Miracle-dz/UniFAR-FTUs huggingface dataset:
Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L)

Here, we describe the generation of a novel transgenic mouse model of human tauopathy. The rTg(tauP301L)4510 mouse expresses the P301L mutation in tau (4R0N) associated with frontotemporal dementia and parkinsonism linked to chromosome 17. Transgene expression was driven by a forebrain-specific Ca2+ calmodulin kinase II promoter system resulting in high levels of expression in the hippocampus and neocortex. Importantly, transgene expression in this model is induced via the tetracycline-operon responsive element and is suppressed after treatment with doxycycline. Continued transgene expression in rTg(tauP301L)4510 mice results in age-dependent development of many salient characteristics of hereditary human dementia. From an early age, immunohistochemical studies demonstrated abnormal biochemical processing of tau and the presence of pathological conformation- and phosphorylation-dependent epitopes. Neurofibrillary tangle (NFT) pathology was first observed in the neocortex and progressed into the hippocampus and limbic structures with increasing age. Consistent with the formation of NFTs, immunoblots indicated an age-dependent transition of accumulating tau species from Sarkosyl soluble 55 kDa to insoluble hyperphosphorylated 64 kDa. Ultrastructural analysis revealed the presence of straight tau filaments. Furthermore, the effects of tauP301L expression on spatial reference memory were longitudinally tested using the Morris water maze. Compared with nontransgenic age-matched control littermates, rTg(tauP301L)4510 mice developed significant cognitive impairments from 4 months of age. Memory deficits were accompanied by gross forebrain atrophy and a prominent loss of neurons, most strikingly in hippocampal subdivision CA1. Collectively, these data describe a novel transgenic mouse that closely mimics human tauopathy and may represent an important model for the future study of tau-related neurodegenerative disease.
The cytopathology of Actinomyces, Nocardia, and their mimickers

Nocardia species and Actinomyces species are 2 of the most commonly diagnosed filamentous bacteria in routine cytopathology practice. These genera share many overlapping cytomorphologic features, including their thin, beaded, branching, Gram‐positive, GMS‐positive filamentous structures that fragment at their peripheries into bacillary‐ and coccoid‐appearing forms. Features that help distinguish between these 2 microorganisms include the width of their filamentous structures, the angles at which they branch, and their ability or lack thereof to retain a modified acid‐fast stain. In addition to cytomorphologic overlap, overlap in clinical presentation is frequent with pulmonary and mucocutaneous presentations seen in both. Differentiating between Nocardia and Actinomyces is essential because patients with these infections require different approaches to medical management. Both antibiotic susceptibilities and the need for early surgical intervention as part of the treatment plan vary greatly among these 2 groups. This review focuses on the clinical presentation, cytomorphology and staining characteristics that can be useful in identifying and distinguishing between Nocardia and Actinomyces infections, as well as their mimickers.
Cutting Edge: IL-2 Is Essential for TGF-β-Mediated Induction of Foxp3+ T Regulatory Cells

TGF-β is a pluripotent cytokine that is capable of inducing the expression of Foxp3 in naive T lymphocytes. TGF-β-induced cells are phenotypically similar to thymic-derived regulatory T cells in that they are anergic and suppressive. We have examined the cytokine and costimulatory molecule requirements for TGF-β-mediated induction and maintenance of Foxp3 by CD4+Foxp3− cells. IL-2 plays a non-redundant role in TGF-β-induced Foxp3 expression. Other common γ-chain-utilizing cytokines were unable to induce Foxp3 expression in IL-2-deficient T cells. The role of CD28 in the induction of Foxp3 was solely related to its capacity to enhance the endogenous production of IL-2. Foxp3 expression was stable in vitro and in vivo in the absence of IL-2. As TGF-β-induced T regulatory cells can be easily grown in vitro, they may prove useful for the treatment of autoimmune diseases, for the prevention of graft rejection, and graft versus host disease.
In vivo imaging reveals novel aspects of retinal disease progression in Rs1h(-/Y) mice but no therapeutic effect of carbonic anhydrase inhibition.

