Predictions for sea-level rise this century due to melt from Antarctica range from zero to more than one metre. The highest predictions are driven by the controversial marine ice-cliff instability ...(MICI) hypothesis, which assumes that coastal ice cliffs can rapidly collapse after ice shelves disintegrate, as a result of surface and sub-shelf melting caused by global warming. But MICI has not been observed in the modern era and it remains unclear whether it is required to reproduce sea-level variations in the geological past. Here we quantify ice-sheet modelling uncertainties for the original MICI study and show that the probability distributions are skewed towards lower values (under very high greenhouse gas concentrations, the most likely value is 45 centimetres). However, MICI is not required to reproduce sea-level changes due to Antarctic ice loss in the mid-Pliocene epoch, the last interglacial period or 1992-2017; without it we find that the projections agree with previous studies (all 95th percentiles are less than 43 centimetres). We conclude that previous interpretations of these MICI projections over-estimate sea-level rise this century; because the MICI hypothesis is not well constrained, confidence in projections with MICI would require a greater range of observationally constrained models of ice-shelf vulnerability and ice-cliff collapse.
Peptide antibiotics are an abundant and synthetically tractable source of molecular diversity, but they are often cationic and can be cytotoxic, nephrotoxic and/or ototoxic, which has limited their ...clinical development. Here we report structure-guided optimization of an amphipathic peptide, arenicin-3, originally isolated from the marine lugworm Arenicola marina. The peptide induces bacterial membrane permeability and ATP release, with serial passaging resulting in a mutation in mlaC, a phospholipid transport gene. Structure-based design led to AA139, an antibiotic with broad-spectrum in vitro activity against multidrug-resistant and extensively drug-resistant bacteria, including ESBL, carbapenem- and colistin-resistant clinical isolates. The antibiotic induces a 3-4 log reduction in bacterial burden in mouse models of peritonitis, pneumonia and urinary tract infection. Cytotoxicity and haemolysis of the progenitor peptide is ameliorated with AA139, and the 'no observable adverse effect level' (NOAEL) dose in mice is ~10-fold greater than the dose generally required for efficacy in the infection models.
Emerging micro-scale medical devices are showing promise, whether in delivering drugs or extracting diagnostic biomarkers from skin. In progressing these devices through animal models towards ...clinical products, understanding the mechanical properties and skin tissue structure with which they interact will be important. Here, through measurement and analytical modelling, we advanced knowledge of these properties for commonly used laboratory animals and humans (~30 g to ~150 kg). We hypothesised that skin's stiffness is a function of the thickness of its layers through allometric scaling, which could be estimated from knowing a species' body mass. Results suggest that skin layer thicknesses are proportional to body mass with similar composition ratios, inter- and intra-species. Experimental trends showed elastic moduli increased with body mass, except for human skin. To interpret the relationship between species, we developed a simple analytical model for the bulk elastic moduli of skin, which correlated well with experimental data. Our model suggest that layer thicknesses may be a key driver of structural stiffness, as the skin layer constituents are physically and therefore mechanically similar between species. Our findings help advance the knowledge of mammalian skin mechanical properties, providing a route towards streamlined micro-device research and development onto clinical use.
The fatty acyl composition of phospholipids determines the biophysical character of membranes and impacts the function of membrane proteins. Here, we define a nuclear receptor pathway for the dynamic ...modulation of membrane composition in response to changes in cellular lipid metabolism. Ligand activation of liver X receptors (LXRs) preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids through induction of the remodeling enzyme Lpcat3. Promotion of Lpcat3 activity ameliorates endoplasmic reticulum (ER) stress induced by saturated free fatty acids in vitro or by hepatic lipid accumulation in vivo. Conversely, Lpcat3 knockdown in liver exacerbates ER stress and inflammation. Mechanistically, Lpcat3 modulates inflammation both by regulating inflammatory kinase activation through changes in membrane composition and by affecting substrate availability for inflammatory mediator production. These results outline an endogenous mechanism for the preservation of membrane homeostasis during lipid stress and identify Lpcat3 as an important mediator of LXR effects on metabolism.
