Publications by authors named "Dieter Hoffmann"

51 Publications

Invasive pulmonary aspergillosis in critically ill patients with severe COVID-19 pneumonia: Results from the prospective AspCOVID-19 study.

PLoS One 2021 17;16(3):e0238825. Epub 2021 Mar 17.

Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.

Background: Superinfections, including invasive pulmonary aspergillosis (IPA), are well-known complications of critically ill patients with severe viral pneumonia. Aim of this study was to evaluate the incidence, risk factors and outcome of IPA in critically ill patients with severe COVID-19 pneumonia.

Methods: We prospectively screened 32 critically ill patients with severe COVID-19 pneumonia for a time period of 28 days using a standardized study protocol for oberservation of developement of COVID-19 associated invasive pulmonary aspergillosis (CAPA). We collected laboratory, microbiological, virological and clinical parameters at defined timepoints in combination with galactomannan-antigen-detection from nondirected bronchial lavage (NBL). We used logistic regression analyses to assess if COVID-19 was independently associated with IPA and compared it with matched controls.

Findings: CAPA was diagnosed at a median of 4 days after ICU admission in 11/32 (34%) of critically ill patients with severe COVID-19 pneumonia as compared to 8% in the control cohort. In the COVID-19 cohort, mean age, APACHE II score and ICU mortality were higher in patients with CAPA than in patients without CAPA (36% versus 9.5%; p<0.001). ICU stay (21 versus 17 days; p = 0.340) and days of mechanical ventilation (20 versus 15 days; p = 0.570) were not different between both groups. In regression analysis COVID-19 and APACHE II score were independently associated with IPA.

Interpretation: CAPA is highly prevalent and associated with a high mortality rate. COVID-19 is independently associated with invasive pulmonary aspergillosis. A standardized screening and diagnostic approach as presented in our study can help to identify affected patients at an early stage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238825PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968651PMC
March 2021

Linear B-Cell Epitopes in Human Norovirus GII.4 Capsid Protein Elicit Blockade Antibodies.

Vaccines (Basel) 2021 Jan 14;9(1). Epub 2021 Jan 14.

Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany.

Human norovirus (HuNoV) is the leading cause of nonbacterial gastroenteritis worldwide with the GII.4 genotype accounting for over 80% of infections. The major capsid protein of GII.4 variants is evolving rapidly, resulting in new epidemic variants with altered antigenic potentials that must be considered for the development of an effective vaccine. In this study, we identify and characterize linear blockade B-cell epitopes in HuNoV GII.4. Five unique linear B-cell epitopes, namely P2A, P2B, P2C, P2D, and P2E, were predicted on the surface-exposed regions of the capsid protein. Evolving of the surface-exposed epitopes over time was found to correlate with the emergence of new GII.4 outbreak variants. Molecular dynamic simulation (MD) analysis and molecular docking revealed that amino acid substitutions in the putative epitopes P2B, P2C, and P2D could be associated with immune escape and the appearance of new GII.4 variants by affecting solvent accessibility and flexibility of the antigenic sites and histo-blood group antigens (HBAG) binding. Testing the synthetic peptides in wild-type mice, epitopes P2B (336-355), P2C (367-384), and P2D (390-400) were recognized as GII.4-specific linear blockade epitopes with the blocking rate of 68, 55 and 28%, respectively. Blocking rate was found to increase to 80% using the pooled serum of epitopes P2B and P2C. These data provide a strategy for expanding the broad blockade potential of vaccines for prevention of NoV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines9010052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830539PMC
January 2021

Observation of a high degree of stopping for laser-accelerated intense proton beams in dense ionized matter.

Nat Commun 2020 Oct 14;11(1):5157. Epub 2020 Oct 14.

MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an, 710049, China.

Intense particle beams generated from the interaction of ultrahigh intensity lasers with sample foils provide options in radiography, high-yield neutron sources, high-energy-density-matter generation, and ion fast ignition. An accurate understanding of beam transportation behavior in dense matter is crucial for all these applications. Here we report the experimental evidence on one order of magnitude enhancement of intense laser-accelerated proton beam stopping in dense ionized matter, in comparison with the current-widely used models describing individual ion stopping in matter. Supported by particle-in-cell (PIC) simulations, we attribute the enhancement to the strong decelerating electric field approaching 1 GV/m that can be created by the beam-driven return current. This collective effect plays the dominant role in the stopping of laser-accelerated intense proton beams in dense ionized matter. This finding is essential for the optimum design of ion driven fast ignition and inertial confinement fusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18986-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560615PMC
October 2020

Multicentre comparison of quantitative PCR-based assays to detect SARS-CoV-2, Germany, March 2020.

Euro Surveill 2020 06;25(24)

German Center for Infection Research, Partner Site Munich and Associated Partner Site Charité, Berlin and Associated Partner Site Frankfurt, Germany.

