The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently ...proposed to be basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses speculating on the role of this host receptor in viral infection and pathogenesis. Here, we report that we are unable to find evidence supporting the role of basigin as a putative spike binding receptor. Recombinant forms of the SARS-CoV-2 spike do not interact with basigin expressed on the surface of human cells, and by using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed basigin-spike binding, we report no evidence for a direct interaction between the viral spike protein to either of the two common isoforms of basigin. Finally, removing basigin from the surface of human lung epithelial cells by CRISPR/Cas9 results in no change in their susceptibility to SARS-CoV-2 infection. Given the pressing need for clarity on which viral targets may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.
The fast and accurate analysis of chiral chemical mixtures is crucial for many applications but remains challenging. Here we use elliptically-polarized femtosecond laser pulses at high repetition ...rates to photoionize chiral molecules. The 3D photoelectron angular distribution produced provides molecular fingerprints, showing a strong forward-backward asymmetry which depends sensitively on the molecular structure and degree of ellipticity. Continuously scanning the laser ellipticity and analyzing the evolution of the rich, multi-dimensional molecular signatures allows us to observe real-time changes in the chemical and chiral content present with unprecedented speed and accuracy. We measure the enantiomeric excess of a compound with an accuracy of 0.4% in 10 min acquisition time, and follow the evolution of a mixture with an accuracy of 5% with a temporal resolution of 3 s. This method is even able to distinguish isomers, which cannot be easily distinguished by mass-spectrometry.
There is a widespread belief that in the 1970s, two conflicting theories of the adhesion of a spherical particle to a substrate were published: the JKR and DMT theories. And that the dispute was ...resolved when Tabor introduced a parameter
μ
, such that for small
μ
, DMT was correct, while for large
μ
, JKR was correct. We point out that there never were two theories of contact: the dispute was about the magnitude of the pull-off force (with an implication that since the DMT value was obtained by a
thermodynamic
method, it must be correct). And what Tabor actually said was simply that for large
μ
, the neglect of surface forces in the JKR theory was acceptable, and that he distrusted the neglect of deformation by the large surface forces immediately outside the Hertzian contact in the DMT theory. We point out the errors in both the DMT/MDT thermodynamic method and the MDT force method (preferred by MDT) but also argue that once Derjaguin and his collaborators (MYD) established that Hertzian geometry does not occur, no theory based on that geometry should be taken seriously. Derjaguin’s well-merited fame rests on more important contributions.
In the past decade, attosecond technology has opened up the investigation of ultrafast electronic processes in atoms, simple molecules, and solids. Here, we report the application of isolated ...attosecond pulses to prompt ionization of the amino acid phenylalanine and the subsequent detection of ultrafast dynamics on a sub–4.5-femtosecond temporal scale, which is shorter than the vibrational response of the molecule. The ability to initiate and observe such electronic dynamics in polyatomic molecules represents a crucial step forward in attosecond science, which is progressively moving toward the investigation of more and more complex systems.
Abstract
To be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen,
Mycobacterium tuberculosis
. However, how host cell microenvironments affect ...antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.
Efficient behavior involves the coordinated activity of large-scale brain networks, but the way in which these networks interact is uncertain. One theory is that the salience network (SN)—which ...includes the anterior cingulate cortex, presupplementary motor area, and anterior insulae—regulates dynamic changes in other networks. If this is the case, then damage to the structural connectivity of the SN should disrupt the regulation of associated networks. To investigate this hypothesis, we studied a group of 57 patients with cognitive impairments following traumatic brain injury (TBI) and 25 control subjects using the stop-signal task. The pattern of brain activity associated with stop-signal task performance was studied by using functional MRI, and the structural integrity of network connections was quantified by using diffusion tensor imaging. Efficient inhibitory control was associated with rapid deactivation within parts of the default mode network (DMN), including the precuneus and posterior cingulate cortex. TBI patients showed a failure of DMN deactivation, which was associated with an impairment of inhibitory control. TBI frequently results in traumatic axonal injury, which can disconnect brain networks by damaging white matter tracts. The abnormality of DMN function was specifically predicted by the amount of white matter damage in the SN tract connecting the right anterior insulae to the presupplementary motor area and dorsal anterior cingulate cortex. The results provide evidence that structural integrity of the SN is necessary for the efficient regulation of activity in the DMN, and that a failure of this regulation leads to inefficient cognitive control.
1. Using data on the spatial distribution of the British avifauna, we address three basic questions about the spatial structure of assemblages: (i) Is there a relationship between species richness ...(alpha diversity) and spatial turnover of species (beta diversity)? (ii) Do high richness locations have fewer species in common with neighbouring areas than low richness locations?, and (iii) Are any such relationships contingent on spatial scale (resolution or quadrat area), and do they reflect the operation of a particular kind of species-area relationship (SAR)? 2. For all measures of spatial turnover, we found a negative relationship with species richness. This held across all scales, with the exception of turnover measured as βsim. 3. Higher richness areas were found to have more species in common with neighbouring areas. 4. The logarithmic SAR fitted better than the power SAR overall, and fitted significantly better in areas with low richness and high turnover. 5. Spatial patterns of both turnover and richness vary with scale. The finest scale richness pattern (10 km) and the coarse scale richness pattern (90 km) are statistically unrelated. The same is true of the turnover patterns. 6. With coarsening scale, locations of the most species-rich quadrats move north. This observed sensitivity of richness 'hotspot' location to spatial scale has implications for conservation biology, e.g. the location of a reserve selected on the basis of maximum richness may change considerably with reserve size or scale of analysis. 7. Average turnover measured using indices declined with coarsening scale, but the average number of species gained or lost between neighbouring quadrats was essentially scale invariant at 10-13 species, despite mean richness rising from 80 to 146 species (across an 81-fold area increase). We show that this kind of scale invariance is consistent with the logarithmic SAR.
The classical Fuller and Tabor theory of rough surface adhesion is reviewed, and its limited applicability noted. New results using an extension of the JKR adhesion theory to include the effect of ...van der Waals adhesion forces are described. These show the influence of the Tabor parameter μ: moderate values of µ (µ<100) lead to increased forces during loading, and so are found to predict much lower hysteresis losses. A further extension is to replace the GW surface roughness model used by Fuller and Tabor by a model based on the Nayak model of a surface as a random field, as in the Bush, Gibson and Thomas (BGT) theory of non-adhesive contact. The results are qualitatively the same, and the differences may well be largely due to the necessary redefinition of the adhesion index using the rms profile curvature in place of the asperity radius of curvature used in the GW model. `
To image β-amyloid (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to ...Alzheimer disease (AD).
Patients 11 months to 17 years after moderate-severe TBI underwent (11)C-Pittsburgh compound B ((11)C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of (11)C-PiB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with (11)C-PiB BPND.
Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased (11)C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum.
Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.
The skin graft was born in 1869 and since then, surgeons have been using split skin grafts for wound repair. Nevertheless, this asset fails the big burn patient, who deserves an elastic, mobile and ...robust outcome but who receives the poorest possible outcome based on donor site paucity. Negating the need for the skin graft requires an autologous composite cultured skin and a material capable of temporising the burn wound for four weeks until the composite is produced. A novel, biodegradable polyurethane chemistry has been used to create two such products. This paper describes the design, production, optimisation and evaluation of several iterations of these products. The evaluation has occurred in a variety of models, both in vitro and in vivo, employing Hunterian scientific principles, and embracing Hunter's love and appreciation of comparative anatomy. The process has culminated in significant human experience in complex wounds and extensive burn injury. Used serially, the products offer robust and elastic healing in deep burns of any size within 6 weeks of injury.
PDF