PURPOSE X-linked juvenile retinoschisis (XLRS) is the most common juvenile maculopathy in men and is caused by mutations in the gene encoding retinoschisin (RS1). Evidence in the literature on the therapeutic effect of carboanhydrase inhibitors (CAIs) to treat schisis formation in the retina has remained equivocal. Here, we evaluate the effect of the CAI dorzolamide on the structural and functional disease progression in the mouse model for XLRS (Rs1h(-/y)). METHODS Rs1h (-/y) mice were treated unilaterally with dorzolamide eye drops (Trusopt(®) 20 mg/mL) every 12 h for 2 weeks starting on postnatal day 14 (n = 27). Changes of retinal structure were monitored by confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography 12 h, 14 days, 4 weeks, 2 months, and 6 months after completion of the treatment. RESULTS Schisis formation (peak at 3 months) preceded photoreceptor degeneration and hyper-fluorescence (peak at 7 months). Structural pathology was most severe in the superior hemi-retina with previously unreported hyper-fluorescent lesions. Quantitative analysis showed no significant differences regarding the inner or outer retinal thickness of the treated vs. untreated eyes 12 h after the completion of treatment (IRT(12 h) = -1.29 ± 1.89 μm; ORT(12 h) = 0.61 ± 2.08 μm; mean ± 95%CI) or at any later time point. CONCLUSION Time line analysis after short-term treatment with CAI failed to show short-, intermediate-, or long-term evidence of structural improvement in Rs1h(-/y) mice. Schisis formation in the inner retina peaked at the age of 3 months and was followed by photoreceptor degeneration predominantly in the superior hemi-retina. Previously unreported hyper-fluorescent lesions co-register with structural retinal pathologies.
Differentiation of growth signal requirement of B lymphocyte precursor is directed by expression of immunoglobulin.

During B cell differentiation, at least three stages can be defined in terms of their growth signal requirement by using two different growth signals, which are recombinant interleukin 7 (IL‐7) and a stromal cell clone PA6 which does not produce IL‐7; first a PA6 dependent stage, second a PA6 + IL‐7 dependent stage and third an IL‐7 dependent stage. In order to test the possibility that this differentiation of growth signal requirement is controlled by the expression of functional immunoglobulin molecules, we have investigated the frequencies of PA6 + IL‐7 dependent and IL‐7 dependent cells which are present in the bone marrow of either mu‐chain or kappa‐chain gene transgenic mice. In a mu‐chain gene transgenic mouse, the frequency of PA6 + IL‐7 dependent cells is selectively reduced, while that of IL‐7 dependent cells is selectively reduced in a kappa‐chain gene transgenic mouse. This result suggests that expression of a functional mu‐chain gene drives PA6 + IL‐7 dependent cells to differentiate into the subsequent IL‐7 dependent stage. Likewise, when mu‐chain positive IL‐7 dependent cells express a functional light‐chain gene, their growth signal requirement changes into an IL‐7 unreactive stage.
Effects of Color Appeal, Perceived Risk and Culture on User's Decision in Presence of Warning Banner Message

Color is present in every aspect of human life, and color is driving our decisions. In the digital computer warning realm, in which a warning message is a communication mechanism, color represents an important design element, which aims at preventing the hazard and reducing negative outcomes from the user’s action. Interestingly, we are lacking the understanding of how color appeal influences behavioral intentions in culturally distinct countries when it comes to paying more attention to warning messages. We conducted a cross-cultural investigation by running an online experiment, followed by a survey of 258 participants from the United States and India. Supported by the color-in-context theory, we found that culture is an important dimension in the specific warning message context in which color appeal is a salient antecedent to behavioral intentions in culturally distinct countries. We derive several theoretical contributions and practitioners’ insights.
Regulation of Smad7 Promoter by Direct Association with Smad3 and Smad4*

