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A segmented contact method for the measurement of optical gain is developed for the case of strong current spreading. A simple model of current spreading in a ridge laser with a segmented contact is proposed and analyzed. We show that current spreading effects should be taken into account in lasers with low threshold current densities and high "opening" voltages. When applied to interband cascade lasers, the method gives an internal optical loss of ~10-17 cm-1 and a differential gain of ~2.9 cm/A at 80 K, which agrees well with previously reported Hakki-Paoli data. The limitations of the technique are discussed. [ABSTRACT FROM AUTHOR]

A new alkaloid, isostenine ( 1 ), together with two known ones neotuberostemonine ( 2 ) and bisdehydroneotuberostemonine ( 3 ) were isolated from the root of Stemona collinsae . Their structures were determined by various spectral methods. [ABSTRACT FROM AUTHOR]

Studies Swiss theologian Hans Urs von Balthasar as an interpreter of Western culture and analyzes his theological synthesis as an attempt at an integration of theology in culture. What characterizes the Western civilization Balthasar has embodied; Attempt to integrate theology and culture; Depiction of the economy of salvation.

Keywords: Alzheimer's disease; neurodegenration; autoimmunity; T cell responses; transcriptomics; neuroantigens EN Alzheimer's disease neurodegenration autoimmunity T cell responses transcriptomics neuroantigens N.PAG N.PAG 1 01/18/21 20210113 NES 210113 In the original article, we neglected to include the funder NIH/NIA, P30 AG066462 to KM. Alzheimer's disease, neurodegenration, autoimmunity, T cell responses, transcriptomics, neuroantigens. [Extracted from the article]

Despite the prevalence and medical significance of human cytomegalovirus (HCMV) infections, a systematic analysis of the targets of T cell recognition in humans that spans the entire genome and includes recently described potential novel open reading frames (ORFs) is not available. Here, we screened a library of epitopes predicted to bind HLA class II that spans over 350 different HCMV ORFs and includes ~150 previously described and ~200 recently described potential novel ORFs by using an ex vivo gamma interferon (IFN-γ) FluoroSpot assay. We identified 235 unique HCMVspecific epitopes derived from 100 ORFs, some previously described as immunodominant and others that were not previously described to be immunogenic. Of those, 41 belong to the set of recently reported novel ORFs, thus providing evidence that at least some of these are actually expressed in vivo in humans. These data reveal that the breadth of the human T cell response to HCMV is much greater than previously thought. The ORFs and epitopes identified will help elucidate how T cell immunity relates to HCMV pathogenesis and instruct ongoing HCMV vaccine research. IMPORTANCE To understand the crucial role of adaptive immunity in controlling cytomegalovirus infection and disease, we systematically analyzed the CMV "ORFeome" to identify new CMV epitopes targeted primarily by CD4 T cells in humans. Our study identified >200 new T cell epitopes derived from both canonical and novel ORFs, highlighting the substantial breadth of the anti-CMV T cell response and providing new targets for vaccine design. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxins (BoNT) are potential biothreat agents due to their high lethality, potency, and ease of distribution, thus the development of antitoxins is a high priority to the US government. This study examined pre-clinical pharmacokinetic studies in rats of four oligoclonal anti-BoNT mAb-based therapeutics (NTM-1631, NTM-1632, NTM-1633, NTM-1634) for five BoNT serotypes (A, B, E, C, and D). NTM-1631, NTM-1632, and NTM-1633 each consist of three IgG1 mAbs, each with a distinct human or humanized variable region which bind to distinct epitopes on BoNT serotype A, B, or E respectively. NTM-1634 consists of four human immunoglobulin G1 (IgG1) mAbs binding BoNT C/D mosaic toxins. The mechanism of these antitoxins requires that three antibodies simultaneously bind toxin to achieve rapid clearance. Rats (total 378) displayed no adverse clinical signs attributed to antibody treatment from any of the antitoxins. Pharmacokinetic evaluation demonstrated that the individual mAbs are slowly eliminated, exhibiting dose-dependent exposure and long elimination half-lives ranging from 6.5 days to 10 days. There were no consistent differences observed between males and females or among the individual antibodies in each formulation in half-life. Anti-drug antibodies (ADA) were observed, as expected for human antibodies administered to rats. The results presented were used to support the clinical investigation of antibody-based botulism antitoxins. [ABSTRACT FROM AUTHOR]