Containment strategies and clinical management of coronavirus disease (COVID-19) patients during the current pandemic depend on reliable diagnostic PCR assays for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we compare 11 different RT-PCR test systems used in seven diagnostic laboratories in Germany in March 2020. While most assays performed well, we identified detection problems in a commonly used assay that may have resulted in false-negative test results during the first weeks of the pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2807/1560-7917.ES.2020.25.24.2001057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315722PMC
June 2020

Diode-pumped cw Alexandrite laser with temporally stable 6.5 W in TEM operation with prospect of power scaling.

Opt Express 2020 May;28(11):15761-15769

We present the design of a longitudinally diode-pumped Alexandrite laser in continuous-wave operation and resulting performance data. A laser power of 6.5 W in fundamental mode operation was measured, which is, to the best of our knowledge, the highest laser power in fundamental mode operation yet reported. The laser crystal was pumped by two diode modules emitting at 637 nm. The pump radiation was polarization-combined and spatially symmetrized. The laser operates at an output power of 6.5 W with an optical-to-optical efficiency of 26%, temporally stable output with stability of 8% on ms timescale, a beam quality of M = 1.1 in both spatial directions and emission of an output wavelength of 752 nm. Measurements of the thermal dioptric power at pumping intensities up to 9.5 kW/cm support the appropriate approach of the design. Based on our results, we estimate the potential and show our concept for future scaling of the output power.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OE.391274DOI Listing
May 2020

Clinical and Epidemiological Features of a Family Cluster of Symptomatic and Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

J Pediatric Infect Dis Soc 2020 Jul;9(3):362-365

German Center for Infection Research, Munich Partner Site, Germany.

In a family experiencing coronavirus disease 2019, the parents and 2 children aged 2 and 5 years became infected but the youngest child was not infected. Both children initially shed infectious virus, but cleared the virus after 5 to 6 days in the nasopharynx. However, viral RNA was continuously detected in the children's stool for more than 4 weeks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jpids/piaa060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313851PMC
July 2020

Evolutionary Response to Climate Change in Migratory Pied Flycatchers.

Curr Biol 2019 11 24;29(21):3714-3719.e4. Epub 2019 Oct 24.

Hanhofer Straße 35a, Harthausen 67376, Germany.

Climate change is rapidly advancing spring phenology [1-3] but at different rates in different species [1, 4]. Whether these advances are solely driven by phenotypic plasticity [2, 5] or also involve evolution is hotly debated (e.g., [5-7]). In some species, including avian long-distance migrants, plastic responses to early springs may be constrained by inherited circannual timing programs [8, 9], making evolutionary adjustment the only viable mechanism for keeping pace with shifting phenology [5, 10]. This constraint may be contributing to population declines in migratory species [5, 10-12]. To test whether a migrant's timing program has evolved [10, 12], we replicated an experimental study of the annual cycle of long-distance migratory pied flycatchers (Ficedula hypoleuca) after 21 years of warming. Flycatchers are a model for studying constrained ecological responses to climate change [6, 10, 12, 13]. We show that the phase of the flycatcher circannual clock controlling spring moult, migration, and reproductive timing advanced by 9 days. A nearby wild population mirrored these changes, concurrently advancing egg-laying by 11 days. Furthermore, the time window during which wild flycatcher reproductive timing was most sensitive to ambient temperature advanced by 0.8 days year. These results support a role of phenotypic evolution [14] in changing spring phenology [15, 16]. We suggest that the timing programs of long-distance migratory birds may have greater adaptive potential than previously thought, leaving some scope for evolutionary rescue in a changing climate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cub.2019.08.072DOI Listing
November 2019

Quantitation of norovirus-specific IgG before and after infection in immunocompromised patients.

Braz J Microbiol 2020 Mar 26;51(1):183-187. Epub 2019 Oct 26.

Institute of Virology, Technische Universität und Helmholtz Zentrum München, Munich, Germany.

Noroviruses (NoV) cause the majority of non-bacterial gastroenteritis cases worldwide, with genotype II.4 being the most common. The aim of our study was to quantitate norovirus-specific IgG in immunocompromised patients before and after laboratory-confirmed norovirus infection. A quantitative ELISA was developed by coating ELISA plates with recombinantly expressed P domain of GII.1 capsid protein. After testing mouse sera drawn before and after immunization with GII.1- and GII.4 P domain, sera from GII.1- and GII.4 infected patients were tested. The assay reliably detected preexisting NoV-specific IgG antibodies. Sera drawn after infection showed increased antibody concentrations. Antibodies elicited by GII.1- and GII.4 infections could be detected with coated GII.1 capsid protein. IgG levels remained constant during the first week and then increased in the second week after laboratory diagnosis. The results show that immunocompromised patients elicited IgG responses to NoV infections that could be reliably detected with our quantitative ELISA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s42770-019-00176-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058766PMC
March 2020

Targeted in-vitro-stimulation reveals highly proliferative multi-virus-specific human central memory T cells as candidates for prophylactic T cell therapy.

PLoS One 2019 30;14(9):e0223258. Epub 2019 Sep 30.

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.

