complete resection of all seizure onset associated tissue. Seizure free patients had resection of 64.1% of the seizure onset electrode associated tissue, compared to 35.2% in the not seizure free patients (P = 0.05). Resection of tissue associated with infrequent seizure onsets did not appear to be important for seizure freedom. Resecting ≥ 90% of the electrodes from the predominant seizure contacts predicted post-operative seizure freedom (P = 0.007). The best predictor of seizure freedom was resecting ≥ 90% of tissue involved in majority of a patient’s seizures. Resection of tissue under infrequent seizure onset electrodes was not necessary for seizure freedom.
Synaptic connectivity in the midget‐parvocellular pathway of primate central retina

The synaptic connectivity of OFF midget bipolar cells was investigated in the central retina of two primate species, the New World common marmoset monkey, Callithrix jacchus, and the Old World macaque monkey, Macaca fascicularis. In marmosets, dichromatic and trichromatic animals were compared. Bipolar output synapses were identified with antibodies against ribbon proteins (kinesin, C‐terminal binding protein 2) or with an antiserum that recognizes postsynaptic glutamate receptor clusters (GluR4). The midget bipolar cells were identified immunocytochemically with antibodies to CD15 (marmoset) or an antiserum to recoverin (macaque). In marmosets, midget ganglion cells were retrogradely labeled from the parvocellular layers of the dorsal lateral geniculate nucleus. Consistent with previous studies of Old World primates, in marmoset, midget bipolar cells contacted midget ganglion cells at a ratio of 1:1. The number of output synapses made by OFF midget bipolar cells was quantified for 104 cells in two dichromatic marmosets, 108 cells in one trichromatic marmoset, and 118 cells in one macaque. The number of output synapses was comparable for all animals, ranging from 10–71 in the dichromatic marmoset (average 29.7 ± 12.4 SD), 12–86 in the trichromatic marmoset (average 28.6 ± 11.7 SD) and 9–48 in the macaque (average 26.5 ± 9.3 SD) per axon terminal. In all animals the number of output synapses per axon terminal showed a unimodal distribution. Our results suggest that the midget circuitry is comparable in dichromatic and trichromatic animals. J. Comp. Neurol. 494:260–274, 2006. © 2005 Wiley‐Liss, Inc.
A deeply conserved, noncanonical miRNA hosted by ribosomal DNA

Advances in small RNA sequencing technologies and comparative genomics have fueled comprehensive microRNA (miRNA) gene annotations in humans and model organisms. Although new miRNAs continue to be discovered in recent years, these have universally been lowly expressed, recently evolved, and of debatable endogenous activity, leading to the general assumption that virtually all biologically important miRNAs have been identified. Here, we analyzed small RNAs that emanate from the highly repetitive rDNA arrays of Drosophila. In addition to endo-siRNAs derived from sense and antisense strands of the pre-rRNA sequence, we unexpectedly identified a novel, deeply conserved, noncanonical miRNA. Although this miRNA is widely expressed, this miRNA was not identified by previous studies due to bioinformatics filters removing such repetitive sequences. Deep-sequencing data provide clear evidence for specific processing with precisely defined 5′ and 3′ ends. Furthermore, we demonstrate that the mature miRNA species is incorporated in the effector complexes and has detectable trans regulatory activity. Processing of this miRNA requires Dicer-1, whereas the Drosha–Pasha complex is dispensable. The miRNA hairpin sequence is located in the internal transcribed spacer 1 region of rDNA and is highly conserved among Dipteran species that were separated from their common ancestor ∼100 million years ago. Our results suggest that biologically active miRNA genes may remain unidentified even in well-studied organisms.
Cryptococcus Strains with Different Pathogenic Potentials Have Diverse Protein Secretomes

ABSTRACT Secreted proteins are the frontline between the host and pathogen. In mammalian hosts, secreted proteins enable invasive infection and can modulate the host immune response. Cryptococcosis, caused by pathogenic Cryptococcus species, begins when inhaled infectious propagules establish to produce pulmonary infection, which, if not resolved, can disseminate to the central nervous system to cause meningoencephalitis. Strains of Cryptococcus species differ in their capacity to cause disease, and the mechanisms underlying this are not well understood. To investigate the role of secreted proteins in disease, we determined the secretome for three genome strains of Cryptococcus species, including a hypovirulent and a hypervirulent strain of C. gattii and a virulent strain of C. neoformans. Sixty-seven unique proteins were identified, with different numbers and types of proteins secreted by each strain. The secretomes of the virulent strains were largely limited to proteolytic and hydrolytic enzymes, while the hypovirulent strain had a diverse secretome, including non-conventionally secreted canonical cytosolic and immunogenic proteins that have been implicated in virulence. The hypovirulent strain cannot establish pulmonary infection in a mouse model, but strains of this genotype have caused human meningitis. To directly test brain infection, we used intracranial inoculation and found that the hypovirulent strain was substantially more invasive than its hypervirulent counterpart. We suggest that immunogenic proteins secreted by this strain invoke a host response that limits pulmonary infection but that there can be invasive growth and damage if infection reaches the brain. Given their known role in virulence, it is possible that non-conventionally secreted proteins mediate this process.
A Decline in Glial Cell-Line-Derived Neurotrophic Factor Expression Is Associated with Impaired Regeneration after Long-Term Schwann Cell Denervation

