Miracle-dz/UniFAR-FTUs huggingface dataset:
DynaDock: A new molecular dynamics‐based algorithm for protein–peptide docking including receptor flexibility

Molecular docking programs play an important role in drug development and many well‐established methods exist. However, there are two situations for which the performance of most approaches is still not satisfactory, namely inclusion of receptor flexibility and docking of large, flexible ligands like peptides. In this publication a new approach is presented for docking peptides into flexible receptors. For this purpose a two step procedure was developed: first, the protein–peptide conformational space is scanned and approximate ligand poses are identified and second, the identified ligand poses are refined by a new molecular dynamics‐based method, optimized potential molecular dynamics (OPMD). The OPMD approach uses soft‐core potentials for the protein–peptide interactions and applies a new optimization scheme to the soft‐core potential. Comparison with refinement results obtained by conventional molecular dynamics and a soft‐core scaling approach shows significant improvements in the sampling capability for the OPMD method. Thus, the number of starting poses needed for successful refinement is much lower than for the other methods. The algorithm was evaluated on 15 protein–peptide complexes with 2–16mer peptides. Docking poses with peptide RMSD values <2.10 Å from the equilibrated experimental structures were obtained in all cases. For four systems docking into the unbound receptor structures was performed, leading to peptide RMSD values <2.12 Å. Using a specifically fitted scoring function in 11 of 15 cases the best scoring poses featured a peptide RMSD ≤2.10 Å. Proteins 2010. © 2009 Wiley‐Liss, Inc.
Analysis of interleukin-activated human gingival fibroblasts: modulation of chemokine responses by female hormones.

BACKGROUND The female sex hormones are known to affect the response of numerous tissues to an immune challenge. Because such hormones normally fluctuate during puberty, pregnancy, and the menstrual cycle, more information about the hormonal modulation of such responses in the oral cavity is needed. Gingival fibroblasts (GF), major components of the oral tissues, are potentially sources for inflammatory mediators. METHODS Macroarrays specific for cytokines and related proteins were used to examine the regulation of gene expression in GF under serum-free, resting conditions, after immune challenge with interleukin-1beta (IL-1beta), and in the presence of IL-1beta plus a progestin, +/-17beta-estradiol. Additional studies used enzymelinked immunosorbent assays (ELISAs) to test for secreted chemokines after the same treatments. RESULTS Of the 392 genes on the macroarray, 66 were up- or downregulated at least 2-fold relative to the unstimulated control in an average of six different sub-lines. Chemokines represented the largest group (18%) of these regulated genes. Numerous genes whose expression was upregulated by IL-1beta were modulated downward by IL-1beta plus progestin, +/-17beta-estradiol. Measurements of the secretion of IL-8, a CXC chemokine, and MCP-1, a CC chemokine, confirmed the inhibitory effect of a progestin on these genes. CONCLUSIONS Gingival fibroblasts are active participants in the immune response in the oral cavity, and may potentially produce many chemokine signals after exposure to IL-1beta. GF can attract neutrophils, monocytes, eosinophils, and fibroblasts to the area of injury, and aid in the wound repair process. The concentration of female sex hormones, especially progestin, may significantly affect these signaling systems.
Myocardial Metabolism in Type 1 Diabetic Patients Without Coronary Artery Disease

Myocaridal exchange of metabolic substrates was investigated in eight Type 1 diabetic patients with angiographically normal coronary arteries and seven normal control subjects, after an overnight fast. Simultaneous samples of arterial and coronary sinus blood were collected for analysis of the major metabolic substrates. Myocardial blood flow was measured by the thermodilution technique. Although the Type 1 patients were hyperglycaemic (10.0 ± 2.0 (± SE) mmol I‐1) myocardial glucose uptake was lower than in control subjects (27 ± 6 vs 42 ± 5 μmol min‐1 1.73 m‐2, p < 0.05). The net balance of lactate and pyruvate across the myocardium showed a net release in Type 1 patients (13.4 ± 2.7 μmol min‐1 1.73 m‐2 and 1.3 ± 0.2 μmol min‐1 1.73 m‐2, respectively) and a net uptake in control subjects (2.2 ± 0.7 μmol min‐1 1.73 m‐2 and 3.5 ± 0.3 μmol min‐1 1.73 m‐2, both p < 0.01). Myocardial uptake of ketone bodies was significantly higher in diabetic patients (37.0 ± 6.3) μmol min‐1 1.73 m‐2) than in control subjects (10.1 ± 3.4 μmol min‐1 1.73 m‐2, p < 0.01). Non‐esterified fatty acid (NEFA) uptake was significantly greater in the diabetic patients than in control subjects (44.1 ± 7.0) vs 24.1 ± 5.1 μmol min‐1 1.73 m‐2, p < 0.01). Net balance of glucose, lactate, and pyruvate across the myocardium was inversely and significantly related to that of NEFAs and ketone bodies (p < 0.01). Myocardial carbohydrate uptake is markedly impaired in Type 1 diabetic patients with angiographically intact coronary vessels. Ketones and NEFA represent the major fuel for the diabetic myocardium. Thus, in diabetes, myocardial lactate metabolism may be profoundly altered independently of coronary artery disease.
Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis

