Miracle-dz/UniFAR-FTUs huggingface dataset:
Down-regulation of IL-12 by topical corticosteroids in chronic atopic dermatitis.

BACKGROUND Previous reports indicate that IL-12 may be involved in the development of chronic atopic dermatitis. However, the cellular source of this cytokine in the skin and its expression during successful treatment of the skin lesions are not known. OBJECTIVE Our purpose was to delineate the precise in situ localization of IL-12 and its modulation under topical treatment with corticosteroids. METHODS Skin biopsy specimens were obtained from nonlesional, lesional, and treated skin of patients with atopic dermatitis and from healthy skin of nonatopic control subjects. IL-12 was investigated by real-time quantitative reverse transcriptase-PCR and immunohistochemistry. RESULTS Expression of IL-12 p40 mRNA was significantly enhanced in lesional skin from atopic dermatitis and strongly down-regulated after treatment with topical corticosteroids for 9 to 10 days. In contrast, similar levels of IL-12 p35 transcripts were found in all the samples without any significant differences after treatment. In addition, a strong enhancement of IL-12 immunoreactivity was observed on the mononuclear cell infiltrate in the lesional skin samples, which was also markedly reduced after treatment. IL-12 immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells and macrophages as well as some Langerhans cells. CONCLUSION Our data suggest that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for up-regulating production of IFN-gamma in chronic lesions and strengthen the idea that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis.
Advances in Open Microsurgery for Cerebral Aneurysms.

BACKGROUND Endovascular techniques introduced strong extrinsic forces that provoked reactive changes in aneurysm surgery. Microsurgery has become less invasive, more appealing to patients, lower risk, and efficacious for complex aneurysms, particularly those unfavorable for or failing endovascular therapy. OBJECTIVE To review specific advances in open microsurgery for aneurysms. METHODS A university-based, single-surgeon practice was examined for the use of minimally invasive craniotomies, surgical management of recurrence after coiling, the use of intracranial-intracranial bypass techniques, and cerebrovascular volume-outcome relationships. RESULTS The mini-pterional, lateral supraorbital, and orbital-pterional craniotomies are minimally invasive alternatives to standard craniotomies. Mini-pterional and lateral supraorbital craniotomies were used in one-fourth of unruptured patients, increasing from 22% to 28%, whereas 15% of patients underwent orbital-pterional craniotomies and trended upward from 11% to 20%. Seventy-four patients were treated for coil recurrences (2.3% of all aneurysms) with direct clip occlusion (77%), clip occlusion after coil extraction (7%), or parent artery occlusion with bypass (16%). Intracranial-intracranial bypass (in situ bypass, reimplantation, reanastomosis, and intracranial grafts) transformed the management of giant aneurysms and made the surgical treatment of posterior inferior cerebellar artery aneurysms competitive with endovascular therapy. Centralization maximized the volume-outcome relationships observed with clipping. CONCLUSION Aneurysm microsurgery has embraced minimalism, tailoring the exposure to the patient's anatomy with the smallest possible craniotomy that provides adequate exposure. The development of intracranial-intracranial bypasses is an important advancement that makes microsurgery a competitive option for complex and recurrent aneurysms. Trends toward centralizing aneurysm surgery in tertiary centers optimize results achievable with open microsurgery.
Multiple substrate binding sites in the ribozyme from Bacillus subtilis RNase P.

The ribozyme from Bacillus subtilis RNase P (P RNA) recognizes an RNA structure consisting of the acceptor stem and the T stem‐loop of tRNA substrates. An in vitro selection experiment was carried out to obtain potential RNA substrates that may interact with the P RNA differently from the tRNA substrate. Using a P RNA‐derived ribozyme that contains most, if not all, of the structural elements thought to be involved in active site formation of P RNA, but lacks the putative binding site for the T stem‐loop of tRNA, a single RNA substrate was isolated after nine rounds of selection. This RNA is a competent substrate for the ribozyme used in selection as well as for the full‐length P RNA. Biochemical characterization shows that this selected substrate interacts at a different site compared with the tRNA substrate. The selection experiment also identified a self‐cleaving RNA seemingly different from other known ribozymes. These results indicate that a biological ribozyme can contain different binding sites for different RNA substrates. This alternate binding site model suggests a simple mechanism for evolving existing ribozymes to recognize RNA substrates of diverse structures.
Cinnamic Acid Derivatives Acting against Aspergillus Fungi.Taq Polymerase I a Potential Molecular Target