Adoptive T cell therapy (ACT) has become a treatment option for viral reactivations in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Animal models have shown that pathogen-specific central memory T cells (TCM) are protective even at low numbers and show long-term survival, extensive proliferation and high plasticity after adoptive transfer. Concomitantly, our own recent clinical data demonstrate that minimal doses of purified (not in-vitro- expanded) human CMV epitope-specific T cells can be sufficient to clear viremia. However, it remains to be determined if human virus-specific TCM show the same promising features for ACT as their murine counterparts. Using a peptide specific proliferation assay (PSPA) we studied the human Adenovirus- (AdV), Cytomegalovirus- (CMV) and Epstein-Barr virus- (EBV) specific TCM repertoires and determined their functional and proliferative capacities in vitro. TCM products were generated from buffy coats, as well as from non-mobilized and mobilized apheresis products either by flow cytometry-based cell sorting or magnetic cell enrichment using reversible Fab-Streptamers. Adjusted to virus serology and human leukocyte antigen (HLA)-typing, donor samples were analyzed with MHC multimer- and intracellular cytokine staining (ICS) before and after PSPA. TCM cultures showed strong proliferation of a plethora of functional virus-specific T cells. Using PSPA, we could unveil tiniest virus epitope-specific TCM populations, which had remained undetectable in conventional ex-vivo-staining. Furthermore, we could confirm these characteristics for mobilized apheresis- and GMP-grade Fab-Streptamer-purified TCM products. Consequently, we conclude that TCM bare high potential for prophylactic low-dose ACT. In addition, use of Fab-Streptamer-purified TCM allows circumventing regulatory restrictions typically found in conventional ACT product generation. These GMP-compatible TCM can now be used as a broad-spectrum antiviral T cell prophylaxis in alloHSCT patients and PSPA is going to be an indispensable tool for advanced TCM characterization during concomitant immune monitoring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768573PMC
March 2020

Generation of recombinant MVA-norovirus: a comparison study of bacterial artificial chromosome- and marker-based systems.

Virol J 2019 08 9;16(1):100. Epub 2019 Aug 9.

Institute of Virology, Faculty of Medicine, Technische Universität München, Munich, Germany.

Background: Recombinant Modified Vaccinia Virus Ankara has been employed as a safe and potent viral vector vaccine against infectious diseases and cancer. We generated recMVAs encoding norovirus GII.4 genotype capsid protein by using a marker-based approach and a BAC-based system. In the marker-based approach, the capsid gene together with a reporter gene was introduced into the MVA genome in DF-1 cells. Several rounds of plaque purification were carried out to get rid of the WT-MVA. In the BAC-based approach, recMVA-BAC was produced by en passant recombineering in E. coli. Subsequently, the recMVAs were rescued in DF-1 cells using a helper rabbit fibroma virus. The BAC backbone and the helper virus were eliminated by passaging in DF-1 cells. Biochemical characteristics of the recMVAs were studied.

Results: We found the purification of the rare spontaneous recombinants time-consuming in the marker-based system. In contrast, the BAC-based system rapidly inserted the gene of interest in E. coli by en passant recombineering before virion production in DF-1 cells. The elimination of the reporter gene was found to be faster and more efficient in the BAC-based approach. With Western blotting and electron microscopy, we could prove successful capsid protein expression and proper virus-assembly, respectively. The MVA-BAC produced higher recombinant virus titers and infected DF-1 cells more efficiently.

Conclusions: Comparing both methods, we conclude that, in contrast to the tedious and time-consuming traditional method, the MVA-BAC system allows us to quickly generate high titer recMVAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12985-019-1212-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688233PMC
August 2019

Training Load, Immune Status, and Clinical Outcomes in Young Athletes: A Controlled, Prospective, Longitudinal Study.

Front Physiol 2018 23;9:120. Epub 2018 Mar 23.

Department of Sports Medicine, Humboldt-University, Charité University Medicine, Berlin, Germany.

Beside positive effects on athlete's health, competitive sport can be linked with an increased risk of illness and injury. Because of high relative increases in training, additional physical and psychological strains, and an earlier specialization and professionalization, adolescent athletes needs an increased attention. Training can alter the immune system by inducing a temporary immunosuppression, finally developing infection symptoms. Previous studies identified Epstein Barr Virus (EBV) as potential indicator for the immune status. In addition to the identification of triggering risk factors for recurrent infections, the aim was to determine the interaction between training load, stress sense, immunological parameters, and clinical symptoms. A controlled, prospective, longitudinal study on young athletes ( = 274, mean age: 13.8 ± 1.5 yrs) was conducted between 2010 and 2014. Also 285 controls (students, who did not perform competitive sports, mean age: 14.5 ± 1.9 yrs) were recruited. Athletes were examined 3 times each year to determine the effects of stress factors (training load: training hours per week [Th/w]) on selected outcome parameters (clinical [susceptibility to infection, WURSS-21: 21-item ], immunological, psychological end points). As part of each visit, EBV serostatus and EBV-specific IgG tiers were studied longitudinally as potential immune markers. Athletes (A) trained 14.9 ± 5.6 h weekly. Controls (C) showed no lower stress levels compared to athletes ( = 0.387). Twelve percent of athletes reported recurrent infections (C: 8.5%, = 0.153), the presence of an upper respiratory tract infection (URTI) was achieved in 30.7%. EBV seroprevalence of athletes was 60.3% (C: 56.6%, = 0.339). Mean EBV-specific IgG titer of athletes was 166 ± 115 U/ml (C: 137 ± 112 U/ml, = 0.030). With increasing Th/w, higher stress levels were observed ( < 0.001). Analyzes of WURSS-21 data revealed no relationship to training load ( = 0.323). Also, training load had no relation to EBV serostatus ( = 0.057) or the level of EBV-specific IgG titers ( = 0.364). Young elite athletes showed no increased sense of stress, no higher prevalence of recurrent infections, and no different EBV-specific serological parameters compared to controls. Also, no direct relationship between training loads, clinical complaints, and EBV-specific immune responses was found. With increasing training loads athletes felt more stressed, but significant associations to EBV-specific serological parameters were absent. In summary, EBV serostatus and EBV-specific IgG titers do not allow risk stratification for impaired health. Further investigations are needed to identify additional risk factors and immune markers, with the aim to avoid inappropriate strains by early detection and following intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2018.00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876235PMC
March 2018