Multiple sclerosis is an inflammatory disease of the central nervous system characterized by inflammation, demyelination, axonal degeneration and accumulation of neurological disability. Previously, we demonstrated that stem cells constitute a possible endogenous source for remyelination. We now addressed the question of whether neurogenesis can occur in neuroinflammatory lesions. We demonstrated that, in experimental autoimmune encephalomyelitis, induced in rats 1,1′‐dioctadecyl‐6,6′‐di(4sulphopentyl)‐3,3,3′,3′tetramethylindocarbocyanin(DiI)‐labelled ependymal cells not only proliferated but descendants migrated to the area of neuroinflammation and differentiated into cells expressing the neuronal markers β‐III‐tubulin and NeuN. Furthermore, these cells were immunoreactive for bromodeoxyuridine and PCNA, markers for cells undergoing cell proliferation. Using the whole‐cell patch‐clamp technique on freshly isolated 1, DiI‐labelled cells from spinal cord lesions we demonstrated the ability of these cells to fire overshooting action potentials similar to those of immature neurones. We thus provide the first evidence for the initiation of neurogenesis in neuroinflammatory lesions in the adult spinal cord.
Dominant Role for TL1A/DR3 Pathway in IL-12 plus IL-18-Induced IFN-γ Production by Peripheral Blood and Mucosal CCR9+ T Lymphocytes1

The TNF-like cytokine TL1A augments IFN-γ production by anti-CD3 plus anti-CD28 and IL-12/IL-18-stimulated peripheral blood (PB) T cells. However, only a small subset of PB T cells respond to TL1A stimulation with IFN-γ production. PB CCR9+ T cells represent a small subset of circulating T cells with mucosal T cell characteristics and a Th1/Tr1 cytokine profile. In the current study, we show that TL1A enhanced IFN-γ production by TCR- or CD2/CD28-stimulated CCR9+CD4+ PB T cells. However, TL1A had the most pronounced effect on augmenting IFN-γ production by IL-12/IL-18-primed CCR9+CD4+ PB T cells. TL1A enhanced both the percentage and the mean fluorescence intensity of IFN-γ in CCR9+CD4+ T cells as assessed by intracellular cytokine staining. IL-12 plus IL-18 up-regulated DR3 expression in CCR9+CD4+ T cells but had negligible effect on CCR9−CD4+ T cells. CCR9+CD4+ T cells isolated from the small intestine showed a 37- to 105-fold enhancement of IFN-γ production when TL1A was added to the IL-12/IL18 cytokine combination. Cell membrane-expressed TL1A was preferentially expressed in CCR9+CD4+ PB T cells, and a blocking anti-TL1A mAb inhibited IFN-γ production by cytokine-primed CCR9+CD4+ T cells by ∼50%. Our data show that the TL1A/DR3 pathway plays a dominant role in the ultimate level of cytokine-induced IFN-γ production by CCR9+ mucosal and gut-homing PB T cells and could play an important role in Th1-mediated intestinal diseases, such as Crohn’s disease, where increased expression of IL-12, IL-18, TL1A, and DR3 converge in the inflamed intestinal mucosa.
Annual rhythms of luteinizing hormone, follicle-stimulating hormone, prolactin and testosterone in the serum of male rhesus monkeys.

Six male rhesus monkeys were kept under rigidly controlled conditions for 1-2 years. During August of the first year a thyrotrophin releasing hormone (TRH) test was performed on each of the monkeys by giving 10 microgram TRH as a bolus injection. Significantly increased serum prolactin levels occurred 15 min after the injection. After a training period of 2 months, during which blood samples were collected every other day by puncture of the saphenous vein, blood was collected three times a week for 14 months. Serum levels of prolactin, LH, FSH and testosterone were measured by radioimmunoassay. Mean serum prolactin levels increased significantly during June, July and August in all six animals. Peak levels were observed in August and September and then levels declined gradually to reach a minimum in April and May. Mean serum testosterone levels closely paralleled the annual pattern of prolactin. Mean serum LH levels significantly decreased during the time when mean serum prolactin and testosterone levels were increasing and they increased again at the time of decreasing mean prolactin levels, i.e. mean serum LH and prolactin were negatively correlated. In individual monkeys, however, a rigid negative correlation between serum prolactin and LH could not be demonstrated. Mean serum FSH levels did not change significantly.
Lymphoproliferative disorders and other tumors complicating immunodeficiencies.