Smad7 is a regulatory Smad protein that is able to antagonize signal transduction by transforming growth factor-β (TGF-β) and activin receptors. To characterize the regulation of Smad7 at the transcriptional level, we isolated the promoter region of the mouse Smad7 gene. When the Smad7 promoter luciferase reporter gene (−408 and +112 bp) was expressed in human hepatoma (HepG2) cells, its transcriptional activity was increased following TGF-β or activin treatment. In addition, this region of the Smad7 promoter was stimulated by ectopic expression of Smad3 as well as constitutively active TGF-β and activin receptors, indicating that Smad7 transcription was modulated by the signaling downstream those two receptors. A gel mobility shift assay indicated that a DNA fragment spanning −408 to −126 base pairs (bp) was able to directly bind purified Smad4. Furthermore, a consensus Smad3-Smad4 binding element (SBE) was discovered in this region of the promoter with a palindromic sequence of GTCTAGAC. A 33-bp Smad7 promoter fragment containing this SBE was able to bind Smad3 and Smad4. In human embryonic kidney 293 cells, the expression of constitutively active TGF-β type I receptor was able to induce the formation of a Smad3- and Smad4-containing nuclear protein complex that bound the SBE. In HepG2 cells, TGF-β1 treatment could induce the formation of an endogenous SBE-binding complex. Taken together, these data provided the first evidence that Smad7 transcription is regulated by TGF-β and activin signaling through direct binding of Smad3 and Smad4 to the Smad7 promoter.
[Physiopathologic relationship between interstitial cystitis and rheumatic, autoimmune, and chronic inflammatory diseases].

OBJECTIVES To evaluate the current knowledge about interstitial cystitis pathophysiology and its relationship with rheumatic, autoimmune and chronic inflammatory diseases. METHODS Literature search under "interstitial cystitis pathophysiology" either clinical or experimental trials and reports, in Medline, PubMed, Digital Urology Journal and Doctor's Guide, in addition to our own clinical research experience results. RESULTS Both human and experimental trials show resemblances between interstitial cystitis and rheumatic, autoimmune, and chronic inflammatory diseases on clinical presentations, pathophysiology. Some interstitial cystitis patients show the bladder infiltrated with specific mononuclear cells, high incidence of circulating antinuclear antibodies, good response to anti-inflammatory and/or immunosuppressive therapies. Interstitial cystitis in association with rheumatic, autoimmune and chronic inflammatory diseases is very common. Many patients with systemic lupus erythematosus, Sjögren syndrome and fibromyalgia syndrome show antibodies against urothelium and/or muscle cells and/or other connective tissue components of urinary bladder. Systemic lupus erythematosus and Sjögren syndrome are the autoimmune diseases which bear strongest similarity with interstitial cystitis. Moreover, rheumatoid arthritis, chronic pelvic pain syndrome, irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, Evan's syndrome and atopic dermatitis share some pathogenic characteristics. CONCLUSIONS Nowadays, interstitial cystitis pathophysiology is unknown. Based on clinical presentations, epidemiology, pathology and laboratory findings and treatment response, there is an important correlation among interstitial cystitis and rheumatic, autoimmune and chronic inflammatory diseases. These disorders may share some pathophysiologic mechanisms. Rigorous studies of pathophysiology of these group of diseases are needed to confirm consistently this approach for such conditions.
B  1+ Phase mapping at 7 T and its application for in vivo electrical conductivity mapping

In this study, a new approach to measure local electrical conductivity in tissue is presented, which is based on the propagating B 1+ phase and the homogeneous Helmholtz equation. This new MRI technique might open future opportunities for tumor and lesion characterization based on conductivity differences, while it may also find application in radio frequency safety assessment. Prerequisites for conductivity mapping using only the B 1+ phase (instead of the complex B +1 field) are addressed. Furthermore it was found that the B 1+ phase can be derived directly from the measurable transceive phase arg(B +1 B −1 ) in the head. Validation for a human head excited by a 7 T‐birdcage coil using simulations and measurements showed that it is possible to measure in vivo conductivity patterns in the brain using B 1+ phase information only. Conductivity contrast between different brain tissues is clearly observed. The measured mean values for white matter, gray matter and cerebrospinal fluid differed 54%, 26%, and −13% respectively from literature values. The proposed method for B 1+ phase measurements is very suited for in vivo applications, as the measurement is short (less than a minute per imaged slice) and exposes the patient to low RF power, contrary to earlier proposed approaches. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.
Lymphocyte traffic and homing in autoimmune thyroid disorders.