Primary Cytomegalovirus Infection in Seronegative Kidney Transplant Patients Is Associated with Protracted Cold Ischemic Time of Seropositive Donor Organs.

PLoS One 2017 27;12(1):e0171035. Epub 2017 Jan 27.

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.

Human Cytomegalovirus (CMV) can lead to primary infection or reactivation in CMV-seronegative or -seropositive kidney transplant recipients, respectively. Complications comprise severe end-organ diseases and acute or chronic transplant rejection. Risk for CMV manifestation is stratified according to the CMV-IgG-serostatus, with donor+/recipient- (D+/R-) patients carrying the highest risk for CMV-replication. However, risk factors predisposing for primary infection in CMV-seronegative recipients are still not fully elucidated. Therefore, we monitored D+/R- high-risk patients undergoing kidney transplantation in combination with antiviral prophylaxis for the incidence of CMV-viremia for a median follow-up time of 784 days (156-1155 days). In this period, we analyzed the functional CMV-specific T cell response by intracellular cytokine staining and CMV-serology by ELISA. Only four of eight D+/R- patients developed clinically relevant CMV-viremia followed by seroconversion. Viremia triggered expansion of functional CMV-specific T cells correlating with protection against secondary CMV-reactivations. In contrast, all other patients remained permanently aviremic and showed no immunological correlate of infection after discontinuation of antiviral prophylaxis for up to three years. Comparing cold ischemic times (CIT) of viremic (median = 1020 min; 720-1080 min) and aviremic patients (median = 335 min; 120-660 min) revealed significantly (p = 0.0286) protracted CIT in patients with primary CMV-infection. Taken together, primary CMV-infection affects only a subgroup of D+/R- patients correlating with length of CIT. Therefore, patients with extended CIT should be thoroughly monitored for CMV-replication well beyond discontinuation of antiviral prophylaxis. In contrast, patients with short CIT remained permanently uninfected and might benefit from shorter prophylactic treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271354PMC
August 2017

1.95  μm-pumped OP-GaAs optical parametric oscillator with 10.6  μm idler wavelength.

Opt Lett 2016 Sep;41(18):4225-8

We report on an optical parametric oscillator that generates output idler wavelengths around 10.6 μm. On the basis of orientation-patterned gallium arsenide (OP-GaAs) as a nonlinear medium and a 1.95 μm ns-pulsed pump laser, a signal-resonant bow-tie resonator was designed in order to maximize the output power at moderate intensities well below the damage threshold of the optical components. With this setup, the average idler output power at 50 kHz and 100 ns idler pulse length was more than 800 mW, which corresponds to a pulse energy of 16 μJ. The maximum quantum conversion efficiency of 36.8% is the highest value measured so far for comparable setups to the best of our knowledge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OL.41.004225DOI Listing
September 2016

CD25+ FoxP3+ Memory CD4 T Cells Are Frequent Targets of HIV Infection In Vivo.

J Virol 2016 10 29;90(20):8954-67. Epub 2016 Sep 29.

Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Munich, Germany German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany

Unlabelled: Interleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replication in vitro and facilitates homeostatic proliferation of CD25(+) FoxP3(+) CD4(+) T cells. CD25(+) FoxP3(+) CD4(+) T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25(+) FoxP3(+) CD4(+) T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV(+) and HIV(-) study volunteers. Different memory CD4(+) T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV(+) subjects, 51% (median) of CD25(+) FoxP3(+) CD4(+) T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67(+) cells were detected in CD25(+) FoxP3(+) memory CD4(+) T cells (median, 27.6%) in comparison to CD25(-) FoxP3(-) memory CD4(+) T cells (median, 4.1%; P < 0.0001). HIV DNA content was 15-fold higher in CD25(+) FoxP3(+) memory CD4(+) T cells than in CD25(-) FoxP3(-) T cells (P = 0.003). EnvV1V3 sequences derived from CD25(+) FoxP3(+) memory CD4(+) T cells did not preferentially cluster with plasma-derived sequences. Quasi-identical cell-plasma sequence pairs were rare, and their proportion decreased with the estimated HIV infection duration. These data suggest that specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells might facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. The contribution of this cell population to plasma virion production remains unclear.