The mosquito-borne Zika virus (ZIKV) has spread rapidly into regions where dengue virus (DENV) is endemic, and flavivirus cross-reactive T cell responses have been observed repeatedly in animal models and in humans. Preexisting cellular immunity to DENV is thought to contribute to protection in subsequent ZIKV infection, but the epitope targets of cross-reactive T cell responses have not been comprehensively identified. Using human blood samples from the regions of Nicaragua and Sri Lanka where DENV is endemic that were collected before the global spread of ZIKV in 2016, we employed an in vitro expansion strategy to map ZIKV T cell epitopes in ZIKV-unexposed, DENV-seropositive donors. We identified 93 epitopes across the ZIKV proteome, and we observed patterns of immunodominance that were dependent on antigen size and sequence identity to DENV. We confirmed the immunogenicity of these epitopes through a computational HLA binding analysis, and we showed that cross-reactive T cells specifically recognize ZIKV peptides homologous to DENV sequences. We also found that these CD4 responses were derived from the memory T cell compartment. These data have implications for understanding the dynamics of flavivirus-specific T cell immunity in areas of endemicity. [ABSTRACT FROM AUTHOR]

An array of gene silencing pathways share a common early step: Dicer cleaves double-stranded RNA (dsRNA) into ∼20–25 nucleotide fragments that direct the silencing machinery to specific targets. A recent report in Cell reveals how Dicer''s two RNase III domains collaborate during dsRNA processing and sets the stage for a deeper understanding of Dicer''s roles in later phases of silencing complex assembly. [Copyright &y& Elsevier]

Background: Interferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway. Methods: We performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death. Results: We show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins. Conclusions: Our results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance. [ABSTRACT FROM AUTHOR]

Unwanted immune responses against protein therapeutics can reduce efficacy or lead to adverse reactions. T-cell responses are key in the development of such responses, and are directed against immunodominant regions within the protein sequence, often associated with binding to several allelic variants of HLA class II molecules (promiscuous binders). Herein, we report a novel computational strategy to predict 'de-immunized' peptides, based on previous studies of erythropoietin protein immunogenicity. This algorithm (or method) first predicts promiscuous binding regions within the target protein sequence and then identifies residue substitutions predicted to reduce HLA binding. Further, this method anticipates the effect of any given substitution on flanking peptides, thereby circumventing the creation of nascent HLA-binding regions. As a proof-of-principle, the algorithm was applied to Vatreptacog α, an engineered Factor VII molecule associated with unintended immunogenicity. The algorithm correctly predicted the two immunogenic peptides containing the engineered residues. As a further validation, we selected and evaluated the immunogenicity of seven substitutions predicted to simultaneously reduce HLA binding for both peptides, five control substitutions with no predicted reduction in HLA-binding capacity, and additional flanking region controls. In vitro immunogenicity was detected in 21·4% of the cultures of peptides predicted to have reduced HLA binding and 11·4% of the flanking regions, compared with 46% for the cultures of the peptides predicted to be immunogenic. This method has been implemented as an interactive application, freely available online at . [ABSTRACT FROM AUTHOR]

• Induction heating can lower the reaction temperature by 30 ˚C. • Induction heating can achieve a minimal temperature gradient in the catalyst bed. • Low power consumption and high production can be reached with the bed design. The application of induction heating (IH) to provide heat for chemical reactions has received great attention due to its potential to electrify chemical reactions. Biomass-based production of acetaldehyde from ethanol has gained rising interest since it provides an alternative sustainable method instead of the fossil-fuel-based output using acetylene and formaldehyde in the presence of a catalyst. The dehydrogenation of ethanol can be catalyzed by supported copper catalysts. The reaction is typically carried out at high temperatures, around 250–300 °C, without oxygen. The resulting product mixture usually contains acetaldehyde, as well as other byproducts such as ethylene and hydrogen gas. The acetaldehyde can be separated from the other components using distillation or other separation techniques. In this work, we studied the catalyst activity with IH for the first time and achieved high ethanol conversion and acetaldehyde selectivity at a temperature of 30 ˚C lower than that with conventional furnace heating (CFH). A transport model was applied to design the catalyst bed configuration and improve the catalyst activity, stability, and energy efficiency by minimizing the temperature gradient. Our work suggests that the temperature distribution and the fast compensation of heat loss through IH are critical for the catalyst behavior. Both high production efficiency and energy efficiency can be achieved with IH, such that it can be an efficient and environment-friendly heating method for the chemical industry. [ABSTRACT FROM AUTHOR]