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An efficient route for delivering specific proteins and peptides into neurons could greatly accelerate the development of therapies for various diseases, especially those involving intracellular defects such as Parkinson disease. Here we report the novel use of polybutylcyanoacrylate nanoparticles for delivery of intact, functional proteins into neurons and neuronal cell lines. Uptake of these particles is primarily dependent on endocytosis via the low density lipoprotein receptor. The nanoparticles are rapidly turned over and display minimal toxicity to cultured neurons. Delivery of three different functional cargo proteins is demonstrated. When primary neuronal cultures are treated with recombinant Escherichia coli beta-galactosidase as nanoparticle cargo, persistent enzyme activity is measured beyond the period of nanoparticle degradation. Delivery of the small GTPase rhoG induces neurite outgrowth and differentiation in PC12 cells. Finally, a monoclonal antibody directed against synuclein is capable of interacting with endogenous alpha-synuclein in cultured neurons following delivery via nanoparticles. Polybutylcyanoacrylate nanoparticles are thus useful for intracellular protein delivery in vitro and have potential as carriers of therapeutic proteins for treatment of neuronal disorders in vivo.
The cell division cycle protein 37 (Cdc37) and the 90-kDa heat shock protein (Hsp90) are molecular chaperones, which are crucial elements in the protein signaling pathway. The largest class of client proteins for Cdc37 and Hsp90 are protein kinases. The catalytic domains of these kinases are stabilized by Cdc37, and their proper folding and functioning is dependent on Hsp90. Here, we present the x-ray crystal structure of the 16-kDa middle domain of human Cdc37 at 1.88 angstroms resolution and the structure of this domain in complex with the 23-kDa N-terminal domain of human Hsp90 based on heteronuclear solution state NMR data and docking. Our results demonstrate that the middle domain of Cdc37 exists as a monomer. NMR and mutagenesis experiments reveal Leu-205 in Cdc37 as a key residue enabling complex formation. These findings can be very useful in the development of small molecule inhibitors against cancer.
The single nucleotide polymorphism 118A>G of the human micro-opioid receptor gene OPRM1, which leads to an exchange of the amino acid asparagine (N) to aspartic acid (D) at position 40 of the extracellular receptor region, alters the in vivo effects of opioids to different degrees in pain-processing brain regions. The most pronounced N40D effects were found in brain regions involved in the sensory processing of pain intensity. Using the mu-opioid receptor-specific agonist DAMGO, we analyzed the micro-opioid receptor signaling, expression, and binding affinity in human brain tissue sampled postmortem from the secondary somatosensory area (SII) and from the ventral posterior part of the lateral thalamus, two regions involved in the sensory processing and transmission of nociceptive information. We show that the main effect of the N40D micro-opioid receptor variant is a reduction of the agonist-induced receptor signaling efficacy. In the SII region of homo- and heterozygous carriers of the variant 118G allele (n=18), DAMGO was only 62% as efficient (p=0.002) as in homozygous carriers of the wild-type 118A allele (n=15). In contrast, the number of [3H]DAMGO binding sites was unaffected. Hence, the micro-opioid receptor G-protein coupling efficacy in SII of carriers of the 118G variant was only 58% as efficient as in homozygous carriers of the 118A allele (p<0.001). The thalamus was unaffected by the OPRM1 118A>G SNP. In conclusion, we provide a molecular basis for the reduced clinical effects of opioid analgesics in carriers of mu-opioid receptor variant N40D.
Thirteen species of skippers (six newly described; Lepidoptera: Hesperiidae: Hesperiinae: Hesperiini) from higher elevations of Mexico and Central America are reviewed. These are included in four genera (one newly described), some with proposed new combinations. Onespa Steinhauser, 1974, originally described as monotypic, is shown to include three species in addition to its type species, Onespa nubis Steinhauser, 1974. One of these, Atrytone gala Godman, 1900, that has been misplaced in several genera since its description, represents a new combination. The other two species, distributed in montane habitats in northwestern Mexico and in Costa Rica, are described as new. Buzyges Godman, 1900, distributed in Mexico and Central America and also formerly considered monotypic, is shown to embrace four species. Besides the type species, Buzyges idothea Godman, 1900, two species long placed in Poanes Scudder, 1872, Pamphila rolla Mabille, 1883, and Poanes benito Freeman, 1979, are included as new combinations. Another species, known only from Costa Rica, is described as new. These are united by several superficial characters, but especially by genital morphology of both sexes. Librita Evans, 1955, was described to include three species of which one, Librita raspa Evans, 1955, was subsequently removed. Augiades heras Godman, 1900 is here also removed from Librita and placed in a new genus with three previously undescribed species. This completes the disintegration of Librita, which is now monotypic. The four genera, although exhibiting similarities suggesting potential alliance, differ in their unique combinations of several superficial and genital traits from each other and other hesperiine skippers.
