Search

Semiclassical Maxwell-Bloch equations for spontaneous emission noise yield a generalized variable-waveguide model for examining the spatio-temporal dynamics of gain-guided semiconductor laser arrays. The model shows that the dynamics of the arrays are independent of spontaneous emission noise effects but are highly sensitive to mode beating. Noise-driven rate equations and carrier distribution-related permittivity profiles elucidate the laser field and optical field confinement, respectively.

We have designed a chimeric protein by connecting a circular permutant of the α-spectrin SH3 domain to the proline-rich decapeptide APSYSPPPPP with a three-residue link. Our aim was to obtain a single-chain protein with a tertiary fold that would mimic the binding between SH3 domains and proline-rich peptides. A comparison of the circular-dichroism and fluorescence spectra of the purified chimera and the SH3 circular permutant showed that the proline-rich sequence occupies the putative SH3 binding site in a similar conformation and with comparable interactions to those found in complexes between SH3 and proline-rich peptides. Differential scanning calorimetry indicated that the interactions in the binding motif interface are highly cooperative with the rest of the structure and thus the protein unfolds in a two-state process. The chimera is more stable than the circular permutant SH3 by 6–8 kJ mol−1 at 25°C and the difference in their unfolding enthalpy is approximately 32 kJ mol−1, which coincides with the values found for the binding of proline-rich peptides to SH3 domains. This type of chimeric protein may be useful in designing SH3 peptide ligands with improved affinity and specificity. [Copyright &y& Elsevier]

An abstract of the article "Echocardiographic prognostic factors in pulmonary arterial hypertension," by R. Tello Meneses and colleagues is presented.

An abstract of the article "Echocardiographic determinants of functional capacity in pulmonary arterial hypertension," by C. Jimenez Lopez-Guarch and colleagues is presented.

Protein mechanical stability determines the function of a myriad of proteins, especially proteins from the extracellular matrix. Failure to maintain protein mechanical stability may result in diseases and disorders such as cancer, cardiomyopathies, or muscular dystrophy. Thus, developing mutation-free approaches to enhance and control the mechanical stability of proteins using pharmacology-based methods may have important implications in drug development and discovery. Here, we present the first approach that employs computational high-throughput virtual screening and molecular docking to search for small molecules in chemical libraries that function as mechano-regulators of the stability of human cluster of differentiation 4, receptor of HIV-1. Using single-molecule force spectroscopy, we prove that these small molecules can increase the mechanical stability of CD4D1D2 domains over 4-fold in addition to modifying the mechanical unfolding pathways. Our experiments demonstrate that chemical libraries are a source of mechanoactive molecules and that drug discovery approaches provide the foundation of a new type of molecular function, that is, mechano-regulation, paving the way toward mechanopharmacology., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA (hDRAGA) mice generate antigen-specific class switched antibodies to several pathogens, but whether they do so in HIV infection and the extent to which their secondary lymphoid tissues (sLT) support germinal center responses is unknown. hDRAGA mice were evaluated for their ability to support HIV replication, generate virus-specific antibody responses, develop splenocyte subsets, and organize sLT architecture. hDRAGA mice supported persistent HIV replication and developed modest levels of gp41-specific human IgM and IgG. Spleens from uninfected and HIV infected hDRAGA mice contained differentiated B and CD4 + T cell subsets including germinal center (GC) B cells and T follicular helper cells (TFH); relative expansions of TFH and CD8 + T cells, but not GC B cells, occurred in HIV-infected hDRAGA mice compared to uninfected animals. Immunofluorescent staining of spleen and mesenteric lymph node sections demonstrated atypical morphology. Most CD4 + and CD8 + T cells resided within CD20 hi areas. CD20 hi areas lacked canonical germinal centers, as defined by staining for IgD - Ki67 + cells. No human follicular dendritic cells (FDC) were detected. Mouse FDC were distributed broadly throughout both CD20 hi and CD20 lo regions of sLT. HIV RNA particles were detected by in situ hybridization within CD20 + areas and some co-localized with mouse FDC. Viral RNA + cells were more concentrated within CD20 hi compared to CD20 lo areas of sLT, but differences were diminished in spleen and eliminated in mesenteric lymph nodes when adjusted for CD4 + cell frequency. Thus, hDRAGA mice recapitulated multiple aspects of HIV pathogenesis including HIV replication, relative expansions in TFH and CD8 + T cells, and modest HIV-specific antibody production. Nevertheless, classical germinal center morphology in sLT was not observed, which may account for the inefficient expansion of GC B cells and generation of low titer human antibody responses to HIV-1 in this model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ollerton, Folkvord, Peachman, Shashikumar, Morrison, Jagodzinski, Peel, Khreiss, D’Aquila, Casares, Rao and Connick.)

