Are There Options to Prevent Early Occurring Deaths in Acute Myocardial Infarction: Prospective Evaluation of All < 24 h In-Hospital Deaths, 2004-2006-The MONICA/KORA Augsburg Infarction Registry

Objectives: To provide valid clinical data of early in-hospital deaths with presumed acute myocardial infarction (AMI) who are often not included in clinical trials or registries. Methods: From August 2004 to August 2006 all patients (age 25-84 years) dying within 24 h after hospitalization in a large tertiary care academic teaching hospital were screened regarding an underlying cardiovascular cause of death. Results: After validation, 79 out of 1,352 patients remained with a final diagnosis of AMI. Sixty-six percent of these experienced prehospital cardiac arrest or shock. In 37% no resuscitation attempts were performed in-hospital, the most common reason being multimorbidity. Only 23% could be transferred to coronary angiography for revascularisation attempts. An independent panel of clinicians judged that only in one patient would another management strategy have been promising. Of interest, 33% of the deceased patients had typical or atypical chest pain the days before the lethal event. Conclusion: A large percentage of AMI patients who died soon after hospitalization were in critical circulatory state directly before hospitalization. In 37%, in-hospital resuscitation attempts were omitted for understandable reasons. Options for improvement in acute care in the investigated setting were not found. However, in one third of the cases earlier preventive measures might have been reasonable. Copyright (C) 2010 S. Karger AG, Base

Harmonic emission from cluster nanoplasmas subject to intense short laser pulses

Harmonic emission from cluster nanoplasmas subject to short intense infrared laser pulses is studied. In a previous publication [M. Kundu et al., Phys. Rev. A 76, 033201 (2007)] we reported particle-in-cell simulation results showing resonant enhancements of low-order harmonics when the Mie plasma frequency of the ionizing and expanding cluster resonates with the respective harmonic frequency. Simultaneously we found that high-order harmonics were barely present in the spectrum, even at high intensities. The current paper is focused on the analytical modeling of the process. We show that dynamical stochasticity owing to nonlinear resonance inhibits the emission of high order harmonics.Comment: 12 pages, 7 figures, RevTe

PULP AND FIBER CHARACTERIZATION OF WHEAT STRAW AND EUCALUPTUS PULPS - A COMPARISON

The response to refining of wheat straw and eucalyptus pulps as well as the relationships between refining, fiber properties, and paper properties are described in this paper. Pulps were bleached applying different bleaching sequences and thereafter refined to varying degrees. Pulp and fiber properties were investigated and set into relation to the final sheet properties. The results show that wheat straw pulps respond to refining more easily than eucalyptus pulps and that the differences are due mainly to morphological and ultrastructural differences as well as fines content and xylan content. The development of strength properties of the different pulps was found to be strongly correlated to the number of dislocations, i.e. weak points in the fiber wall, as well as to the morphological appearance of the pulp fibers after refining. A higher initial number and a faster development of dislocations together with the creation of large amounts of fines explain the slower and lower development of strength properties of wheat straw pulps than of eucalyptus pulps. Removal of fines from wheat straw pulps improved not only the drainability of the pulp suspension but also the mechanical and optical sheet properties. This indicates that the fines in the wheat straw pulps act mainly as filler with low bonding properties. The fact that fractionated D(EOP)D wheat straw pulps can deliver good mechanical sheet properties at very good drainability with no or only minor refining is very interesting when evaluating the potential of replacing or partially replacing eucalyptus with domestic Chinese raw materials in furnishes for production of different paper products

The orphan receptor ERRα interferes with steroid signaling

The estrogen receptor-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily that has been shown to interfere with the estrogen-signaling pathway. In this report, we demonstrate that ERRα also cross-talks with signaling driven by other steroid hormones. Treatment of human prostatic cells with a specific ERRα inverse agonist reduces the expression of several androgen-responsive genes, in a manner that does not involve perturbation of androgen receptor expression or activity. Furthermore, ERRα activates the expression of androgen response elements (ARE)-containing promoters, such as that of the prostate cancer marker PSA, in an ARE-dependent manner. In addition, promoters containing a steroid response element can be activated by all members of the ERR orphan receptor subfamily, and this, even in the presence of antisteroid compounds

Functional cooperation between CREM and GCNF directs gene expression in haploid male germ cells

Cellular differentiation and development of germ cells critically depend on a coordinated activation and repression of specific genes. The underlying regulation mechanisms, however, still lack a lot of understanding. Here, we describe that both the testis-specific transcriptional activator CREMτ (cAMP response element modulator tau) and the repressor GCNF (germ cell nuclear factor) have an overlapping binding site which alone is sufficient to direct cell type-specific expression in vivo in a heterologous promoter context. Expression of the transgene driven by the CREM/GCNF site is detectable in spermatids, but not in any somatic tissue or at any other stages during germ cell differentiation. CREMτ acts as an activator of gene transcription whereas GCNF suppresses this activity. Both factors compete for binding to the same DNA response element. Effective binding of CREM and GCNF highly depends on composition and epigenetic modification of the binding site. We also discovered that CREM and GCNF bind to each other via their DNA binding domains, indicating a complex interaction between the two factors. There are several testis-specific target genes that are regulated by CREM and GCNF in a reciprocal manner, showing a similar activation pattern as during spermatogenesis. Our data indicate that a single common binding site for CREM and GCNF is sufficient to specifically direct gene transcription in a tissue-, cell type- and differentiation-specific manner