Sepsis is caused by infection and often followed by an overwhelming inflammatory response. This can lead to shock, organ failure and even death. Each year approximately 60,000 people die in Germany due to sepsis. There is good evidence that sepsis is associated with failure of the hypothalamic-pituitary-adrenal-axis. In patients with sepsis, glucocorticoids (e.g. corticosterone, cortisol) released from adrenal glands play an essential role in preventing an excessive pro-inflammatory response. Adrenal insufficiency occurs in a large number of patients with septic shock and is associated with an increased mortality. In the innate immune system, Toll-like receptors (TLRs) play a crucial role in its onset by recognizing pathogenassociated molecules. It is well known that there are interactions between the immune and endocrine stress systems; glucocorticoids and TLRs regulate each other in a bi-directional way. Therefore, a coordinated response of the adrenal and immune system is of vital importance for survival during severe inflammation. This experimental study focuses on the role of TLR-2, TLR-4 and TLR-9 during adrenal stress. The results show that in mice, the absence of TLR-2 and TLR-4, but not TLR-9 leads to altered adrenal morphology, relating to size and cellular structure. However, this alteration does not appear to compromise the phenotype of TLR knock-out mice. Mice deficient of TLR-2, 4 and 9 are not able to respond adequately to inflammatory stress induced by their potential ligands lipopolysaccharide (LPS), lipoteichoic acid (LTA) or cytidine phosphate guanosine-oligodeoxynucleotides (CpG-ODN). This impaired adrenal stress response appears to be associated with a decrease in systemic and intra-adrenal cytokine expressions. Taken together, these results suggest that TLR-2, 4 and 9 are key players in the immuno-endocrine response during inflammation and SIRS. In conclusion, TLRs play a crucial role in the immune-adrenal crosstalk. This close functional relationship needs to be considered in the treatment of inflammatory diseases where an intact adrenal stress response is required. Furthermore, TLR polymorphisms could contribute to the underlying mechanisms of impaired adrenal stress response in patients with bacterial sepsis
[MesnacnacZn(μ-H)]2 (1) was synthesized by reaction of MesnacnacZnI with either an equimolar amount of KNH(iPr)BH3 or an excess of NaH and characterized by multinuclear NMR and IR spectroscopy as well as X-ray diffraction. Two polymorphs of 1 were found and their structures determined on single crystals.
A characterization of the ultra-fine aerosol particle counter COPAS (COndensation PArticle counting System) for operation on board the Russian high altitude research aircraft M-55 Geophysika is presented. The COPAS instrument consists of an aerosol inlet and two dual-channel continuous flow Condensation Particle Counters (CPCs) operated with the chlorofluorocarbon FC-43. It operates at pressures between 400 and 50 hPa for aerosol detection in the particle diameter (dp) range from 6 nm up to 1 micro m. The aerosol inlet, designed for the M-55, is characterized with respect to aspiration, transmission, and transport losses. The experimental characterization of counting efficiencies of three CPCs yields dp50 (50% detection particle diameter) of 6 nm, 11 nm, and 15 nm at temperature differences (DeltaT) between saturator and condenser of 17°C, 30°C, and 33°C, respectively. Non-volatile particles are quantified with a fourth CPC, with dp50=11 nm. It includes an aerosol heating line (250°C) to evaporate H2SO4-H2O particles of 11 nm<dp<200 nm at pressures between 70 and 300 hPa. An instrumental in-flight inter-comparison of the different COPAS CPCs yields correlation coefficients of 0.996 and 0.985. The particle emission index for the M-55 in the range of 1.4–8.4×10 16 kg -1 fuel burned has been estimated based on measurements of the Geophysika's own exhaust.