In the peripheral nervous system, regeneration of motor and sensory axons into chronically denervated distal nerve segments is impaired compared to regeneration into acutely denervated nerves. In order to find possible causes for this phenomenon we examined the changes in the expression pattern of the glial cell-line-derived neurotrophic factor (GDNF) family of growth factors and their receptors in chronically denervated rat sciatic nerves as a function of time with or without regeneration. Among the GDNF family of growth factors, only GDNF mRNA expression was rapidly upregulated in Schwann cells as early as 48 h after denervation. This upregulation peaked at 1 week and then declined to minimal levels by 6 months of denervation. The changes in the protein expression paralleled the changes in the expression of the GDNF mRNA. The mRNAs for receptors GFRalpha-1 and GFRalpha-2 were upregulated only after maximal GDNF upregulation and remained elevated as late as 6 months. There were no significant changes in the expression of GFRalpha-3 or the tyrosine kinase coreceptor, RET. When we examined the expression of GDNF in a delayed regeneration paradigm, there was no upregulation in the distal chronically denervated tibial nerve even when the freshly axotomized peroneal branch of the sciatic nerve was sutured to the distal tibial nerve. This study suggests that one of the reasons for impaired regeneration into chronically denervated peripheral nerves may be the inability of Schwann cells to maintain important trophic support for both motor and sensory neurons.
Ceftaroline potency among 9 US Census regions: report from the 2010 AWARE Program.

Ceftaroline is a new antibacterial agent that is active against the major bacterial pathogens found in acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. The 2010 Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Surveillance Program in the United States collected a total of 8434 bacterial isolates from 65 US medical centers across 9 US regions. The isolates were cultured and tested for susceptibility to ceftaroline and comparator agents by reference minimum inhibitory concentration (MIC) methods. An analysis by US Census Bureau region demonstrated that Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), and coagulase-negative staphylococci (CoNS), including methicillin-resistant CoNS, were particularly susceptible to ceftaroline (MIC(90), 1 and 0.5 µg/mL respectively). The MRSA rate was 50.0% overall, which varied from a low of 44.6% in the South Atlantic region to a high of 53.1% in the Mountain region. Susceptibility among MRSA for ceftaroline ranged from 96.7% in the West South Central region to 100% in the West North Central region. All MRSA isolates were inhibited at a ceftaroline MIC of ≤ 2 μg/mL, and 98.4% were inhibited at a ceftaroline MIC of ≤ 1 μg/mL. In general, regional differences in activity among staphylococci, streptococci, Haemophilus spp. , and Moraxella catarrhalis were minimal due to the high potency of ceftaroline. Greater differences in activity were observed among the Enterobacteriaceae due to the greater diversity of organism types and resistance mechanisms, including those producing extended-spectrum β-lactamase enzymes.
Reinforcing and subjective effects of several anorectics in normal human volunteers.

A discrete-trial choice procedure was used to examine the reinforcing and subjective effects of four anorectic drugs (mazindol, benzphetamine, phenylpropanolamine and phenmetrazine) in groups of normal healthy adults. For each experiment, subjects first sampled placebo and a dose of one of the drugs (mazindol: 0.5, 1.0 and 2.0 mg; benzphetamine: 25 and 50 mg; phenylpropanolamine: 12.5, 25 and 50 mg; phenmetrazine: 25 and 50 mg; all p.o.). Subjects were then allowed to choose between drug and placebo on five separate occasions. The relative frequency with which active drug was chosen over placebo was used as an index of the drug's reinforcing efficacy. Subjective effects were measured with an experimental version of the Profile of Mood States, a short form of the Addiction Research Center Inventory and a series of visual analog scales. The rank order for reinforcing efficacy was benzphetamine approximately phenmetrazine greater than placebo greater than phenylpropanolamine much greater than mazindol. Ratings of drug liking were positively correlated with number of drug choices for each drug. Benzphetamine and phenmetrazine produced subjective effects characteristic of amphetamine-like drugs and increased ratings of drug liking. Mazindol produced only dysphoric subjective effects and decreased ratings of drug liking. Phenylpropanolamine had no significant effects on subjective measures or drug-liking ratings. These findings are consistent with the presumed dependence potential of these compounds, and demonstrate the validity of this experimental paradigm for assessing the reinforcing effects of anorectics in normal human volunteers.
Psychometric properties of the Generalized Anxiety Disorder Inventory in a Canadian sample