Lymphoproliferative disorders and selected carcinomas which occur as complications of primary or secondary immunodeficiencies are frequently fatal. The incidence rates of these cancers vary from 1% to as high as 25% among specific groups of persons with primary (genetically-determined) immunodeficiencies as well as acquired immunodeficiencies, including immunosuppressed organ transplant recipients and individuals infected with HIV. Lymphoproliferative disorders including Epstein Barr virus (EBV) associated B cell lymphoproliferative disease (BLPD) and Hodgkin's disease represent the predominant category of tumors in both primary and acquired immunodeficiencies. EBV is an important cofactor common to many, but not all, B cell "lymphomas. " Immunodeficient individuals who are at risk for developing EBV BLPD may demonstrate both inadequate immune responses to the virus as well as generalized immunoregulatory dysfunction reflected as imbalances in cytokine production favoring the proliferation of transformed B lymphocytes. Historically, the success of treatment of lymphoproliferative disorders in immunodeficiencies with conventional multi agent chemotherapies and/or radiation has been limited by unfavorable tumor response rates and high morbidity and mortality related to intercurrent opportunistic infections. With improvements in supportive care and the use of recombinant biologic response modifiers such as alpha interferon and/or other immunotherapies to treat EBV BLPD, survival of immunodeficient hosts following tumor diagnosis may improve. In addition to lymphoproliferative disorders, patients with congenital immunodeficiencies associated with IgA deficiency (including ataxia telangiectasia and Common Variable Immunodeficiency) are at increased risk for gastrointestinal carcinomas. Early detection and surgical excision of such tumors can result in prolonged survival in such patients.
A Generalized Additive Model Combining Principal Component Analysis for PM2.5 Concentration Estimation

As an extension of the traditional Land Use Regression (LUR) modelling, the generalized additive model (GAM) was developed in recent years to explore the non-linear relationships between PM2.5 concentrations and the factors impacting it. However, these studies did not consider the loss of information regarding predictor variables. To address this challenge, a generalized additive model combining principal component analysis (PCA–GAM) was proposed to estimate PM2.5 concentrations in this study. The reliability of PCA–GAM for estimating PM2.5 concentrations was tested in the Beijing-Tianjin-Hebei (BTH) region over a one-year period as a case study. The results showed that PCA–GAM outperforms traditional LUR modelling with relatively higher adjusted R2 (0.94) and lower RMSE (4.08 µg/m3). The CV-adjusted R2 (0.92) is high and close to the model-adjusted R2, proving the robustness of the PCA–GAM model. The PCA–GAM model enhances PM2.5 estimate accuracy by improving the usage of the effective predictor variables. Therefore, it can be concluded that PCA–GAM is a promising method for air pollution mapping and could be useful for decision makers taking a series of measures to combat air pollution.
Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype.

We analyzed a genetic polymorphism of Fc gamma receptor IIIa (CD16) that is present on position 158 (Phe or Val) in the membrane-proximal, IgG-binding domain. With a polymerase chain reaction-based allele-specific restriction analysis assay we genotyped 87 donors and found gene frequencies of 0.57 and 0.43 for Fc gammaRIIIA-158F and -158V, respectively. A clear linkage was observed between the Fc gammaRIIIA-158F and -48L genotypes on the one hand and the Fc gammaRIIIA-158V and -48H or -48R genotypes on the other hand (chi2 test; P < .001). To determine the functional consequences of this Fc gammaRIIIa-158V/F polymorphism, we performed IgG binding experiments with natural killer (NK) cells from genotyped donors. All donors were also typed for the recently described triallelic Fc gammaRIIIa-48L/R/H polymorphism. NK cells were treated with lactic acid to remove cell-associated IgG. Fc gammaRIIIa(NK)-158F bound significantly less IgG1, IgG3, and IgG4 than did Fc gammaRIIIa(NK)-158V, irrespective of the Fc gammaRIIIa-48 phenotype. Moreover, freshly isolated NK cells from Fc gammaRIIIa-158VV individuals carried significantly more cytophilic IgG than did NK cells from Fc gammaRIIIa-158FF individuals. In addition, CD16 monoclonal antibody (MoAb) MEM154 bound more strongly to Fc gammaRIIIa-158V, compared with -158F, again independently of the Fc gammaRIIIa-48 phenotype. The binding of MoAb B73.1 was not influenced by the Fc gammaRIIIa-158V/F polymorphism, but proved to depend solely on the amino acid present at position 48 of Fc gammaRIIIa. In conclusion, the previously reported differences in IgG binding among the three Fc gammaRIIIa-48L/R/H isoforms are a consequence of the linked, biallelic Fc gammaRIIIa-158V/F polymorphism at amino-acid position 158.
Human Spermatozoa and Temperature: The Elephant in the Room