The human immunodeficiency virus (HIV) had spread unrecognized in the human population as sexually transmitted disease and was finally identified by its disease AIDS in 1981. Even after the isolation of the causative agent in 1983, the burden and death rate of AIDS accelerated worldwide especially in young people despite the confection of new drugs capable to inhibit virus replication since 1997. However, at least in industrialised countries, this trend could be reversed by the introduction of combination therapy strategies. The design of new drugs is on going; besides the inhibition of the three enzymes of HIV for replication and maturation (reverse transcriptase, integrase and protease), further drugs inhibits fusion of viral and cellular membranes and virus maturation. On the other hand, viral diagnostics had been considerably improved since the emergence of HIV. There was a need to identify infected people correctly, to follow up the course of immune reconstitution of patients by measuring viral load and CD4 cells, and to analyse drug escape mutations leading to drug resistance. Both the development of drugs and the refined diagnostics have been transferred to the treatment of patients infected with hepatitis B virus (HBV) and hepatitis C virus (HCV). This progress is not completed; there are beneficial aspects in the response of the scientific community to the HIV burden for the management of other viral diseases. These aspects are described in this contribution. Further aspects as handling a stigmatising disease, education of self-responsiveness within sexual relationships, and ways for confection of a protective vaccine are not covered.
This book presents a study of the life history of Mtoro bin Mwinyi Bakari (c. 1869 - 1927). Mtoro bin Mwinyi Bakari grew up and studied Islamic Sciences in Bagamoyo, Tanzania. He became a Swahili lecturer and author in Germany and is known to have written Desturi za Wasuaheli, an important work in Swahili culture. The book introduces the wider historical context of his writings, and, in particular, reconstructs the racism and discrimination in both the colonial and metropolitan contexts, features which negatively influenced his career and his life as a whole. The study also offers insights into contributions of the colonized to the study of African languages and cultures during this same historical context.
Introduction Impaired renal function and/or pre-existing atherosclerosis in the deceased donor increase the risk of delayed graft function and impaired long-term renal function in kidney transplant recipients. Case presentation We report delayed graft function occurring simultaneously in two kidney transplant recipients, aged 57-years-old and 39-years-old, who received renal allografts from the same deceased donor. The 62-year-old donor died of cardiac arrest during an asthmatic state. Renal-allograft biopsies performed in both kidney recipients because of delayed graft function revealed cholesterol-crystal embolism. An empiric statin therapy in addition to low-dose acetylsalicylic acid was initiated. After 10 and 6 hemodialysis sessions every 48 hours, respectively, both renal allografts started to function. Glomerular filtration rates at discharge were 26 ml/min/1.73 m2 and 23.9 ml/min/1.73 m2, and remained stable in follow-up examinations. Possible donor and surgical procedure-dependent causes for cholesterol-crystal embolism are discussed. Conclusion Cholesterol-crystal embolism should be considered as a cause for delayed graft function and long-term impaired renal allograft function, especially in the older donor population.
Background: In this interdisciplinary project, the biological effects of heavy ions are compared to those of X-rays using tissue slice culture preparations from rodents and humans. Advantages of this biological model are the conservation of an organotypic environment and the independency from genetic immortalization strategies used to generate cell lines. Its open access allows easy treatment and observation via live-imaging microscopy. Materials and methods: Rat brains and human brain tumor tissue are cut into 300 micro m thick tissue slices. These slices are cultivated using a membrane-based culture system and kept in an incubator at 37°C until treatment. The slices are treated with X-rays at the radiation facility of the University Hospital in Frankfurt at doses of up to 40 Gy. The heavy ion irradiations were performed at the UNILAC facility at GSI with different ions of 11.4 A MeV and fluences ranging from 0.5–10 x 106 particles/cm². Using 3D-confocal microscopy, cell-death and immune cell activation of the irradiated slices are analyzed. Planning of the irradiation experiments is done with simulation programs developed at GSI and FIAS. Results: After receiving a single application of either X-rays or heavy ions, slices were kept in culture for up to 9d post irradiation. DNA damage was visualized using gamma H2AXstaining. Here, a dose-dependent increase and time-dependent decrease could clearly be observed for the X-ray irradiation. Slices irradiated with heavy ions showed less gamma H2AX-positive cells distributed evenly throughout the slice, even though particles were calculated to penetrate only 90–100 micro m into the slice. Conclusions: Single irradiations of brain tissue, even at high doses of 40 Gy, will result neither in tissue damage visible on a macroscopic level nor necrosis. This is in line with the view that the brain is highly radio-resistant. However, DNA damage can be detected very well in tissue slices using gamma H2AX-immuno staining. Thus, slice cultures are an excellent tool to study radiation-induced damage and repair mechanisms in living tissues.