Some members of a series of cinnamic acid derivatives possess promising inhibitory activities in cellular assays against fungi of the Aspergillus genus. In order to search for a possible molecular target of such compounds, their role as Taq polymerase I inhibitors was studied. Four of the compounds studied displayed IC50 values within the range of those considered active as DNA polymerase inhibitors when searching for new cytotoxic molecules. The results obtained in our molecular modeling study appear to show that the inhibitory activity depends on the presence of a stabilizing interaction between the phenylpropanoid derivatives and the residues Asp610, Thr664, Phe667, Tyr671, and Asp785 located in the active site of Taq polymerase I. Also, it is possible to assert that the polymerization of DNA would be the molecular target of cinnamic acid derivatives with antifungal activity, which correlates with the inhibition of Taq polymerase I and the quantitative descriptor for the lipophilia (ClogP).
A new approach to chromosome-wide analysis of X-linked markers identifies new associations in Asian and European case-parent triads of orofacial clefts

Background GWAS discoveries on the X-chromosome are underrepresented in the literature primarily because the analytical tools that have been applied were originally designed for autosomal markers. Our objective here is to employ a new robust and flexible tool for chromosome-wide analysis of X-linked markers in complex traits. Orofacial clefts are good candidates for such analysis because of the consistently observed excess of females with cleft palate only (CPO) and excess of males with cleft lip with or without cleft palate (CL/P). Methods Genotypes for 14,486 X-chromosome SNPs in 1,291 Asian and 1,118 European isolated cleft triads were available from a previously published GWAS. The R-package HAPLIN enables genome-wide–level analyses as well as statistical power simulations for a range of biologic scenarios. We analyzed isolated CL/P and isolated CPO for each ethnicity in HAPLIN, using a sliding-window approach to haplotype analysis and two different statistical models, with and without X-inactivation in females. Results There was a larger number of associations in the Asian versus the European sample, and similar to previous reports that have analyzed the same GWAS dataset using different methods, we identified associations with EFNB1/PJA1 and DMD. In addition, new associations were detected with several other genes, among which KLHL4, TBX22, CPXCR1 and BCOR were noteworthy because of their roles in clefting syndromes. A few of the associations were only detected by one particular X-inactivation model, whereas a few others were only detected in one sex. Discussion/Conclusion We found new support for the involvement of X-linked variants in isolated clefts. The associations were specific for ethnicity, sex and model parameterization, highlighting the need for flexible tools that are capable of detecting and estimating such effects. Further efforts are needed to verify and elucidate the potential roles of EFNB1/PJA1, KLHL4, TBX22, CPXCR1 and BCOR in isolated clefts.
Intraoperative Imaging of Positron Emission Tomographic Radiotracers Using Cerenkov Luminescence Emissions

Imaging the location and extent of cancer provides invaluable information before, during, and after surgery. The majority of “image-guided” methods that use, for example, positron emission tomography (PET) involve preoperative imaging and do not provide real-time information during surgery. It is now well established that the inherent optical emissions (Cerenkov radiation) from various β-emitting radionuclides can be visualized by Cerenkov luminescence imaging (CLI). Here we report the full characterization of CLI using the positron-emitting radiotracer 89Zr-DFO-trastuzumab for target-specific, quantitative imaging of HER2/neu-positive tumors in vivo. We also provide the first demonstration of the feasibility of using CLI for true image-guided, intraoperative surgical resection of tumors. Analysis of optical CLIs provided accurate, quantitative information on radiotracer biodistribution and tissue uptake that correlated well with the concordant PET images. CLI, PET, and biodistribution studies revealed target-specific uptake of 89Zr-DFO-trastuzumab in BT-474 (HER2/neu positive) versus MDA-MB-468 (HER2/neu negative) xenografts in the same mice. Competitive inhibition (blocking) studies followed by CLI also confirmed the in vivo immunoreactivity and specificity of 89Zr-DFO-trastuzumab for HER2/neu. Overall, these results strongly support the continued development of CLI as a preclinical and possible clinical tool for use in molecular imaging and surgical procedures for accurately defining tumor margins.
Dendritic Cells Transmit Human Immunodeficiency Virus Type 1 to Monocytes and Monocyte-Derived Macrophages

