The Whorf hypothesis holds that we view the world filtered through the semantic categories of our native language. Over the years, consensus has oscillated between embrace and dismissal of this ...hypothesis. Here, we review recent findings on the naming and perception of color, and argue that in this semantic domain the Whorf hypothesis is half right, in two different ways: (1) language influences color perception primarily in half the visual field, and (2) color naming across languages is shaped by both universal and language-specific forces. To the extent that these findings generalize to other semantic domains they suggest a possible resolution of the debate over the Whorf hypothesis.
The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of ...novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents.
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•Hybridization of oseltamivir with heteroaryl groups generated novel anti-influenza agents.•Compound 6f and 10i displayed IC50 values at nM level against neuraminidase of a clinical isolate.•In silico ADME predictions showed that 6f and 10i had comparable properties with oseltamivir.•Molecular docking studies showed 6f and 10i adopted different binding modes with neuraminidase.
The coronavirus disease 2019 (COVID-19) pandemic has posed substantial challenges to the formulation of preventive interventions, particularly since the effects of physical distancing measures and ...upcoming vaccines on reducing susceptible social contacts and eventually halting transmission remain unclear. Here, using anonymized mobile geolocation data in China, we devise a mobility-associated social contact index to quantify the impact of both physical distancing and vaccination measures in a unified way. Building on this index, our epidemiological model reveals that vaccination combined with physical distancing can contain resurgences without relying on stay-at-home restrictions, whereas a gradual vaccination process alone cannot achieve this. Further, for cities with medium population density, vaccination can reduce the duration of physical distancing by 36% to 78%, whereas for cities with high population density, infection numbers can be well-controlled through moderate physical distancing. These findings improve our understanding of the joint effects of vaccination and physical distancing with respect to a city's population density and social contact patterns.
We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly ...(I:C)/LyoVec or infection-related cytokine TNF-α to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1β, CCL5, and CXCL10 production, and antiviral interferon-β and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13. Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3
eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4
CRTH2
Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.
The nature of color categories in the world's languages is contested. One major view holds that color categories are organized around universal focal colors, whereas an opposing view holds instead ...that categories are defined at their boundaries by linguistic convention. Both of these standardly opposed views are challenged by existing data. Here, we argue for a third view based on a proposal by Jameson and D'Andrade Jameson KA, D'Andrade RG (1997) in Color Categories in Thought and Language, eds Hardin CL, Maffi L (Cambridge Univ Press, Cambridge, U.K.), pp 295-319: that color naming across languages reflects optimal or near-optimal divisions of an irregularly shaped perceptual color space. We formalize this idea, test it against color-naming data from a broad range of languages and show that it accounts for universal tendencies in color naming while also accommodating some observed cross-language variation.
Human stem cell-derived models of development and neurodegenerative diseases are challenged by cellular immaturity in vitro. Microengineered organ-on-chip (or Organ-Chip) systems are designed to ...emulate microvolume cytoarchitecture and enable co-culture of distinct cell types. Brain microvascular endothelial cells (BMECs) share common signaling pathways with neurons early in development, but their contribution to human neuronal maturation is largely unknown. To study this interaction and influence of microculture, we derived both spinal motor neurons and BMECs from human induced pluripotent stem cells and observed increased calcium transient function and Chip-specific gene expression in Organ-Chips compared with 96-well plates. Seeding BMECs in the Organ-Chip led to vascular-neural interaction and specific gene activation that further enhanced neuronal function and in vivo-like signatures. The results show that the vascular system has specific maturation effects on spinal cord neural tissue, and the use of Organ-Chips can move stem cell models closer to an in vivo condition.
•iPSC-derived neural and vascular tissue interact in Organ-Chip•Chip culture enhances neuron function and signaling•iPSC-derived vasculature affects neuron development and neuron-vasculature pathways•BMECs co-cultured on Chip co-culture activate in vivo spinal cord developmental genes
Sances et al. combine Organ-Chip technology with human induced pluripotent stem cell-derived spinal motor neurons to study the maturation effects of Organ-Chip culture. By including microvascular cells also derived from the same patient line, the authors show enhancement of neuronal function, reproduction of vascular-neuron pathways, and specific gene activation that resembles in vivo spinal cord development.
Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we ...demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.
Research addressing the occurrence, fate and effects of pharmaceuticals in the aquatic environment has expanded rapidly over the past two decades, primarily due to the development of improved ...chemical analysis methods. Significant research gaps still remain, however, including a lack of longer term, repeated monitoring of rivers, determination of temporal and spatial changes in pharmaceutical concentrations, and inputs from sources other than wastewater treatment plants (WWTPs), such as combined sewer overflows (CSOs). In addressing these gaps it was found that the five pharmaceuticals studied were routinely (51–94% of the time) present in effluents and receiving waters at concentrations ranging from single ng to μg L−1. Mean concentrations were in the tens to hundreds ng L−1 range and CSOs appear to be a significant source of pharmaceuticals to water courses in addition to WWTPs. Receiving water concentrations varied throughout the day although there were no pronounced peaks at particular times. Similarly, concentrations varied throughout the year although no consistent patterns were observed. No dissipation of the study compounds was found over a 5 km length of river despite no other known inputs to the river. In conclusion, pharmaceuticals are routinely present in semi-rural and urban rivers and require management alongside more traditional pollutants.
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Pharmaceuticals were routinely present in effluent and receiving waters.Mean concentrations were in the range of tens to hundreds ng l-1.Peak concentrations reached almost 5 μg l-1.Combined sewer overflows (CSOs) are a source of pharmaceuticals.No dissipation of pharmaceuticals was found over a 5 km length of river.
A range of pharmaceuticals were routinely present in effluent and receiving waters and were not found to dissipate over a 5 km length of river.
The threat of a pandemic outbreak of influenza virus A H5N1 has become a major concern worldwide. The nucleoprotein (NP) of the virus binds the RNA genome and acts as a key adaptor between the virus ...and the host cell. It, therefore, plays an important structural and functional role and represents an attractive drug target. Here, we report the 3.3-Å crystal structure of H5N1 NP, which is composed of a head domain, a body domain, and a tail loop. Our structure resolves the important linker segments (residues 397-401, 429-437) that connect the tail loop with the remainder of the molecule and a flexible, basic loop (residues 73-91) located in an arginine-rich groove surrounding Arg150. Using surface plasmon resonance, we found the basic loop and arginine-rich groove, but mostly a protruding element containing Arg174 and Arg175, to be important in RNA binding by NP. We also used our crystal structure to build a ring-shaped assembly of nine NP subunits to model the miniribonucleoprotein particle previously visualized by electron microscopy. Our study of H5N1 NP provides insight into the oligomerization interface and the RNA-binding groove, which are attractive drug targets, and it identifies the epitopes that might be used for universal vaccine development.--Ng, A. K.-L., Zhang, H., Tan, K., Li, Z., Liu, J.-h., Chan, P. K.-S., Li, S.-M., Chan, W.-Y., Au, S. W.-N., Joachimiak, A., Walz, T., Wang, J.-H., Shaw, P.-C. Structure of the influenza virus A H5N1 nucleoprotein: implications for RNA binding, oligomerization, and vaccine design.
Influenza virus continuously evolves to escape human adaptive immunity and generates seasonal epidemics. Therefore, influenza vaccine strains need to be updated annually for the upcoming flu season ...to ensure vaccine effectiveness. We develop a computational approach, beth-1, to forecast virus evolution and select representative virus for influenza vaccine. The method involves modelling site-wise mutation fitness. Informed by virus genome and population sero-positivity, we calibrate transition time of mutations and project the fitness landscape to future time, based on which beth-1 selects the optimal vaccine strain. In season-to-season prediction in historical data for the influenza A pH1N1 and H3N2 viruses, beth-1 demonstrates superior genetic matching compared to existing approaches. In prospective validations, the model shows superior or non-inferior genetic matching and neutralization against circulating virus in mice immunization experiments compared to the current vaccine. The method offers a promising and ready-to-use tool to facilitate vaccine strain selection for the influenza virus through capturing heterogeneous evolutionary dynamics over genome space-time and linking molecular variants to population immune response.
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