Background Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. Results Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells. A subsequent systematic analysis of a panel of 14 chemosensitive and chemoresistant neuroblastoma cell lines in vitro and in animal experiments indicated a consistent shift to a more pro-angiogenic phenotype in chemoresistant neuroblastoma cells. The molecular mechanims underlying increased pro-angiogenic activity of neuroblastoma cells are individual and differ between the investigated chemoresistant cell lines. Treatment of animals carrying doxorubicin-resistant neuroblastoma xenografts with doxorubicin, a cytotoxic drug known to exert anti-angiogenic activity, resulted in decreased tumour vessel formation and growth indicating chemoresistance-associated enhanced pro-angiogenic activity to be relevant for tumour progression and to represent a potential therapeutic target. Conclusions A bioinformatics approach allowed to identify a relevant chemoresistance-associated shift in neuroblastoma cell biology. The chemoresistance-associated enhanced pro-angiogenic activity observed in neuroblastoma cells is relevant for tumour progression and represents a potential therapeutic target.
Background The differential diagnosis between follicular thyroid adenoma and minimal invasive follicular thyroid carcinoma is often difficult for several reasons. One major aspect is the lack of typical cytological criteria in well differentiated specimens. New marker molecules, shown by poly- or monoclonal antibodies proved helpful. Methods We performed global gene expression analysis of 12 follicular thyroid tumours (4 follicular adenomas, 4 minimal invasive follicular carcinomas and 4 widely invasive follicular carcinomas), followed by immunohistochemical staining of 149 cases. The specificity of the antibody was validated by western blot analysis Results In gene expression analysis QPRT was detected as differently expressed between follicular thyroid adenoma and follicular thyroid carcinoma. QPRT protein could be detected by immunohistochemistry in 65% of follicular thyroid carcinomas including minimal invasive variant and only 22% of follicular adenomas. Conclusion Consequently, QPRT is a potential new marker for the immunohistochemical screening of follicular thyroid nodules.
Biventricular pacing has been suggested in end-stage heart failure. We present a 59-year-old patient undergoing second re-do CABG (coronary artery bypass graft) and carotid artery endarterectomy. Ejection fraction was 15%, QRS-width 175 ms. Following the carotid and CABG procedure, an implanted single-chamber ICD (implantable cardioverter defibrillator) was upgraded to permanent biventricular DDD pacing by implantation of one epicardial left ventricular and one epicardial atrial electrode. At follow-up two months postoperatively ejection fraction had significantly improved to 45%, the patient underwent stress test with adequate load and reported a good quality of life.
U1-snRNA is an integral part of the U1 ribonucleoprotein pivotal for pre-mRNA splicing. Toll-like receptor (TLR) signaling has recently been associated with immunoregulatory capacities of U1-snRNA. Using lung A549 epithelial/carcinoma cells, we report for the first time on interferon regulatory factor (IRF)-3 activation initiated by endosomally delivered U1-snRNA. This was associated with expression of the IRF3-inducible genes interferon-b (IFN-b), CXCL10/IP-10 and indoleamine 2,3-dioxygenase. Mutational analysis of the U1-snRNA-activated IFN-b promoter confirmed the crucial role of the PRDIII element, previously proven pivotal for promoter activation by IRF3. Notably, expression of these parameters was suppressed by bafilomycin A1, an inhibitor of endosomal acidification, implicating endosomal TLR activation. Since resiquimod, an agonist of TLR7/8, failed to stimulate A549 cells, data suggest TLR3 to be of prime relevance for cellular activation. To assess the overall regulatory potential of U1-snRNA-activated epithelial cells on cytokine production, co-cultivation with peripheral blood mononuclear cells (PBMC) was performed. Interestingly, A549 cells activated by U1-snRNA reinforced phytohemagglutinin-induced interleukin-10 release by PBMC but suppressed that of tumor necrosis factor-a, indicating an antiinflammatory potential of U1-snRNA. Since U1-snRNA is enriched in apoptotic bodies and epithelial cells are capable of performing efferocytosis, the present data in particular connect to immunobiological aspects of apoptosis at host/environment interfaces.
