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The combined density functional theory and multireference configuration interaction (DFT/MRCI) method is a powerful tool for the calculation of excited electronic states of large molecules. Selleckchem Lithocholic acid There exists, however, a large amount of superfluous configurations in a typical DFT/MRCI wave function. We show that this deadwood may be effectively removed using a simple configuration pruning algorithm based on second-order Epstein-Nesbet perturbation theory. The resulting method, which we denote p-DFT/MRCI, is shown to result in orders of magnitude saving in computational timings, while retaining the accuracy of the original DFT/MRCI method.Amyloid fibrils are structurally heterogeneous protein aggregates that are implicated in a wide range of neurodegenerative and other proteopathic diseases. These fibrils exist in a variety of different tertiary and higher-level structures, and this exhibited polymorphism greatly complicates any structural study of amyloid fibrils. In this work, we demonstrate a method of using polarization-resolved microscopy to directly observe the structural heterogeneity of individual amyloid fibrils using amyloid-bound fluorophores. We formulate a mathematical quantity, helical anisotropy, which utilizes the polarized emission of amyloid-bound fluorophores to report on the local structure of individual fibrils. Using this method, we show how model amyloid fibrils generated from short peptides exhibit diverse structural properties both between different fibrils and within a single fibril, in a manner that is replicated for fibrils assembled from longer proteins. Our method represents an accessible and easily adaptable technique by which polymorphism in the structure of amyloid fibrils can be probed. Additionally, the methodology we describe here can be easily extended to the study of other fibrillar and otherwise ordered supramolecular structures.

Asthma is a heterogenous disease that can be classified into eosinophilic (type 2-high) and noneosinophilic (type 2-low) endotypes. The type 2-low endotype of asthma can be characterized by the presence of neutrophilic airway inflammation that is poorly responsive to corticosteroids. Dysregulated innate immune responses to microbial products including Toll-like receptor (TLR) ligands have been associated with the pathogenesis of neutrophilic asthma. The key molecules that regulate inflammatory responses in individuals with neutrophilic asthma remain unclear. We previously reported that the immunoregulatory receptor neuropilin-2 (NRP2) is expressed by murine and human alveolar macrophage(AM) and suppresses lipopolysaccharide (LPS)-induced neutrophilic airway inflammation.

Here, we investigated the immunoregulatory role of NRP2 in a mouse model of neutrophilic asthma.

We found that TLR ligands, but not T helper 2 (Th2)-promoting adjuvants, induced NRP2 expression by AM. Using an LPS-mediated model of neutrophilic asthma, we demonstrate that NRP2 was increased in AMand other lung antigen-presenting cells following airway challenge with antigen. Conditional deletion of NRP2 in myeloid cells exacerbated airway inflammation in a neutrophilic asthma model. In contrast, myeloid-specific ablation of NRP2 did not affect airway inflammation in a Th2-mediated eosinophilic asthma model. Myeloid-specific ablation of NRP2 did not affect Th1/Th17 responses to inhaled antigens or expression of neutrophil chemokines but rather resulted in impaired efferocytosis by AM, which is necessary for effective resolution of airway inflammation.

Our findings suggest that NRP2 is a negative regulator of airway inflammation associated with neutrophilic asthma.

