Expertise from the humanities and social sciences is essential for governmental responses to COVID-19

Researchers from the humanities and social sciences can help governments emerge and recover from COVID-19, yet their perspectives continue to be ignored and marginalised. Humanities and social science research can provide the political, historical, cultural, social, and economic insights to deepen our understanding of the pandemic, how it has been experienced, how to overcome it, and how best to learn from it

The prosequence of procaricain forms an α-helical domain that prevents access to the substrate-binding cleft

AbstractBackground Cysteine proteases are involved in a variety of cellular processes including cartilage degradation in arthritis, the progression of Alzheimer's disease and cancer invasion: these enzymes are therefore of immense biological importance. Caricain is the most basic of the cysteine proteases found in the latex of Carica papaya. It is a member of the papain superfamily and is homologous to other plant and animal cysteine proteases. Caricain is naturally expressed as an inactive zymogen called procaricain. The inactive form of the protease contains an inhibitory proregion which consists of an additional 106 N-terminal amino acids; the proregion is removed upon activation.Results The crystal structure of procaricain has been refined to 3.2 å resolution; the final model consists of three non-crystallographically related molecules. The proregion of caricain forms a separate globular domain which binds to the C-terminal domain of mature caricain. The proregion also contains an extended polypeptide chain which runs through the substrate-binding cleft, in the opposite direction to that of the substrate, and connects to the N terminus of the mature region. The mature region does not undergo any conformational change on activation.Conclusions We conclude that the rate-limiting step in the in vitro activation of procaricain is the dissociation of the prodomain, which is then followed by proteolytic cleavage of the extended polypeptide chain of the proregion. The prodomain provides a stable scaffold which may facilitate the folding of the C-terminal lobe of procaricain

Immobilising Microalgae and Cyanobacteria as Biocomposites: New Opportunities to Intensify Algae Biotechnology and Bioprocessing

There is a groundswell of interest in applying phototrophic microorganisms, specifically microalgae and cyanobacteria, for biotechnology and ecosystem service applications. However, there are inherent challenges associated with conventional routes to their deployment (using ponds, raceways and photobioreactors) which are synonymous with suspension cultivation techniques. Cultivation as biofilms partly ameliorates these issues; however, based on the principles of process intensification, by taking a step beyond biofilms and exploiting nature inspired artificial cell immobilisation, new opportunities become available, particularly for applications requiring extensive deployment periods (e.g., carbon capture and wastewater bioremediation). We explore the rationale for, and approaches to immobilised cultivation, in particular the application of latex-based polymer immobilisation as living biocomposites. We discuss how biocomposites can be optimised at the design stage based on mass transfer limitations. Finally, we predict that biocomposites will have a defining role in realising the deployment of metabolically engineered organisms for real world applications that may tip the balance of risk towards their environmental deployment

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Modulating serine palmitoyl transferase (SPT) expression and activity unveils a crucial role in lipid-induced insulin resistance in rat skeletal muscle cells

International audienceSaturated fatty acids, such as palmitate, promote accumulation of ceramide which impairs activation and signaling of protein kinase B (PKB/Akt) to important end-points such as glucose transport. Serine Palmitoyl Transferase (SPT) is a key enzyme regulating ceramide synthesis from palmitate and represents a potential molecular target in curbing lipid-induced insulin resistance. Here we explore effects of palmitate upon insulin action in L6 muscle cells in which SPT expression/activity have been reduced by shRNA or sustained incubation with myriocin, a SPT inhibitor. Incubation of L6 myotubes with palmitate (16h) increases intramyocellular ceramide and reduces insulin-stimulated PKB activation and glucose uptake. PKB inhibition was not associated with impaired IRS signaling and was ameliorated by short-term treatment with myriocin. Silencing SPT expression (~90%) by shRNA or chronic cell incubation with myriocin (7 days) markedly suppressed SPT activity and palmitate-driven ceramide synthesis. However, challenging these muscle cells with palmitate still inhibited the hormonal activation of PKB. This inhibition was associated with reduced IRS1/p85-PI3-kinase coupling that arises from diverting palmitate towards greater DAG synthesis, which elevates IRS1 serine phosphorylation via activation of DAG-sensitive PKCs. Treatment of SPT-shRNA cells or those treated chronically with myriocin with PKC inhibitors antagonised palmitate-induced loss in insulin signaling. The findings indicate that SPT plays a crucial role in desensitizing muscle cells to insulin in response to incubation with palmitate. Whilst short-term inhibition of SPT ameliorates palmitate/ceramide-induced insulin resistance, sustained loss/reduction in SPT expression/activity promotes greater partitioning of palmitate towards DAG synthesis, which impacts negatively upon IRS1-directed insulin signaling