ABSTRACT Previous studies have shown that human immunodeficiency virus type 1 (HIV-1) exploits dendritic cells (DC) to replicate and spread among CD4+ T cells. To explain the predominance of non-syncytium-inducing (NSI) over syncytium-inducing (SI) strains during the initial viremia of HIV, we investigated the ability of blood monocyte (Mo)-derived DC to transmit HIV-1 to CD4+ cells of the monocytoid lineage. First, we demonstrate that in our system, DC are able to transmit NSI strains, but not SI strains, of HIV-1 to fresh blood Mo and to Mo-derived macrophages (MDM). To establish a productive infection, a 10-fold-lower amount of virus was necessary for DC-mediated transmission of HIV-1 to Mo than in case of cell-free infection. Second, immature CD83− DC (imDC) transmit virus to Mo and MDM with higher efficacy compared to mature CD83+DC (maDC); this finding is in contrast to data previously obtained with CD4+ T cells. Third, maturation from imDC to maDC efficiently silenced expression of β2-integrins CD11b, CD11c, and CD18 by maDC. Moreover, monoclonal antibody against CD18 inhibited transmission of HIV-1 from imDC to Mo. We propose that the adhesion molecules of the CD11/CD18 family, involved in cell-cell interactions of DC with the microenvironment, may play a major role in imDC-mediated HIV-1 infection of Mo and MDM.
Nonesterified galacturonic acid sequence homology of pectins.

The methyl ester distribution of pectins was studied with a recently developed enzymatic method. Endopolygalacturonase of Kluyveromyces fragilis was used to degrade pectin and the composition of the degradation products was determined with high-performance anion-exchange chromatography at pH 5. Three characteristics indicative for the distribution of nonesterified galacturonic acid residues were obtained: the percentage of nonesterified galacturonic acid residues liberated of the total number of nonesterified galacturonic acid in the undigested polymer, the proportion of nonesterified mono-, di-, and trigalacturonic acid released, and the ratio of the sum of the peak areas of methyl ester containing oligomers divided by the sum of the peak areas of the nonesterified oligomers detected. From these characteristics and the degree of methyl esterification, the mean sequence similarity of the methyl ester distributions was calculated. Computational techniques commonly employed in the determination of the sequence similarity of DNA and proteins were used to discriminate the various types of distributions found and to construct a distance tree. In general, three types of methyl ester distributions could be discerned in pectin: random, high, and blockwise esterified. This report is the first to describe a parametric approach for the comparison of the substituent distribution in polymers. The importance of this novel approach in the study of the methyl ester distribution and the functional properties of pectin is discussed.
Epidemiology of osteoarthritis: an update

Purpose of reviewAs the most common arthritis and a leading cause of chronic disability, osteoarthritis is associated with substantial cost to the individual and to society. Epidemiologic studies have supplied, in addition to incidence, prevalence and risk factor data, much of what is known about the natural history of osteoarthritis. Recent findingsEspecially given the anticipated increase in osteoarthritis prevalence, the need to identify risk factors for incident osteoarthritis, osteoarthritis progression, osteoarthritis-associated physical function decline, and disability is a high priority. As this review illustrates, the emphasis has shifted in osteoarthritis epidemiology towards the identification of risk factors for osteoarthritis progression rather than incidence. SummarySeveral risk factors for progression are emerging, many of which are impairments or pathology in the local joint organ environment. This shift in focus relates in part to the concept that local risk factors might ultimately be targeted to delay osteoarthritis progression or to enhance the effect of a disease-modifying drug.
Encapsulation of p‐THPP into Nanoparticles: Cellular Uptake, Subcellular Localization and Effect of Serum on Photodynamic Activity ¶