Importance: Despite recent advances in the understanding of AIDS virus pathogenesis, which cell subsets support HIV infection and replication in vivo is incompletely understood. In vitro, the IL-2 signaling pathway and IL-2-dependent cell cycle induction are essential for HIV infection of stimulated T cells. CD25(+) FoxP3(+) memory CD4 T cells, often referred to as regulatory CD4 T cells, depend on IL-2 signaling for homeostatic proliferation in vivo Our results show that CD25(+) FoxP3(+) memory CD4(+) T cells often express the HIV coreceptor CCR5, are significantly more proliferative, and contain more HIV DNA than CD25(-) FoxP3(-) memory CD4 T cell subsets. The specific cellular characteristics of CD25(+) FoxP3(+) memory CD4(+) T cells probably facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. However, the contribution of this cell subset to plasma viremia remains unclear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00612-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5044822PMC
October 2016

Obituary: Walter Kohn (1923-2016).

Nat Mater 2016 06;15(7):704

Max Planck Institute for the History of Science, Berlin, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nmat4669DOI Listing
June 2016

Clara Haber, nee Immerwahr (1870-1915): Life, Work and Legacy.

Z Anorg Allg Chem 2016 Mar 11;642(6):437-448. Epub 2016 Mar 11.

Fritz Haber Institute of the Max Planck Society, Faradayweg 4-6, 14195 Berlin, Germany.

We examine the life, work, and legacy of Clara Haber, nee Immerwahr, who became the first woman to earn a doctorate from the University of Breslau, in 1900. In 1901 she married the chemist Fritz Haber. With no employment available for female scientists, Clara freelanced as an instructor in the continued education of women, mainly housewives, while struggling not to become a housewife herself. Her duties as a designated head of a posh household hardly brought fulfillment to her life. The outbreak of WWI further exacerbated the situation, as Fritz Haber applied himself in extraordinary ways to aid the German war effort. The night that he celebrated the "success" of the first chlorine cloud attack, Clara committed suicide. We found little evidence to support claims that Clara was an outspoken pacifist who took her life because of her disapproval of Fritz Haber's involvement in chemical warfare. We conclude by examining "the myth of Clara Immerwahr" that took root in the 1990s from the perspective offered by the available scholarly sources, including some untapped ones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/zaac.201600035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825402PMC
March 2016

Herpes simplex virus in bronchoalveolar lavage fluid of medical intensive care unit patients: Association with lung injury and outcome.

J Crit Care 2016 Apr 8;32:138-44. Epub 2015 Dec 8.

II. Medizinische Klinik und Poliklinik. Klinikum rechts der Isar der Technischen Universität München, 81675 München, Germany.

Purpose: In intensive care unit (ICU) patients in whom bronchoalveolar lavage fluid (BALF) was analyzed for suspected infectious pulmonary disease, we investigated the association of herpes simplex virus (HSV) in the BALF with lung injury and patient outcome.

Materials And Methods: In this retrospective cohort study, we included 201 patients treated in a medical ICU of a German university hospital in whom BALF samples were analyzed for the presence of HSV using quantitative polymerase chain reaction analysis.

Results: Eighty-seven patients (43%) were HSV-negative, and 114 patients (57%) were HSV-positive. At the day of BALF sampling (day 0), there was no clinically relevant (or statistically significant) difference in the Modified Clinical Pulmonary Infection Score, Lung Injury Score, and single indicator transpulmonary thermodilution-derived extravascular lung water index and pulmonary vascular permeability index between HSV-negative patients and HSV-positive patients or HSV-positive patients with greater than 10(5) HSV copies/mL. The ICU and hospital length of stay was statistically significantly longer in HSV-positive patients compared with HSV-negative patients. Intensive care unit and hospital mortality was not statistically significantly different between the groups.

Conclusions: We did not find a clinically relevant or statistically significant association of HSV in the BALF of medical ICU patients with lung injury or with ICU and hospital mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcrc.2015.11.019DOI Listing
April 2016

Interferon-γ and Tumor Necrosis Factor-α Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis.

Gastroenterology 2016 Jan 28;150(1):194-205. Epub 2015 Sep 28.

Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany; German Center for Infection Research, Munich and Hannover, Germany. Electronic address:

Background & Aims: Viral clearance involves immune cell cytolysis of infected cells. However, studies of hepatitis B virus (HBV) infection in chimpanzees have indicated that cytokines released by T cells also can promote viral clearance via noncytolytic processes. We investigated the noncytolytic mechanisms by which T cells eliminate HBV from infected hepatocytes.