CFTR: A Cysteine at Position 338 in TM6 Senses a Positive Electrostatic Potential in the Pore

We investigated the accessibility to protons and thiol-directed reagents of a cysteine substituted at position 338 in transmembrane segment 6 (TM6) of CFTR to test the hypothesis that T338 resides in the pore. Xenopus oocytes expressing T338C CFTR exhibited pH-dependent changes in g(Cl) and I-V shape that were specific to the substituted cysteine. The apparent pK(a) of T338C CFTR was more acidic than that expected for a cysteine or similar simple thiols in aqueous solution. The pK(a) was shifted toward alkaline values when a nearby positive charge (R334) was substituted with neutral or negatively charged residues, consistent with the predicted influence of the positive charge of R334, and perhaps other residues, on the titration of a cysteine at 338. The relative rates of chemical modification of T338C CFTR by MTSET(+) and MTSES(−) were also altered by the charge at 334. These observations support a model for CFTR that places T338 within the anion conduction path. The apparent pK(a) of a cysteine substituted at 338 and the relative rates of reaction of charged thiol-directed reagents provide a crude measure of a positive electrostatic potential that may be due to R334 and other residues near this position in the pore

Impact-generated hydrothermal systems on Earth and Mars

It has long been suggested that hydrothermal systems might have provided habitats for the origin and evolution of early life on Earth, and possibly other planets such as Mars. In this contribution we show that most impact events that result in the formation of complex impact craters (i.e., >2-4 and >5-10. km diameter on Earth and Mars, respectively) are potentially capable of generating a hydrothermal system. Consideration of the impact cratering record on Earth suggests that the presence of an impact crater lake is critical for determining the longevity and size of the hydrothermal system. We show that there are six main locations within and around impact craters on Earth where impact-generated hydrothermal deposits can form: (1) crater-fill impact melt rocks and melt-bearing breccias; (2) interior of central uplifts; (3) outer margin of central uplifts; (4) impact ejecta deposits; (5) crater rim region; and (6) post-impact crater lake sediments. We suggest that these six locations are applicable to Mars as well. Evidence for impact-generated hydrothermal alteration ranges from discrete vugs and veins to pervasive alteration depending on the setting and nature of the system. A variety of hydrothermal minerals have been documented in terrestrial impact structures and these can be grouped into three broad categories: (1) hydrothermally-altered target-rock assemblages; (2) primary hydrothermal minerals precipitated from solutions; and (3) secondary assemblages formed by the alteration of primary hydrothermal minerals. Target lithology and the origin of the hydrothermal fluids strongly influences the hydrothermal mineral assemblages formed in these post-impact hydrothermal systems. There is a growing body of evidence for impact-generated hydrothermal activity on Mars; although further detailed studies using high-resolution imagery and multispectral information are required. Such studies have only been done in detail for a handful of martian craters. The best example so far is from Toro Crater (Marzo, G.A., Davila, A.F., Tornabene, L.L., Dohm, J.M., Fairèn, A.G., Gross, C., Kneissl, T., Bishop, J.L., Roush, T.L., Mckay, C.P. [2010]. Icarus 208, 667-683). We also present new evidence for impact-generated hydrothermal deposits within an unnamed ∼32-km diameter crater ∼350. km away from Toro and within the larger Holden Crater. Synthesizing observations of impact craters on Earth and Mars, we suggest that if there was life on Mars early in its history, then hydrothermal deposits associated with impact craters may provide the best, and most numerous, opportunities for finding preserved evidence for life on Mars. Moreover, hydrothermally altered and precipitated rocks can provide nutrients and habitats for life long after hydrothermal activity has ceased