The Generalized Anxiety Disorder Inventory is a recently developed self-report measure that assesses symptoms of generalized anxiety disorder. Its psychometric properties have not been investigated further since its original development. The current study investigated its psychometric properties in a Canadian student/community sample. Exploratory principal component analysis replicated the original three-component structure. The total scale and subscales demonstrated excellent internal consistency reliability (α = 0.84–0.94) and correlated strongly with the Penn State Worry Questionnaire (r = 0.41–0.74, all ps <0.001) and Generalized Anxiety Disorder-7 (r = 0.55–0.84, all ps <0.001). However, only the total scale and cognitive subscale (r = 0.48–0.49, all ps <0.05) significantly predicted generalized anxiety disorder diagnosis established by diagnostic interview. The somatic subscale in particular may require revision to improve predictive validity. Revision may also be necessary given changes in required somatic symptoms for generalized anxiety disorder diagnostic criteria in more recent versions of the Diagnostic and Statistical Manual of Mental Disorders (i.e. although major changes occurred from Diagnostic and Statistical Manual of Mental Disorders-III-R to Diagnostic and Statistical Manual of Mental Disorders-IV, changes in Diagnostic and Statistical Manual of Mental Disorders-5 were minimal) and the possibility of changes in the upcoming 11th revision of the International Classification of Diseases.
Constrained Recombination in an Example-based Machine Translation System

Constraints in natural language processing play an important role. In this paper we show which impact (word-order) constraints have on the translation re-sults, when they are applied in the recombination step of a linear EBMT sys-tem. Both the baseline EBMT system and the constrained one are implemented during this research. In the experiments we use two language-pairs (Romanian-English and Romanian-German), in both directions of translations. In these language constellations, Romanian, an in-ﬂected language with Latin root, is considered under-resourced. This aspect makes the process of translation even more challenging.
Selective cyclooxygenase-2 inhibition directly increases human vascular reactivity to norepinephrine during acute inflammation.

AIMS The use of cyclooxygenase-2 (COX-2) inhibitors has been reported to be associated with detrimental vascular events. The aim of our study was to evaluate the role of COX-2 activity in the control of human vascular tone under inflammatory conditions. METHODS AND RESULTS Using organ bath experiments, the contraction induced by norepinephrine (NE), U46619, acetylcholine, and KCl was performed on isolated human internal mammary arteries (IMA) cultured in the presence or absence of both interleukin-1beta (IL-1beta) and lipopolysaccharide (LPS) with or without endothelium. Under these conditions the COX (cyclooxygenase) isoforms were detected by immunohistochemistry and western blot, and the prostaglandins (PG) and thromboxane (Tx) released were measured using an enzyme immunoassay kit. A significant decrease in the maximal effect induced by NE but not by other stimuli was observed in the IL-1beta- and LPS-treated preparations after 6 and 24 h of culture (-19 +/- 6 and -25 +/- 4%, respectively), an effect that was endothelium independent. Under this inflammatory condition, the COX-2 inhibitors DFU (1 micromol/L), DuP-697 (0.5 micromol/L), and Etoricoxib (1 micromol/L) markedly restored and increased the vascular reactivity to NE. These alterations were not observed with SC-560 (1 micromol/L), a selective COX-1 inhibitor. In addition, the COX-1 isoform was always detected and the COX-2 isoform was only found in human IMA exposed for 6 or 24 h under inflammatory conditions. The COX-2 induction was accompanied by an increase in PGE(2) (prostaglandin E(2)) and PGI(2) (prostaglandin I(2)) release in the culture medium (approximately 2.5-fold) but not with an increase in TxA(2) (thromboxane A(2)) release. CONCLUSION These observations suggest that the inhibition of COX-2 directly potentiates the human vascular tone induced by NE under inflammatory conditions.
Simultaneous Loss of NCKX4 and CNG Channel Desensitization Impairs Olfactory Sensitivity