Methods: We performed a cytokine enzyme-linked immunosorbent assay of serum samples from patients with acute and chronic hepatitis B. Liver biopsy specimens were analyzed by in situ hybridization. HepG2-H1.3 cells, HBV-infected HepaRG cells, and primary human hepatocytes were incubated with interferon-γ (IFNγ) or tumor necrosis factor-α (TNF-α), or co-cultured with T cells. We measured markers of HBV replication, including the covalently closed circular DNA (cccDNA).

Results: Levels of IFNγ and TNF-α were increased in serum samples from patients with acute vs chronic hepatitis B and controls. In human hepatocytes with stably replicating HBV, as well as in HBV-infected primary human hepatocytes or HepaRG cells, IFNγ and TNF-α each induced deamination of cccDNA and interfered with its stability; their effects were additive. HBV-specific T cells, through secretion of IFNγ and TNF-α, inhibited HBV replication and reduced cccDNA in infected cells without the direct contact required for cytolysis. Blocking IFNγ and TNF-α after T-cell stimulation prevented the loss of cccDNA. Deprivation of cccDNA required activation of nuclear APOBEC3 deaminases by the cytokines. In liver biopsy specimens from patients with acute hepatitis B, but not chronic hepatitis B or controls, hepatocytes expressed APOBEC3A and APOBEC3B.

Conclusions: IFNγ and TNF-α, produced by T cells, reduce levels of HBV cccDNA in hepatocytes by inducing deamination and subsequent cccDNA decay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2015.09.026DOI Listing
January 2016

Human papilloma virus is not detectable in samples of urothelial bladder cancer in a central European population: a prospective translational study.

Infect Agent Cancer 2015 21;10:31. Epub 2015 Sep 21.

Department of Virology, Technische Universität/Helmholtz Zentrum München, Munich, Germany.

Background: Previous investigations on the association of human papillomavirus (HPV) and human bladder cancer have led to conflicting results. The aim of this study was to determine if low and high risk HPV play a role in the etiology of superficial low grade and invasive high grade urothelial carcinoma of the bladder.

Methods: We prospectively collected tumor samples of urothelial carcinoma of the bladder from 109 patients treated with transurethral resection or cystectomy, with bladder tissue from transurethral resection of the prostate serving as control. Unfixed, frozen tumor samples were analyzed for the presence of 14 high risk HPV types using real time PCR. Additionally, all specimens were tested for 35 low risk HPV types with a conventional PCR using degenerate primers located in the L1 region. Six frozen samples of cervical carcinoma served as positive controls.

Results: We included 109 cases of bladder cancer with 41 superficial (pTa low grade) tumors, 56 invasive (pT1-T4) high grade tumors and 12 others (pTa high grade + pTis). We have not detected HPV-DNA in any sample (95 % Confidence Interval [CI] 0-3.3 %), superficial tumors (95 % CI 0-6.4 %) or in invasive tumors (95 % CI 0-8.6 %) with correct positive controls.

Conclusions: Using a broad, sensitive assay with prospectively collected specimens of a Central European population we could not detect HPV-DNA in any of the cases. Our results suggest that it is unlikely that HPV infections play a major role in the development of urothelial bladder cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13027-015-0028-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576373PMC
September 2015

Serious outbreak of human metapneumovirus in patients with hematologic malignancies.

Leuk Lymphoma 2016 30;57(3):623-7. Epub 2015 Jun 30.

a III. Medical Department, Technische Universität München , Munich , Germany.

Human metapneumovirus (hMPV) is an important cause of lower respiratory tract infection. In healthy subjects infections are usually mild and rarely necessitate hospitalization. However, more serious outcomes have been described for allogeneic stem cell transplant recipients. This study reports an outbreak of hMPV A2 infection in severely immunocompromised adult hematologic cancer patients in a tertiary care unit. HMPV RNA was detected in bronchoalveolar lavage or produced sputum from patients presenting with typical clinical features. A total of 15 patients were diagnosed in a period of 7 weeks. Molecular subtyping revealed infection with genotype A2a virus, implicating nosocomial transmission. Eleven patients (73%) were treated with intravenous immunoglobulins and ribavirin. Ten patients (65%) presented with severe dyspnea, five (33%) required mechanical ventilation. Four patients (26.6%) died from hMPV-associated pneumonia and consequent multi-organ failure. Thus, hMPV is a critical pathogen for patients with hematologic cancers warranting early detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428194.2015.1067699DOI Listing
December 2016

Potential impact of human papilloma virus on survival of basaloid squamous carcinoma of the head and neck.

Oncotarget 2015 Feb;6(5):3462-70

Department of Otorhinolaryngology, Technical University Munich, München, Germany.

Objectives: Basaloid-squamous-carcinomas (BSCC) have been considered as aggressive variants of common squamous-cell-carcinomas (HNSCC). Recent studies demonstrated a different clinical course depending on the tumour site. The aim of the study is to analyze the histopathologic/clinical features of BSCC/HNSCC resolved by the HPV-status.

Methods: We analysed the histopathologic/clinical features of BSCC (n=59) and HNSCC (n=981), subdivided due to the HPV status. Differences were analysed using Chi square, Fisher exact, and student's t-test. Survival rates were calculated by Kaplan-Meier and log-rank test. Prognostic variables were subsequently evaluated by Cox regression.