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•Induction of Lpcat3 expression by LXRs promotes phospholipid remodeling•LXR-Lpcat3 activation drives unsaturated fatty acid incorporation into phospholipids•Lpcat3 activity in liver modulates lipid-induced ER stress and inflammation•Lpcat3 affects inflammation through regulation of membrane c-Src activity
The Fifth Eriksholm Workshop on "Hearing Impairment and Cognitive Energy" was convened to develop a consensus among interdisciplinary experts about what is known on the topic, gaps in knowledge, the ...use of terminology, priorities for future research, and implications for practice. The general term cognitive energy was chosen to facilitate the broadest possible discussion of the topic. It goes back to who described the effects of attention on perception; he used the term psychic energy for the notion that limited mental resources can be flexibly allocated among perceptual and mental activities. The workshop focused on three main areas: (1) theories, models, concepts, definitions, and frameworks; (2) methods and measures; and (3) knowledge translation. We defined effort as the deliberate allocation of mental resources to overcome obstacles in goal pursuit when carrying out a task, with listening effort applying more specifically when tasks involve listening. We adapted Kahneman's seminal (1973) Capacity Model of Attention to listening and proposed a heuristically useful Framework for Understanding Effortful Listening (FUEL). Our FUEL incorporates the well-known relationship between cognitive demand and the supply of cognitive capacity that is the foundation of cognitive theories of attention. Our FUEL also incorporates a motivation dimension based on complementary theories of motivational intensity, adaptive gain control, and optimal performance, fatigue, and pleasure. Using a three-dimensional illustration, we highlight how listening effort depends not only on hearing difficulties and task demands but also on the listener's motivation to expend mental effort in the challenging situations of everyday life.
The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding ...properties, in contrast to nature's control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the 'vancapticins', possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to 'revitalise' antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors.
Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)
. Vaccines ...that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID
) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.
Bacteria have acquired extensive resistance mechanisms to protect themselves against antibiotic action. Today the bacterial membrane has become one of the “final frontiers” in the search for new ...compounds acting on novel targets to address the threat of multi-drug resistant (MDR) and XDR bacterial pathogens. β-Hairpin antimicrobial peptides are amphipathic, membrane-binding antibiotics that exhibit a broad range of activities against Gram-positive, Gram-negative, and fungal pathogens. However, most members of the class also possess adverse cytotoxicity and hemolytic activity that preclude their development as candidate antimicrobials. We examined peptide hydrophobicity, amphipathicity, and structure to better dissect and understand the correlation between antimicrobial activity and toxicity, membrane binding, and membrane permeability. The hydrophobicity, pI, net charge at physiological pH, and amphipathic moment for the β-hairpin antimicrobial peptides tachyplesin-1, polyphemusin-1, protegrin-1, gomesin, arenicin-3, and thanatin were determined and correlated with key antimicrobial activity and toxicity data. These included antimicrobial activity against five key bacterial pathogens and two fungi, cytotoxicity against human cell lines, and hemolytic activity in human erythrocytes. Observed antimicrobial activity trends correlated with compound amphipathicity and, to a lesser extent, with overall hydrophobicity. Antimicrobial activity increased with amphipathicity, but unfortunately so did toxicity. Of note, tachyplesin-1 was found to be 8-fold more amphipathic than gomesin. These analyses identify tachyplesin-1 as a promising scaffold for rational design and synthetic optimization toward an antibiotic candidate.
Rates of encounters between humans and wildlife are increasing in cities around the world, especially when wildlife overlap with people in time, space and resources. Coyotes (Canis latrans) can make ...use of anthropogenic resources and reported rates of conflict have increased in cities across North America. This increase may be linked to individual differences in the use of human food and developed areas. We compared the relationships between coyote age, sex or health and the use of anthropogenic resources, which we defined as using developed areas over large home ranges, being active during the day, and consuming anthropogenic food. To do so, we applied GPS collars to 19 coyotes and sampled hair for stable isotope analysis. Eleven coyotes appeared to be healthy and eight were visibly infested with sarcoptic mange (Sarcoptes scabiei), a mite that causes hair loss. Diseased coyotes used more developed areas, had larger monthly home ranges, were more active during the day, and assimilated less protein than coyotes that appeared to be healthy. We speculate that anthropogenic food provides a low-quality but easily accessible food source for diseased coyotes, which in turn may increase reliance on it and other anthropogenic resources to promote encounters with people.
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