The seasonality of transport and mixing of air into the lowermost stratosphere (LMS) is studied using distributions of mean age of air and a mass balance approach, based on in-situ observations of SF6 and CO2 during the SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) aircraft campaigns. Combining the information of the mean age of air and the water vapour distributions we demonstrate that the tropospheric air transported into the LMS above the extratropical tropopause layer (ExTL) originates predominantly from the tropical tropopause layer (TTL). The concept of our mass balance is based on simultaneous measurements of the two passive tracers and the assumption that transport into the LMS can be described by age spectra which are superposition of two different modes. Based on this concept we conclude that the stratospheric influence on LMS composition is strongest in April with extreme values of the tropospheric fractions (alpha1) below 20% and that the strongest tropospheric signatures are found in October with alpha1 greater than 80%. Beyond the fractions, our mass balance concept allows us to calculate the associated transit times for transport of tropospheric air from the tropics into the LMS. The shortest transit times (<0.3 years) are derived for the summer, continuously increasing up to 0.8 years by the end of spring. These findings suggest that strong quasi-horizontal mixing across the weak subtropical jet from summer to mid of autumn and the considerably shorter residual transport time-scales within the lower branch of the Brewer-Dobson circulation in summer than in winter dominates the tropospheric influence in the LMS until the beginning of next year's summer.
Medical students are exposed to infectious diseases during the course of their clinical training. Unfortunately, vaccination rates among medical students remain insufficient. However, immunizations against vaccine-preventable diseases should be carried out before the students enter clinical courses. This is vital in order to prevent nosocomial infections. We screened 366 medical students in their first clinical year for hospital-related viral diseases. Serum samples were collected between April and May 2007. Antibody testing was carried out using commercial ELISA systems against measles, mumps, rubella, varicella, hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency virus (HIV). Overall, 63.9% (n=234) of the students were sufficiently vaccinated against HBV. In contrast, 31.7% (n=116) had not received any HBV vaccine dosage, and 4.4% (n=16) had not completed the full vaccine cycle (<3 dosage). Remarkably, two students showed serological markers of resolved HBV infection. In addition, one student was HCV-positive and one was HIV-positive, respectively. The following seronegative rates were found: measles (7.9%), mumps (17.5%), rubella (6.5%), and varicella (2.2%). Further work is needed to identify optimal strategies for improving vaccination rates among medical students. It is imperative to identify and limit possible disparities in immunity of vaccine-preventable diseases before initial patient contact. With regard to the primary diagnosis of serious virus diseases including HBV, HCV and HIV, medical students should be screened for these blood borne pathogens.
Background: Molecular phylogenies are being published increasingly and many biologists rely on the most recent topologies. However, different phylogenetic trees often contain conflicting results and contradict significant background data. Not knowing how reliable traditional knowledge is, a crucial question concerns the quality of newly produced molecular data. The information content of DNA alignments is rarely discussed, as quality statements are mostly restricted to the statistical support of clades. Here we present a case study of a recently published mollusk phylogeny that contains surprising groupings, based on five genes and 108 species, and we apply new or rarely used tools for the analysis of the information content of alignments and for the filtering of noise (masking of random-like alignment regions, split decomposition, phylogenetic networks, quartet mapping). Results: The data are very fragmentary and contain contaminations. We show that that signal-like patterns in the data set are conflicting and partly not distinct and that the reported strong support for a "rather surprising result" (monoplacophorans and chitons form a monophylum Serialia) does not exist at the level of primary homologies. Split-decomposition, quartet mapping and neighbornet analyses reveal conflicting nucleotide patterns and lack of distinct phylogenetic signal for the deeper phylogeny of mollusks. Conclusion: Even though currently a majority of molecular phylogenies are being justified with reference to the 'statistical' support of clades in tree topologies, this confidence seems to be unfounded. Contradictions between phylogenies based on different analyses are already a strong indication of unnoticed pitfalls. The use of tree-independent tools for exploratory analyses of data quality are highly recommended. Concerning the new mollusk phylogeny more convincing evidence is needed.
The transporter associated with antigen processing (TAP) is an essential machine of the adaptive immune system that translocates antigenic peptides from the cytosol into the endoplasmic reticulum lumen for loading of major histocompatibility class I molecules. To examine this ABC transport complex in mechanistic detail, we have established, after extensive screening and optimization, the solubilization, purification, and reconstitution for TAP to preserve its function in each step. This allowed us to determine the substrate-binding stoichiometry of the TAP complex by fluorescence cross-correlation spectroscopy. In addition, the TAP complex shows strict coupling between peptide binding and ATP hydrolysis, revealing no basal ATPase activity in the absence of peptides. These results represent an optimal starting point for detailed mechanistic studies of the transport cycle of TAP by single molecule experiments to analyze single steps of peptide translocation and the stoichiometry between peptide transport and ATP hydrolysis.