Results: Our cohort was congruent with the literature regarding sex, age, metastases, and a predilection in the oropharynx. HNSCC/BSCC did not show a different disease-specific-survival. After UICC matching, univariate analysis revealed a better survival of UICC stage IVa BSCC compared to HNSCC (69% vs. 42%, p=0.022) that was associated with a better response to radio-chemotherapy (p = 0.009). These results referred to the high prevalence of HPV+ (86%) oropharyngeal BSCC. Subgroup analysis demonstrated a better survival of HPV+ oropharyngeal BSCC than HPV- BSCC (p=0.017).

Conclusion: The clinical outcome in BSCC depends on the tumour site and HPV-status. Prospective studies have to evaluate the beneficial application of postoperative radio-chemotherapy in HPV+ BSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413667PMC
http://dx.doi.org/10.18632/oncotarget.3062DOI Listing
February 2015

Suppression of cross coupling in an external resonator for a diode laser bar with 19 single emitters.

Opt Lett 2015 Feb;40(4):641-4

We present an external cavity in a quasi-Littrow configuration for a diode laser bar with 19 single emitters and the individual spectral stabilization, ranging from wavelengths between 970 and 980 nm corresponding to each emitter. The imaging of the vertical waveguide mode onto a blazed grating acting as a diffractive optical element is realized with a beam transformation system that swaps the vertical and lateral axes. Along with a feedback intensity of <10%, the reduction of the divergence due to a beam expander results in high losses for cross coupling modes. We demonstrate the possibility to suppress cross coupling and that even a process-related small smile error has a positive effect on the quality of the spectral stabilization in a quasi-Littrow configuration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OL.40.000641DOI Listing
February 2015

[Carl Friedrich von Weizsäcker (1912-2007): scientist and citizen].

Authors:
Dieter Hoffmann

Acta Hist Leopoldina 2014 (63):23-52

This contribution provides an introductory overview of the life and work of Carl Friedrich von Weizsäcker for the present volume. It presents him as a prominent scholar of the twentieth century. This pupil of Werner Heisenberg made fundamental contributions to physics, specifically, nuclear physics, and after World War II was able to excel as a highly acknowledged philosopher of science and pioneer in twentieth-century conflict and peace research. Beyond science, politics and religion also counted among the defining influences of Weizsäcker's life, which also molded him into civic leadership. This aspect is treated particularly in the second and central part of this article, which discusses and closely documents his membership in the Leopoldina and his engagement elsewhere, particularly in the sphere of East German church activities.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2014

[Introduction. Carl Friedrich von Weizsäcker].

Acta Hist Leopoldina 2014 (63):13-20

View Article and Find Full Text PDF

Download full-text PDF

Source
September 2014

Challenges in RNA virus bioinformatics.

Bioinformatics 2014 Jul 3;30(13):1793-9. Epub 2014 Mar 3.

Friedrich-Schiller-University Jena, Faculty of Mathematics und Computer Science, Leutragraben 1, 07743 Jena, Germany, Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, SIB Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland, Universitätsklinikum Bonn, Institut für Virologie, Sigmund-Freud-Str. 25, 53127 Bonn, Technische Universität Muenchen, Wissenschaftszentrum Weihenstephan, Am Forum 1, 85354 Freising, Helmholtz Center Munich-German Research Center for Environmental Health (GmbH), Institute of Bioinformatics and Systems Biology, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany, Moscow Institute of Physics and Technology, Institutskii Per. 9, Moscow Region, Dolgoprudny 141700, Russia, Institut für theoretische Chemie, Universität Wien, Währingerstraße 17, A-1090 Wien, Austria, Institute of Virology, Technical University of Munich, Trogerstr. 30, 81675 München, Germany, University of Leipzig, Faculty of Mathematics and Computer Science, Institute for Computer Science, Augustusplatz 10, 04109 Leipzig, Germany, Division of Computational Systems Biology, Department of Microbiology and Ecosystem Science, Universität Wien, Althanstraße 14, 1090 Wien, Austria, Department of Computer Science and Interdisciplinary Center of Bioinformatics, University of Leipzig, Härtelstraße 16-18, D-04107 Leipzig, Max Planck Institute for Mathematics in the Sciences, Inselstraße 22, D-04103 Leipzig, Germany and The Santa Fe Institute, 1399 Hyde Park Rd., Santa Fe, NM 87501, USAFriedrich-Schiller-University Jena, Faculty of Mathematics und Computer Science, Leutragraben 1, 07743 Jena, Germany, Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, SIB Swiss Institute of Bioinformatics, CH-4058 Basel, Switzerland, Universitätsklinikum Bonn, Institut für Virologie, Sigmund-Freud-Str. 25, 53127 Bonn, Technische Universität Muenchen, Wissenschaftszentrum Weihenstephan, Am Forum 1, 85354 Freising, Helmholtz

Motivation: Computer-assisted studies of structure, function and evolution of viruses remains a neglected area of research. The attention of bioinformaticians to this interesting and challenging field is far from commensurate with its medical and biotechnological importance. It is telling that out of >200 talks held at ISMB 2013, the largest international bioinformatics conference, only one presentation explicitly dealt with viruses. In contrast to many broad, established and well-organized bioinformatics communities (e.g. structural genomics, ontologies, next-generation sequencing, expression analysis), research groups focusing on viruses can probably be counted on the fingers of two hands.