In vertebrate olfactory sensory neurons (OSNs), Ca2+ plays key roles in both mediating and regulating the olfactory response. Ca2+ enters OSN cilia during the response through the olfactory cyclic nucleotide-gated (CNG) channel and stimulates a depolarizing chloride current by opening the olfactory Ca2+-activated chloride channel to amplify the response. Ca2+ also exerts negative regulation on the olfactory transduction cascade, through mechanisms that include reducing the CNG current by desensitizing the CNG channel via Ca2+/calmodulin (CaM), to reduce the response. Ca2+ is removed from the cilia primarily by the K+-dependent Na+/Ca2+ exchanger 4 (NCKX4), and the removal of Ca2+ leads to closure of the chloride channel and response termination. In this study, we investigate how two mechanisms conventionally considered negative regulatory mechanisms of olfactory transduction, Ca2+ removal by NCKX4, and desensitization of the CNG channel by Ca2+/CaM, interact to regulate the olfactory response. We performed electro-olfactogram (EOG) recordings on the double-mutant mice, NCKX4−/−;CNGB1ΔCaM, which are simultaneously lacking NCKX4 (NCKX4−/−) and Ca2+/CaM-mediated CNG channel desensitization (CNGB1ΔCaM). Despite exhibiting alterations in various response attributes, including termination kinetics and adaption properties, OSNs in either NCKX4−/− mice or CNGB1ΔCaM mice show normal resting sensitivity, as determined by their unchanged EOG response amplitude. We found that OSNs in NCKX4−/−;CNGB1ΔCaM mice displayed markedly reduced EOG amplitude accompanied by alterations in other response attributes. This study suggests that what are conventionally considered negative regulatory mechanisms of olfactory transduction also play a role in setting the resting sensitivity in OSNs. SIGNIFICANCE STATEMENT Sensory receptor cells maintain high sensitivity at rest. Although the mechanisms responsible for setting the resting sensitivity of sensory receptor cells are not well understood, it has generally been assumed that the sensitivity is set primarily by how effectively the components in the activation cascade of sensory transduction can be stimulated. Our findings in mouse olfactory sensory neurons suggest that mechanisms that are primarily responsible for terminating the olfactory response are also critical for proper resting sensitivity.
RNA transport and localized protein synthesis in neurological disorders and neural repair

Neural cells are able to finely tune gene expression through post‐transcriptional mechanisms. Localization of mRNAs to subcellular regions has been detected in neurons, oligodendrocytes, and astrocytes providing these domains with a locally renewable source of proteins. Protein synthesis in dendrites has most frequently been associated with synaptic plasticity, while axonally synthesized proteins appear to facilitate pathfinding and injury responses. For oligodendrocytes, mRNAs encoding several proteins for myelin formation are locally generated suggesting that this mechanism assists in myelination. Astrocytic processes have not been well studied but localization of GFAP mRNA has been demonstrated. Both RNA transport and localized translation are regulated processes. RNA transport appears to be highly selective and, at least in part, the destiny of individual mRNAs is determined in the nucleus. RNA–protein and protein–protein interactions determine which mRNAs are targeted to subcellular regions. Several RNA binding proteins that drive mRNA localization have also been shown to repress translation during transport. Activity of the translational machinery is also regulated in distal neural cell processes. Clinically, disruption of mRNA localization and/or localized mRNA translation may contribute to pathophysiology of fragile X mental retardation and spinal muscular atrophy. Axonal injury has been shown to activate localized protein synthesis, providing both a means to initiate regeneration and retrogradely signal injury to the cell body. Decreased capacity to transport mRNAs and translational machinery into distal processes could jeopardize the ability to respond to injury or local stimuli within axons and dendrites. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007
Introduction to special topic forum management theory and social welfare: Contributions and challenges - eScholarship

© Academy of Management Review.In this Introduction to the Special Topic Forum on Management Theory and Social Welfare, we first provide an overview of the motivation behind the special issue. We then highlight the contributions of the six articles that make up this forum and identify some common themes. We also suggest some reasons why social welfare issues are so difficult to addressin the context of management theory. In addition, we evaluate means of assessing social welfare and urge scholars not to make (or imply) unwarranted wealth creation claims.
Prevalence and predictors of parasuicide in chronic psychosis. UK700 group.

OBJECTIVE This study estimates the prevalence of and risk factors for parasuicide in a large community-based sample of patients with chronic psychosis. METHOD A total of 704 subjects with chronic psychosis were interviewed using a battery of instruments. The 2-year prevalence of parasuicide was estimated and a comparison was made between attempters and nonattempters on a wide range of sociodemographic and clinical variables. RESULTS The 2-year prevalence of parasuicide was 18.8%. Attempters were significantly more likely to be younger, of white ethnic origin, to have a diagnosis of affective disorder, to be currently depressed, to have experienced more auditory hallucinations and to have received treatment with antipsychotic drugs for a longer period. CONCLUSION Parasuicide was found to present a considerable clinical problem in this group. Continual risk assessment is essential to reduce this unacceptably high rate.