The histone code reader Spin1 controls skeletal muscle development

While several studies correlated increased expression of the histone code reader Spin1 with tumor formation or growth, little is known about physiological functions of the protein. We generated Spin1(M5) mice with ablation of Spin1 in myoblast precursors using the Myf5-Cre deleter strain. Most Spin1(M5) mice die shortly after birth displaying severe sarcomere disorganization and necrosis. Surviving Spin1(M5) mice are growth-retarded and exhibit the most prominent defects in soleus, tibialis anterior, and diaphragm muscle. Transcriptome analyses of limb muscle at embryonic day (E) 15.5, E16.5, and at three weeks of age provided evidence for aberrant fetal myogenesis and identified deregulated skeletal muscle (SkM) functional networks. Determination of genome-wide chromatin occupancy in primary myoblast revealed direct Spin1 target genes and suggested that deregulated basic helix-loop-helix transcription factor networks account for developmental defects in Spin1(M5) fetuses. Furthermore, correlating histological and transcriptome analyses, we show that aberrant expression of titin-associated proteins, abnormal glycogen metabolism, and neuromuscular junction defects contribute to SkM pathology in Spin1(M5) mice. Together, we describe the first example of a histone code reader controlling SkM development in mice, which hints at Spin1 as a potential player in human SkM disease

Active Nuclear Receptors Exhibit Highly Correlated AF-2 Domain Motions

Nuclear receptor ligand binding domains (LBDs) convert ligand binding events into changes in gene expression by recruiting transcriptional coregulators to a conserved activation function-2 (AF-2) surface. While most nuclear receptor LBDs form homo- or heterodimers, the human nuclear receptor pregnane X receptor (PXR) forms a unique and essential homodimer and is proposed to assemble into a functional heterotetramer with the retinoid X receptor (RXR). How the homodimer interface, which is located 30 Å from the AF-2, would affect function at this critical surface has remained unclear. By using 20- to 30-ns molecular dynamics simulations on PXR in various oligomerization states, we observed a remarkably high degree of correlated motion in the PXR–RXR heterotetramer, most notably in the four helices that create the AF-2 domain. The function of such correlation may be to create “active-capable” receptor complexes that are ready to bind to transcriptional coactivators. Indeed, we found in additional simulations that active-capable receptor complexes involving other orphan or steroid nuclear receptors also exhibit highly correlated AF-2 domain motions. We further propose a mechanism for the transmission of long-range motions through the nuclear receptor LBD to the AF-2 surface. Taken together, our findings indicate that long-range motions within the LBD scaffold are critical to nuclear receptor function by promoting a mobile AF-2 state ready to bind coactivators

MiR-137 Targets Estrogen-Related Receptor Alpha and Impairs the Proliferative and Migratory Capacity of Breast Cancer Cells

ERRα is an orphan nuclear receptor emerging as a novel biomarker of breast cancer. Over-expression of ERRα in breast tumor is considered as a prognostic factor of poor clinical outcome. The mechanisms underlying the dysexpression of this nuclear receptor, however, are poorly understood. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play important roles in tumor initiation and progression. In the present study, we have identified that the expression of ERRα is regulated by miR-137, a potential tumor suppressor microRNA. The bioinformatics search revealed two putative and highly conserved target-sites for miR-137 located within the ERRα 3′UTR at nt 480–486 and nt 596–602 respectively. Luciferase-reporter assay demonstrated that the two predicted target sites were authentically functional. They mediated the repression of reporter gene expression induced by miR-137 in an additive manner. Moreover, ectopic expression of miR-137 down-regulated ERRα expression at both protein level and mRNA level, and the miR-137 induced ERRα-knockdown contributed to the impaired proliferative and migratory capacity of breast cancer cells. Furthermore, transfection with miR-137mimics suppressed at least two downstream target genes of ERRα–CCNE1 and WNT11, which are important effectors of ERRα implicated in tumor proliferation and migration. Taken together, our results establish a role of miR-137 in negatively regulating ERRα expression and breast cancer cell proliferation and migration. They suggest that manipulating the expression level of ERRα by microRNAs has the potential to influence breast cancer progression

Protein Evolution by Molecular Tinkering: Diversification of the Nuclear Receptor Superfamily from a Ligand-Dependent Ancestor

Phylogenetic reconstruction of the structure and function of the ancestor of the nuclear receptor protein family reveals how functional diversity evolves by subtle tinkering with an ancestral template

Homology modelling and spectroscopy, a never-ending love story

Homology modelling is normally the technique of choice when experimental structure data are not available but three-dimensional coordinates are needed, for example, to aid with detailed interpretation of results of spectroscopic studies. Herein, the state of the art of homology modelling will be described in the light of a series of recent developments, and an overview will be given of the problems and opportunities encountered in this field. The major topic, the accuracy and precision of homology models, will be discussed extensively due to its influence on the reliability of conclusions drawn from the combination of homology models and spectroscopic data. Three real-world examples will illustrate how both homology modelling and spectroscopy can be beneficial for (bio)medical research