Human autoimmune thyroid disorders (AITD) – Graves’disease (GD) and Hashimoto’s thyroiditis (HT) – arecharacterized by reactivity to self thyroid antigens,which may be expressed as destructive inﬂammatory oranti-receptor autoimmune diseases (1–3). In AITD, theautoimmune process is probably initiated by theactivation of autoreactive T cells by an MHC II/selfantigen complex and a co-stimulatory signal thatenables full activation of T cells (1). T cell activation isfollowed by the expression of cell surface antigens andcell adhesion molecules that allows the homing ofimmune cells onto their target organs (1, 2). Thisinvited commentary emphasizes the major eventsregulating lymphocyte trafﬁc in AITD resulting intargeting of circulating lymphocytes to the targetorgans: the thyroid and the orbit. The role of adhesionmolecules in regulating leukocyte localization in AITDwill also be reviewed in a broader perspective.
Cross-cultural adaptation and translation of two pain assessment tools in children and adolescents.

OBJECTIVE To translate, back-translate and cross-culturally adapt the content of the FLACC (Face, Legs, Activity, Cry, Consolability) and Faces Pain Scale-Revised (FPS-R) scales for the evaluation of pain in Brazilian young students and adolescents. METHODS The original scales in English were translated into Brazilian Portuguese. Scales thus obtained were back translated and reviewed. Cross-cultural adaptation included the submission of the reviewed version of the scales to 12 experts to obtain data on comprehensibility, appropriateness and acceptability. A pretest was carried out in a convenience sample (20 patients and 22 health care professionals) to assess the content of the scales. The cancer patients, 7-17 years of age, were receiving care at the outpatient department or in the pediatric ward of the National Cancer Institute. RESULTS After inclusion of the recommendations made by the different professionals who participated in the processes of translation, back-translation and content evaluation of the scales, pretesting showed that 90% and 100% of participants, respectively, understood the content of the scales; the mean score for comprehension ranged from 8.8 to 10.0 in a scale ranging from 1 to 10, with higher scores indicating better understanding. CONCLUSIONS Both scales were found to be easily comprehensible for the evaluation of pain in Brazilian children and adolescents with cancer.
The Relationship Between Balance Confidence and Cognitive Motor Interference in Individuals With Multiple Sclerosis

ABSTRACT Gait and cognitive impairments are compounded when performed simultaneously in individuals with multiple sclerosis (MS), and this is termed cognitive-motor interference (CMI). The authors examined whether CMI is related to balance confidence in individuals with MS. They hypothesized that individuals with low balance confidence would exhibit greater CMI possibly indicating a behavioral modification during dual task conditions. Thirty-four individuals with MS completed Activity-specific Balance Confidence (ABC) scale and a cognitive assessment as well as single and dual task walking trials at a comfortable pace. CMI was calculated as the percent change in walking velocity and cognitive task performance from single- to dual-task conditions and termed dual-task cost (DTC). A correlation analysis was performed to determine the relationships between DTCs of gait and cognitive performance and ABC scores. The correlation analysis revealed no significant association between ABC and DTC of walking velocity (p > .05). A significant relationship between balance confidence and DTCs of cognition was observed. The observed relationships suggest individuals with MS tend to alter their cognitive performance rather than manipulating their gait when confronted with a dual task. Overall, the findings partially support a behavioral explanation of CMI in individuals with MS.
Glyoxalase Activity of Liver from Rats Fed p-Dimethylaminoazobenzene

Reduced glutathione (GSH) is required as coenzyme (12). Since Reaction A is catalyzed at a rate that, within certain limits, is independent of the substrate concentration (18), it belongs to the class of "zero order" reactions, of which the succinoxidase system is a type. Glyoxalase is found in practically all tissues, and in the case of animal tissues it is present in especially high concentrations in liver, kidney, and erythrocytes (2, 19). Notwithstanding the features mentioned above the glyoxalase system has as yet no known function in our schemes of intermediary metabolism. For a long time it was thought that this system was important in glycolysis by serving to convert methylglyoxal, formed presumably from hexosediphosphate, to lactic acid. However, with the following observations, the role of the glyoxalase system has become obscure:
Profile of immunoglobulin heavy chain variable gene repertoires and highly selective detection of malignant clonotypes in acute lymphoblastic leukemia