ABSTRACT Men are notable for low sperm production, relative to that of other large mammals, and often inferior morphology and motility of their spermatozoa. The extent to which temperature plays a role in this picture has been a moot point. However, animal experiments suggest that an increased scrotal temperature of approximately +4°C brought by inguinal clothing has a negative impact on the germinal epithelium and on the epididymis in man. In two animal species with inguinal testes, their transposition to the abdomen, raising the testis temperature by a modest approximate 1.5°C brought reduced sperm production and abnormalities of spermiogenesis (distorted sperm nuclei, shared acrosomes), a picture seen commonly in man alongside morphologically normal spermatids. Reflection of the scrotal epididymis to the abdomen in laboratory animals did not inhibit sperm maturation there, but the consequences of this for other epididymal parameters are mirrored in several features seen in man. In addition to the typically puny form of the human cauda, these include often rapid epididymal sperm transit, rapid capacitation in vitro, a poor sperm reserve (as reflected in the steep decline in sperm numbers in successive ejaculates), and not least, the cauda's failure to maintain the viability of spermatozoa there (reflected in both their mixed potential for motility and the negative outcome of abstinence). Because the number of competent spermatozoa inseminated relates to prompt fertilization and/or incidence of pregnancy in some animal models, the negative effects of scrotal temperature may be an important factor in the need for an average of approximately five cycles of unprotected intercourse in order to establish pregnancy in human females.
Evaluation beschäftigungspolitischer Maßnahmen in Ostdeutschland / An Evaluation of Employment Measures in Eastern Germany

Zusammenfassung Untersucht werden die Beschäftigungseffekte von in Ostdeutschland angewandten Maßnahmen. Gebrauch gemacht wird von ökonometrischen Methoden, die Korrelationen berücksichtigen zwischen Bestimmungsgründen für die Teilnahme an Beschäftigungsmaßnahmen und Determinanten, die die Beschäftigungswahrscheinlichkeit beeinflussen, d.h. lineare Kontrollfunktionen, Instrumentalvariablenschätzer, Random-effects-Schätzer, Pre-Programm-Tests, und Matched-sampling-Methoden sowie eine Kombination finden Berücksichtigung. Die Ergebnisse, die auf Daten des Arbeitsmarkt-Monitors basieren, zeigen, daß die traditionellen Instrumente nach AFG wenig erfolgreich waren. Positive Beschäftigungseffekte lassen sich von Weiterbildungsmaßnahmen, die von Betrieben veranlaßt wurden, identifizieren. Fortbildung und Umschulung, die von den Arbeitsämtern finanziert wird, führt zu keinen einheitlichen Resultaten. Es zeigen sich zunächst negative und später positive Beschäftigungseffekte. Bei Trennung zwischen Frauen und Männern läßt sich dieses Muster nur für letztere feststellen. Auch bei betriebsinterner Fortbildung treten geschlechtspezifische Unterschiede auf. Innerhalb von drei Jahren nach der Maßnahme nehmen bei Männern die positiven Effekte tendenziell zu. Bei Frauen ist der Einfluß am Ende des Zeitraums statistisch nicht mehr gesichert. Summary This article investigates employment effects of short time work, job creation schemes, internal and external training measures sponsered by the public sector or the firms in East Germany. Econometric methods are employed which consider correlations between observed or unobserved determinants to participate in programs and the probability to be employed, unemployed or non-employed: linear control functions, instrumental variable approaches and random effects estimators, pre-program tests, matched sampling methods and a combination. The results based on data of the Labor Market Monitor show that traditional instruments of the AFG are not so successful. Positive employment effects can be identified for external and internal training on the initiative of the firms. The effects of public sector sponsered training programs are mixed. First the effects are negative and later on positive. If it is separated between males and females positive effects can only be detected for the former. While the positive effects of internal training for males have a tendency to increase, for females the effects are insignificant after three periods.
Selective blockade of mGlu5 metabotropic glutamate receptors is hepatoprotective against fulminant hepatic failure induced by lipopolysaccharide and d‐galactosamine in mice