The cellular uptake, localization and efflux of meso‐tetra‐(4‐hydroxyphenyl)porphyrin (p‐THPP)–loaded nanoparticles have been studied in EMT‐6 tumor cells. The effect of blood serum on photocytotoxicity has also been evaluated. Sub–130 nm nanoparticles based on poly(d,l‐lactide‐co‐glycolide) (PLGA) (50:50 PLGA and 75:25 PLGA) and poly(d,l‐lactide) (PLA) have been examined in comparison with free p‐THPP. For all formulations tested, uptake of photosensitizer into cells was dependent on concentration, time and temperature. All nanoparticulate formulations accumulated within the cells to a greater extent relative to free drug. Indeed, the fluorescence intensities measured on EMT‐6 cells treated with p‐THPP–loaded nanoparticulate formulations were at least two‐fold higher than those obtained with free dye. Furthermore, the highest accumulation level was found with PLGA nanoparticles. Fluorescence microscopy revealed that endocytosis is a major intracellular sequestration mechanism of these p‐THPP formulations and that these were localized into early and late endosomes. The efflux study performed on both nonirradiated and irradiated cells indicated that free and p‐THPP–loaded nanoparticles gradually escaped from EMT‐6 cells as a function of time. This was more pronounced when cells were treated with nanoparticles and irradiated, reflecting important photodamage. It was also found that regardless of the nanoparticulate formulations tested, p‐THPP photocytotoxicity was influenced by the concentration of the serum.
Muscle activities during asymmetric trunk angular accelerations

The objective of this study was to characterize trunk muscle and intra‐abdominal pressure behavior during extensions of the trunk when angular trunk acceleration levels and trunk twist were varied during lifting exertions. Since force is related to acceleration, it was believed that changes in trunk acceleration would cause activity changes in the muscles and abdominal cavity pressurization mechanics that load the spine during manual materials handling tasks. The electromyographic activity of 10 trunk muscles and intra‐abdominal pressure were studied in 39 subjects as they moved their trunks under high, medium, and low constant angular acceleration conditions. The results indicated that almost all the muscles were affected by acceleration and asymmetry. Muscle activities of up to 50% of maximum were observed even though a minimal amount of torque was being produced by the back. Coactivation of muscles was also apparent. Muscles located at the greatest distances from the spine such as the latissimus dorsi and oblique groups, increased their activities the most as trunk acceleration increased. Muscles located farthest from the spine also played an important role as the trunk became more asymmetric. Intra‐abdominal pressure changed minimally over the test conditions. The nature of these responses and their impact on spine loading are discussed.
Hepatitis C virus replicative levels and efficiency of genotyping by specific PCR and antibody assay

We studied factors which influence the detection of hepatitis C virus genotypes by the group-specific PCR of the sequence within the core region gene and by the newly developed genotype-specific NS4 antibody assay. Genotyping was performed on 75 hepatitis C virus carriers in Japan, where patients with hepatitis C viremia are exclusively infected with genotype 1b, 2a, and 2b. PCR failed to identify genotypes in 8 (11%) patients, whereas 12 (16%) patients, including the 8 patients mentioned above, could not be genotyped by the serological assay. Serological genotypes showed almost complete agreement with those found by the PCR except that double infection was revealed in only two of the eight patients serologically judged to be coinfected with genotypes 1 and 2. In each assay, disease activity and levels of viremia assessed by a competitive reverse transcription PCR assay were significantly lower in patients infected with untypeable isolates than in those infected with typeable ones (P < 0.01). The PCR could identify the genotypes of isolates from all 64 patients with levels of viremia of > or = 10(6) copies/ml, and the genotype-specific antibody responses were found in 60 (94%) patients. In contrast, isolates from only 3 (27%) of 11 patients with low levels of viremia (< 10(6) copies/ml) could be genotyped by the PCR (P < 0.00001), and these patients showed the genotype-specific antibody responses (P < 0.00001). These findings suggest that low levels of hepatitis C virus replication may reduce the efficiency of genotyping by serological assay as well as by PCR.
Bcl‐2 protects TK6 cells against hydroquinone‐induced apoptosis through PARP‐1 cytoplasm translocation and stabilizing mitochondrial membrane potential