Results: The purpose of this review is to increase awareness among bioinformatics researchers about the pressing needs and unsolved problems of computational virology. We focus primarily on RNA viruses that pose problems to many standard bioinformatics analyses owing to their compact genome organization, fast mutation rate and low evolutionary conservation. We provide an overview of tools and algorithms for handling viral sequencing data, detecting functionally important RNA structures, classifying viral proteins into families and investigating the origin and evolution of viruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btu105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110044PMC
July 2014

High-power dense wavelength division multiplexing of multimode diode laser radiation based on volume Bragg gratings.

Opt Lett 2013 Aug;38(16):3154-7

We present a dense wavelength division multiplexer based on volume Bragg gratings (VBGs) with a channel spacing of Δλ = 1.5 nm. Multiplexing efficiencies of ηSM = 97% have been demonstrated with single-mode, frequency-stabilized diode laser radiation. By use of VBGs in an external-cavity laser we constrict the spectral bandwidth of passively cooled multimode diode laser bars with 19 broad-area emitters to δλ95% = 120 pm. When the multimode high-power diode laser radiation with a beam propagation factor of M(2) ≈ 45 is overlaid, the multiplexing efficiency decreases to ηMM = 85%. Temperature control of the VBGs expands the high-efficiency operation range.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OL.38.003154DOI Listing
August 2013

New norovirus classified as a recombinant GII.g/GII.1 causes an extended foodborne outbreak at a university hospital in Munich.

J Clin Virol 2013 Sep 9;58(1):24-30. Epub 2013 Jul 9.

Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Trogerstr. 30, 81675 Munich, Germany.

Background: Noroviruses are among the most prevalent causative agents for gastroenteritis worldwide. The low infectious dose, its stability in the environment, and its genetic variability enable the virus to cause outbreaks, especially in health care facilities and other similar settings. Genotype II.4 has been most prevalent over the last years.

Objectives: To characterize an extended norovirus outbreak at a university hospital in Munich, Germany, molecularly and epidemiologically.

Study Design: The outbreak affecting more than 100 persons within 3 days was monitored by real time PCR. The rapid onset indicated a food-borne outbreak. Rigorous hygienic measures, including disinfection procedures and closure of wards helped contain the outbreak within 6 days. A 2193 nt sequence covering polymerase (825 nt) and capsid gene (1388 nt) was characterized from 4 specimens derived from different wards and the catering facility.

Results: Our polymerase sequences were classified GII.g, whereas the capsid belonged to GII.1. Recombination analysis revealed a putative breakpoint at a typical location. Our sequenced region clustered with GIIg/GII.1 sequences first detected in Hungary, Belgium, and the US in 2010. p-Distances on nucleic acid level were 0.18 and 0.21, respectively.

Conclusions: Our data establish a novel strain classified as GII.g/GII.1 as the causative agent for an extended outbreak.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcv.2013.06.018DOI Listing
September 2013

Simulation of spectral stabilization of high-power broad-area edge emitting semiconductor lasers.

Opt Express 2013 Jul;21(13):15553-67

Chair for Laser Technology, RWTH Aachen University, 52056 Aachen, Germany.

The simulation of spectral stabilization of broad-area edge-emitting semiconductor diode lasers is presented in this paper. In the reported model light-, temperature- and charge carrier-distributions are solved iteratively in frequency domain for transverse slices along the semiconductor heterostructure using wide-angle finite-difference beam propagation. Depending on the operating current the laser characteristics are evaluated numerically, including near- and far-field patterns of the astigmatic laser beam, optical output power and the emission spectra, with central wavelength and spectral width. The focus of the model lies on the prediction of influences on the spectrum and power characteristics by frequency selective feedback from external optical resonators. Results for the free running and the spectrally stabilized diode are presented.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OE.21.015553DOI Listing
July 2013

Apodized holographic beam combiners for dense wavelength multiplexing based on Gaussian-beam interference.

Opt Lett 2012 Dec;37(24):5205-7

RWTH Aachen University Steinbachstraße 15, Aachen 52074, Germany.

The brightness of high-power diode-laser systems can be significantly increased by using dense wavelength-multiplexing technologies. Among these technologies, state-of-the-art volume holographic gratings (VHGs) are suitable wavelength-selective filters for scaling the power of frequency-stabilized high-power lasers. The frequency spacing is limited due to the sidelobes of the spectral filter characteristic. In this Letter, we present the simulation results of novel apodized VHGs produced by Gaussian-beam interference. Apodized VHGs offer increased sidelobe suppression of up to 22 dB with conventional grating dimensions and, moreover, will improve the spectral brightness of dense wavelength-multiplexing systems by a factor of approximately six.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OL.37.005205DOI Listing
December 2012