The predominant B cell immunoglobulin heavy chain variable gene (IgH‐V) usage and the uniquely rearranged, clonotype‐specific variable‐diversity‐joining region gene (VDJ) sequences were identified in patients with B cell acute lymphoblastic leukemia (B‐ALL) using a novel DNA‐based gene amplification strategy. The approach allows a thorough and sensitive determination of the number of clonal leukemic IgH rearrangements and their precise V gene usage. This strategy may be applied in the detection of minimal residual disease, in surveillance after induction of disease‐free states, and in analyzing the effectiveness of purging autologous bone marrow of malignant clones. An initial primary polymerase chain reaction (PCR), directed by an IgH‐J generic primer and a complement of family‐specific IgH‐V primers, defined the major B cell IgH‐V gene usage. Use of an IgH‐J generic primer supplanted the use of a constant region primer anchor and thus eliminated the need to target mRNA by the traditional RNA reverse transcription–PCR amplification method. Monoclonality of rearranged VDJ bands was further substantiated by high‐resolution denaturant gel electrophoretic analysis. The predominant amplified bands were subcloned and sequenced. By sequencing through VDJ juxtaposed regions, that is, the third complementarity‐determining region, clonotype‐specific primers were developed and used in a secondary clonotype primer‐directed PCR (CPD‐PCR) to detect, with extreme sensitivity and specificity, a unique B cell clone. Analysis of the products of the CPD‐PCR permitted the detection of a single malignant cell among 1 million polyclonal cells and superseded the constraints of prior studies that have provided a limited evaluation of family variable gene repertoire usage. Leukemic clonal rearrangements were detected in 100% of the eight cases of pediatric and two cases of adult B‐ALL studied. Two or more clonal IgH‐VDJ amplified sequences were observed in 50% of the B‐ALL bone marrows analyzed. In two cases, clonotype‐specific oligodeoxynucleotide primers, derived from B‐ALL VDJ sequences, directed the secondary CPD‐PCR, and disease activity was monitored after chemotherapy and allogeneic bone marrow transplantation. J. Leukoc. Biol. 57: 856–864; 1995.
Immunohistochemical analysis of the immune reaction in the nervous system in paraneoplastic encephalomyelitis

We examined frozen sections of frontal cortex, medulla, and dorsal root ganglia from a patient with small-cell lung cancer and paraneoplastic encephalomyelitis, involving the medulla and dorsal root ganglia, with a panel of antibodies reactive for IgG, IgM, C3, B cells, T cells, T cell subsets, macrophages, and class I and II (HLA-DR) major histocompatibility complex (MHC) antigens. We detected an antineuronal antibody (anti-Hu) in the serum and CSF of the patient and found deposits of IgG in the periphery of some neurons in dorsal root ganglia. The infiltrates were almost exclusively T cells with a predominance of CD8-positive cells. Neurons did not express class I or II MHC antigens. Satellite cells in the dorsal root ganglia from the patient and controls were HLA-DR-positive. These data indicate that CD8-positive T cells predominate in the inflammatory infiltrates of paraneoplastic encephalomyelitis. IgG deposits may be relevant in the damage of the sensory neurons.
A Branch and Bound Algorithm for a Class of Biobjective Mixed Integer Programs

Most real-world optimization problems are multiobjective by nature, involving noncomparable objectives. Many of these problems can be formulated in terms of a set of linear objective functions that should be simultaneously optimized over a class of linear constraints. Often there is the complicating factor that some of the variables are required to be integral. The resulting class of problems is named multiobjective mixed integer programming (MOMIP) problems. Solving these kinds of optimization problems exactly requires a method that can generate the whole set of nondominated points (the Pareto-optimal front). In this paper, we first give a survey of the newly developed branch and bound methods for solving MOMIP problems. After that, we propose a new branch and bound method for solving a subclass of MOMIP problems, where only two objectives are allowed, the integer variables are binary, and one of the two objectives has only integer variables. The proposed method is able to find the full set of nondominat.