B cell leukemia/lymphoma‐2 (Bcl‐2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl‐2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)‐induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration‐dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker γ‐H2AX, and production of the DNA damage‐responsive enzyme poly(ADP‐ribose)polymerase‐1 (PARP‐1). Exposure of TK6 cells to HQ leads to an increase in Bcl‐2 and co‐localization with PARP‐1 in the cytoplasm. Inhibition of Bcl‐2 using the BH3 mimetic, ABT‐737, suppressed the PARP‐1 nuclear to cytoplasm translocation and sensitized TK6 cells to HQ‐induced apoptosis through depolarization of the MMP. Western blot analysis indicated that ABT‐737 combined with HQ increased the levels of cleaved PARP and γ‐H2AX, but significantly decreased the level of P53. Thus, ABT‐737 can influence PARP‐1 translocation and induce apoptosis via mitochondria‐mediated apoptotic pathway, independently of P53. In addition, we found that knockdown of PARP‐1 attenuated the HQ‐induced production of cleaved PARP and P53. These results identify Bcl‐2 as a protective mediator of HQ‐induced apoptosis and show that upregulation of Bcl‐2 helps to localize PARP‐1 to the cytoplasm and stabilize MMP. Environ. Mol. Mutagen. 59:49–59, 2018. © 2017 Wiley Periodicals, Inc.
Type I Interferon Mimetics Bypass Vaccinia Virus Decoy Receptor Virulence Factor for Protection of Mice against Lethal Infection

ABSTRACT The canonical model of interferon (IFN) signaling focuses solely on the activation of STAT transcription factors which, according to the model, are initiated by the singular event of cross-linkage of the receptor extracellular domain by the IFN. The IFN has no further function beyond this. The model thus provides no approach to circumventing poxviruses decoy receptors that compete with the IFN receptors for IFNs. This simple event has allowed smallpox virus to decimate human populations throughout the ages. We have developed a noncanonical model of IFN signaling that has resulted in the development of small peptide mimetics to both types I and II IFNs. In this report, we focus on a type I IFN mimetic at positions 152 to 189, IFN-α1(152–189), which corresponds to the C terminus of human IFN-α1. This mimetic functions intracellularly and is thus not recognized by the B18R vaccinia virus decoy receptor. Mimetic synthesized with an attached palmitate (lipo-) for cell penetration protects mice from a lethal dose of vaccinia virus, while the parent IFN-α1 is ineffective. Unlike IFN-α1, the mimetic does not bind to the B18R decoy receptor. It further differs from the parent IFN in that it lacks the toxicity of weight loss and bone marrow suppression in mice while at the same time possessing a strong adjuvant effect on the immune system. The mimetic is thus an innate and adaptive immune regulator that is evidence of the dynamic nature of the noncanonical model of IFN signaling, in stark contrast to the canonical or classical model of signaling.
Mortality Patterns in Coptotermes gestroi (Blattodea: Rhinotermitidae) Following Horizontal Transfer of Nonrepellent and Repellent Insecticides: Effects of Donor:Recipient Ratio and Exposure Time

ABSTRACT The donor: recipient ratio and the time of donor exposure to termiticide required for maximal toxicant transfer among termites are crucial information for the development of termite management plans. Most of the available information on termiticide toxicity came from temperate zonal termite species, whereas little is known about tropical Asian species. In this study, mortality patterns of recipient termites, Coptotermes gestroi (Wasmann) subjected to seven formulated insecticide exposures under different donor exposure times and donor: recipient ratios were examined. For fipronil, lethal transfer was not affected by donor exposure time but was affected by the mixing ratio. The moderate-to-less toxic termiticides (imidacloprid, indoxacarb, bifenthrin, chlorfenapyr, and chlorantraniliprole) required long exposure time and a high mixing ratio to ensure maximal uptake by recipient workers compared with fipronil. For chlorantraniliprole and chlorfenapyr, donors must constitute >30% of the donor-recipient mixture to achieve 100% mortality of the recipient workers. Among the termiticides tested, cyantraniliprole was the most fast-killing insecticide against C. gestroi. The potential of lethal transfer among recipient termites does not necessarily require both high donor exposure time and a high mixing ratio, but the toxicity of a given termiticide against termites must be factored in to achieve colony elimination.