This study was designed to investigate the influence of 2‐methyl‐6‐phenylethynyl pyridine hydrochloride (MPEP), an antagonist of metabotropic glutamate receptor subtype 5, in lipopolysaccharide (LPS) and d‐galactosamine (d‐GalN)‐induced fulminant hepatic failure in mice. Mice were given an intraperitoneal injection of 50 µg kg−1 LPS and 500 mg kg−1 d‐GalN. MPEP (1, 5 and 25 mg kg−1) was administered intraperitoneally 1 h before LPS/d‐GalN injection. Twenty‐four hours after administration of LPS/d‐GalN, plasma was collected and used for biochemical assays. Mice were euthanized and histological analysis and toxicological parameters were carried out in the liver. MPEP, at all doses tested, protected against the increase in aspartate and alanine aminotransferase activities induced by LPS/d‐GalN exposure. Ascorbic acid levels were not altered in all experimental groups. Glutathione S‐transferase activity was increased by administration of LPS/d‐GalN and MPEP did not modify the enzyme activity in mice. MPEP, at the doses of 5 and 25 mg kg−1, was effective in protecting against the decrease in catalase activity caused by LPS/d‐GalN administration in mice. The histological data showed that sections of liver from LPS/d‐GalN‐exposed mice presented extensive injuries. MPEP, at all doses tested, reduced the scores of liver damage and markedly ameliorated the degree of liver damage. The hepatoprotective effect of MPEP on fulminant hepatic failure induced by LPS and d‐GalN in mice was demonstrated. Copyright © 2009 John Wiley & Sons, Ltd.
Tetherin Sensitivity of Influenza A Viruses Is Strain Specific: Role of Hemagglutinin and Neuraminidase

ABSTRACT The expression of the antiviral host cell factor tetherin is induced by interferon and can inhibit the release of enveloped viruses from infected cells. The Vpu protein of HIV-1 antagonizes the antiviral activity of tetherin, and tetherin antagonists with Vpu-like activity have been identified in other viruses. In contrast, it is incompletely understood whether tetherin inhibits influenza A virus (FLUAV) release and whether FLUAV encodes tetherin antagonists. Here, we show that release of several laboratory-adapted FLUAV strains and a seasonal FLUAV strain is inhibited by tetherin, while pandemic FLUAV A/Hamburg/4/2009 is resistant. Studies with a virus-like particle system and analysis of reassortant viruses provided evidence that the viral hemagglutinin (HA) is an important determinant of tetherin antagonism but requires the presence of its cognate neuraminidase (NA) to inhibit tetherin. Finally, tetherin antagonism by FLUAV was dependent on the virion context, since retrovirus release from tetherin-positive cells was not rescued, and correlated with an HA- and NA-dependent reduction in tetherin expression. In sum, our study identifies HA and NA proteins of certain pandemic FLUAV as tetherin antagonists, which has important implications for understanding FLUAV pathogenesis. IMPORTANCE Influenza A virus (FLUAV) infection is responsible for substantial global morbidity and mortality, and understanding how the virus evades the immune defenses of the host may uncover novel targets for antiviral intervention. Tetherin is an antiviral effector molecule of the innate immune system which can contribute to control of viral invasion. However, it has been unclear whether FLUAV is inhibited by tetherin and whether these viruses encode tetherin-antagonizing proteins. Our observation that several pandemic FLUAV strains can counteract tetherin via their HA and NA proteins identifies these proteins as novel tetherin antagonists and indicates that HA/NA-dependent inactivation of innate defenses may contribute to the efficient spread of pandemic FLUAV.
A supramodal network for response inhibition

Response inhibition is the capacity to suppress inappropriate actions and is considered to be a fundamental executive function. This study investigated whether the neural correlates of response inhibition are organized along supramodal or modality-specific principles. For this purpose, we used event-related functional magnetic resonance imaging in a go-nogo task with auditory and visual stimuli. Common activation relating to response inhibition across modalities was observed in a frontoparietal network including the ventrolateral prefrontal cortex. In contrast, there was no modality-specific activation related to response inhibition in the prefrontal cortex. These findings suggest that the neural correlates of response inhibition have a supramodal organization, which is consistent with its role as a core executive function.