Multisensory sensitivity (MSS), observed in some chronic pain patients, may reflect a generalized central nervous system sensitivity. While several surveys measure aspects of MSS, there remains no gold standard. We explored the underlying constructs of 4 MSS-related surveys (80 items in total) using factor analyses using REDCap surveys (N = 614, 58.7% with pain). Four core- and 6 associated-MSS factors were identified from the items assessed. None of these surveys addressed all major sensory systems and most included additional related constructs. A revised version of the Somatosensory Amplification Scale was developed, encompassing 5 core MSS systems: vision, hearing, smell, tactile, and internal bodily sensations: the 12-item Multisensory Amplification Scale (MSAS). The MSAS demonstrated good internal consistency (alpha = 0.82), test-retest reliability (ICC 3,1  = 0.90), and construct validity in the original and in a new, separate cohort (R = 0.54-0.79, P < .0001). Further, the odds of having pain were 2-3.5 times higher in the highest sex-specific MSAS quartile relative to the lowest MSAS quartile, after adjusting for age, sex, BMI, and pain schema (P < .03). The MSAS provides a psychometrically comprehensive, brief, and promising tool for measuring the core-dimensions of MSS. PERSPECTIVE: Multiple multisensory sensitivity (MSS) tools are used, but without exploration of their underlying domains. We found several measures lacking core MSS domains, thus we modified an existing scale to encompass 5 core MSS domains: light, smell, sound, tactile, and internal bodily sensations using only 12 items, with good psychometric properties., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

A range of biopharmaceutical products are used to target Vascular Endothelial Growth Factor (VEGF), including Eylea® (aflibercept, AFL) and Zaltrap® (ziv-aflibercept, ziv-AFL). The first is indicated for ophthalmological diseases such as neovascular (wet) age-related macular degeneration, while the second is used in the treatment of metastatic colorectal cancer. The stability of AFL in prefilled syringes has been widely studied; however, no research has yet been done on the stability of ziv-AFL in polyolefin infusion bags. Therefore, the purpose of the present research is to evaluate the stability of ziv-AFL (Zaltrap®) clinical solutions prepared under aseptic conditions in polyolefin infusion bags at two different concentrations, i.e. 4.0 and 0.6 mg/mL, and stored refrigerated in darkness at 2-8 °C for 14 days. With that aim, the ziv-AFL clinical solutions were assessed by analysing changes in its physicochemical and functional properties. The distribution of the particulates was studied over a range of 0.001-10 μm by Dynamic Light Scattering (DLS); oligomers were analysed by Size-Exclusion High-Performance Chromatography with Diode Array Detection (SE/HLPC-DAD); the secondary structure of the protein was studied by far UV Circular Dichroism (CD) and the tertiary structure by Intrinsic Tryptophan Fluorescence (IT-F) and Intrinsic Protein Fluorescence (IP-F); charge variants were assessed by Strong Cation Exchange Ultra-High-Performance Chromatography with UV detection (SCX/UHPLC-UV); functionality was evaluated by ELISA by measuring the biological activity as manifested in the extension of the immunological reaction of the ziv-AFL with its antigen (VEGF). Neither aggregation nor oligomerization were detected by the techniques mentioned above. Secondary and tertiary structures remained unchanged over the 14-day period, as did charge variants. The functionality observed initially was maintained along time. Therefore, it could be proposed that the ziv-AFL clinical solutions studied showed great physicochemical and functional stability over a period of two weeks, regardless of the concentration, i.e. 4 or 0.6 mg/mL., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

We have engineered a Human Immune System (HIS)-reconstituted mouse strain (DRAGA mouse: HLA-A2. HLA-DR4. Rag1 KO. IL-2Rγc KO. NOD) in which the murine immune system has been replaced by a long-term, functional HIS via infusion of CD34 + hematopoietic stem cells (HSC) from cord blood. Herein, we report that the DRAGA mice can sustain inducible and transmissible H1N1 and H3N2 influenza A viral (IAV) infections. DRAGA female mice were significantly more resilient than the males to the H3N2/Aichi infection, but not to H3N2/Hong Kong, H3N2/Victoria, or H1N1/PR8 sub-lethal infections. Consistently associated with large pulmonary hemorrhagic areas, both human and murine Factor 8 mRNA transcripts were undetectable in the damaged lung tissues but not in livers of DRAGA mice advancing to severe H1N1/PR8 infection. Infected DRAGA mice mounted a neutralizing anti-viral antibody response and developed lung-resident CD103 T cells. These results indicate that the DRAGA mouse model for IAV infections can more closely approximate the human lung pathology and anti-viral immune responses compared to non-HIS mice. This mouse model may also allow further investigations into gender-based resilience to IAV infections, and may potentially be used to evaluate the efficacy of IAV vaccine regimens for humans.