Our findings suggest that NRP2 is a negative regulator of airway inflammation associated with neutrophilic asthma.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an emerging virus in late 2019 causing coronavirus disease 2019 (COVID-19), has caused a catastrophic effect, resulting in an unprecedented global crisis. The immunopathology of COVID-19 appears to be clearly associated with a dysregulated immune response leading to organ failure and death. Similarly, over two billion people worldwide are infected with helminth, with those living in low-middle-income countries disproportionately affected. Helminth infections have been shown to possess immunomodulatory effects in several conditions. Helminth co-infection in COVID-19 patients is one of the potential reasons for global attention to answer why COVID-19 severity is still lower in helminth endemic countries. Recent studies have shown that helminth endemic countries showed fewer cases and deaths so far and helminth co-infection might reduce the severity of COVID-19. Moreover, lessons from other diseases with helminth co-infection have been shown to substantially reduce vaccine efficacy that could also be implicated for COVID-19. This immunomodulatory effect of helminth has intended and unintended consequences, both advantageous and disadvantageous which could decrease the severity of COVID-19 and COVID-19 vaccine efficacy respectively. Herewith, we discuss the overview of COVID-19 immune response, immunomodulatory effects of helminth co-infections in COVID-19, lessons from other diseases, and perspectives on the efficacy of COVID-19 vaccines.DNA methylation is a common epigenetic signalling tool and an important biological process which is widely studied in a large array of species. The presence, level and function of DNA methylation vary greatly across species. In some insects, DNA methylation systems are minimal, and overall methylation rates tend to be low in all studied insect species. Low methylation levels probed by whole-genome bisulphite sequencing require great care with respect to data quality control and interpretation. Here, we introduce BWASP/R, a complete workflow that allows efficient, scalable and entirely reproducible analyses of raw DNA methylation sequencing data. Consistent application of quality control filters and analysis parameters provides fair comparisons among different studies and an integrated view of all experiments on one species. We describe the capabilities of the BWASP/R workflow by re-analysing several publicly available social insect WGBS data sets, comprising 70 samples and cumulatively 147 replicates from four different species. We show that the CpG methylome comprises only about 1.5% of CpG sites in the honeybee genome and that the cumulative data are consistent with genetic signatures of site accessibility and physiological control of methylation levels.Cartilage damage typically starts at its surface, either due to wear or trauma. Treatment of these superficial defects is important in preventing degradation and osteoarthritis. Biomaterials currently used for deep cartilage defects lack appropriate properties for this application. link2 Therefore, we investigated photo-crosslinked gelatin methacryloyl (gelMA) as a candidate for treatment of surface defects. It allows for liquid application, filling of surface defects and forming a protective layer after UV-crosslinking, thereby keeping therapeutic cells in place. gelMA and photo-initiator lithium phenyl-2,4,6-trimethyl-benzoylphosphinate (Li-TPO) concentration were optimized for application as a carrier to create a favorable environment for human articular chondrocytes (hAC). Primary hAC were used in passages 3 and 5, encapsulated into two different gelMA concentrations (7.5 wt% (soft) and 10 wt% (stiff)) and cultivated for 3 weeks with TGF-β3 (0, 1 and 10 ng/mL). Higher TGF-β3 concentrations induced spherical cell morphology independent of gelMA stiffness, while low TGF-β3 concentrations only induced rounded morphology in stiff gelMA. Gene expression did not vary across gel stiffnesses. As a functional model gelMA was loaded with two different cell types (hAC and/or human adipose-derived stem cells [ASC/TERT1]) and applied to human osteochondral osteoarthritic plugs. GelMA attached to the cartilage, smoothened the surface and retained cells in place. Resistance against shear forces was tested using a tribometer, simulating normal human gait and revealing maintained cell viability. In conclusion gelMA is a versatile, biocompatible material with good bonding capabilities to cartilage matrix, allowing sealing and smoothening of superficial cartilage defects while simultaneously delivering therapeutic cells for tissue regeneration.Chitinase 3-like 1 (Chi3L1) is associated with various biological processes, such as inflammation, tissue repair, proliferation, cell survival, invasion, and extracellular matrix remodeling. Recent studies indicated that Chi3L1 is critical for cancer development and metastasis. In this study, we demonstrate that Chi3L1 serum and tissue levels were significantly increased in lung cancer patients compared with controls. link3 We previously developed an anti-Chi3L1-humanized antibody, and here, we investigate its antitumor and antimetastatic effect. The anti-Chi3L1 antibody attenuated tumor growth and metastasis both in vitro and in vivo in a lung cancer mouse model. These inhibitory effects are associated with signal transducer and activator of transcription 6 (STAT6)-dependent M2 polarization inhibition. Proteomics analysis revealed that plasminogen (PLG) interacts with Chi3L1 and affects M2 polarization. Chi3L1 plays a critical role in lung cancer progression, and the anti-Chi3L1 antibody could be a new anticancer therapy.Drug-resistant epilepsy (DRE) affects approximately one-third of the patients with epilepsy. Based on experimental findings from animal models and brain tissue from patients with DRE, different hypotheses have been proposed to explain the cause(s) of drug resistance. One is the intrinsic severity hypothesis that posits that drug resistance is an inherent property of epilepsy related to disease severity. Seizure frequency is one measure of epilepsy severity, but frequency alone is an incomplete measure of severity and does not fully explain basic research and clinical studies on drug resistance; thus, other measures of epilepsy severity are needed. One such measure could be pathological high-frequency oscillations (HFOs), which are believed to reflect the neuronal disturbances responsible for the development of epilepsy and the generation of spontaneous seizures. In this manuscript, we will briefly review the intrinsic severity hypothesis, describe basic and clinical research on HFOs in the epileptic brain, and based on this evidence discuss whether HFOs could be a clinical measure of epilepsy severity. Understanding the mechanisms of DRE is critical for producing breakthroughs in the development and testing of novel strategies for treatment.

Climate change, the increase of travel with infected animals from endemic areas, the introduction of new vectors in these areas and environmental changes caused by human activity, among other factors, have contributed to the establishment and increase of canine vector-borne diseases (CVBDs), several of which are zoonotic and pose a risk to the human population. In Colombia, there are very few studies that address the prevalence of these diseases. The objective of this study was to update the prevalence of cardiopulmonary dirofilariosis, anaplasmosis, ehrlichiosis and Lyme borreliosis in dogs in Barranquilla and Puerto Colombia, areas of northern Colombia.

The present study included 354 dogs presented to veterinary clinics for routine health examination and foundations for stray dogs between November 2016 and July 2018.

The percentage of dogs positive for Ehrlichia spp. was 61.86%, followed by 22.03% for Anaplasma spp., 11.30% positive for Dirofilaria immitis antigens and 0.56% positive for Borrelia burgdorferi.