Powerful proteins from polyp possessing predators

Cnidarians are soft bodied animals possessing complex venom systems which have evolved to allow for the capture of arthropod and vertebrate prey, as well as to defend themselves against such predators. The effects of these venoms on humans, as a result of envenomation, has been studied for many decades, whereas the possibility of using these proteins to fight human disease is in its infancy. Drug discovery utilisation of Cnidarian venoms has been hampered by availability of animals and suitable extraction techniques that allow for study of such protein toxins. Studies of toxins that have been suitably purified for drug discovery have, by in large, only investigated target engagement and negated to investigate other drug like properties such as absorption, dispersion, metabolism, and excretion (ADME). This chapter will review the sourcing of Cnidaria for drug discovery, extraction of venom components, actions of venoms on drug relevant targets and their suitability as drug like molecules

The quadratic spinor Lagrangian is equivalent to the teleparallel theory

The quadratic spinor Lagrangian is shown to be equivalent to the teleparallel / tetrad representation of Einstein's theory. An important consequence is that the energy-momentum density obtained from this quadratic spinor Lagrangian is essentially the same as the ``tensor'' proposed by Moller in 1961.Comment: 10 pages, RevTe

Molecular epidemiology of penicillin-susceptible Staphylococcus aureus bacteremia in Australia and reliability of diagnostic phenotypic susceptibility methods to detect penicillin susceptibility

Background: Defined by the emergence of antibiotic resistant strains, Staphylococcus aureus is a priority bacterial species with high antibiotic resistance. However, a rise in the prevalence of penicillin-susceptible S. aureus (PSSA) bloodstream infections has recently been observed worldwide, including in Australia, where the proportion of methicillin-susceptible S. aureus causing bacteremia identified phenotypically as penicillin-susceptible has increased by over 35%, from 17.5% in 2013 to 23.7% in 2020. Objectives: To determine the population structure of PSSA causing community- and hospital-onset bacteremia in Australia and to evaluate routine phenotypic antimicrobial susceptibility methods to reliably confirm penicillin resistance on blaZ-positive S. aureus initially classified as penicillin-susceptible by the Vitek® 2 automated microbiology system. Results: Whole genome sequencing on 470 PSSA collected in the 2020 Australian Group on Antimicrobial Resistance Australian Staphylococcus aureus Sepsis Outcome Programme identified 84 multilocus sequence types (STs), of which 79 (463 isolates) were grouped into 22 clonal complexes (CCs). The dominant CCs included CC5 (31.9%), CC97 (10.2%), CC45 (10.0%), CC15 (8.7%), and CC188 (4.9%). Many of the CCs had multiple STs and spa types and, based on the immune evasion cluster type, isolates within a CC could be classified into different strains harboring a range of virulence and resistance genes. Phylogenetic analyses of the isolates showed most CCs were represented by one clade. The blaZ gene was identified in 45 (9.6%) PSSA. Although multiclonal, approximately 50% of blaZ-positive PSSA were from CC15 and were found to be genetically distant from the blaZ-negative CC15 PSSA. The broth microdilution, Etest® and cefinase, performed poorly; however, when the appearance of the zone edge was considered; as per the EUCAST and CLSI criteria, disc diffusion detected 100% of blaZ-positive PSSA. Conclusions: In Australia, PSSA bacteremia is not caused by the expansion of a single clone. Approximately 10% of S. aureus classified as penicillin-susceptible by the Vitek® 2 harbored blaZ. Consequently, we recommend that confirmation of Vitek® 2 PSSA be performed using an alternative method, such as disc diffusion with careful interpretation of the zone edge

Managing native and non-native sea lamprey (Petromyzon marinus) through anthropogenic change: A prospective assessment of key threats and uncertainties.

Sea lamprey (Petromyzon marinus) is a species of conservation concern in their native range of the Atlantic coasts of Europe (Near Threatened to Critically Endangered) and North America (Secure to Critically Imperiled), and an invasive species of great economic and ecological concern in the Laurentian Great Lakes. Despite differences in life history strategy (anadromous natives vs adfluvial non-natives), the biology of sea lamprey is sufficiently similar to expect comparable responses to large-scale environmental change. We take a prospective look at the future (50 to 100 years) of sea lamprey management in an era of considerable environmental disturbance, and consider biological responses, management actions, and the future status of populations across the native and non-native ranges. Based on facilitated discussion by a diverse group of international experts, two major but poorly characterized classes of threats to sea lamprey were identified: climate change and socio-political issues. We discuss how climate induced changes affect growth, bioenergetics, and phenology of sea lamprey, and associated effects on control tactics (pesticides and barriers) and conservation. We consider tensions surrounding improving connectivity in the Great Lakes while controlling invasive sea lamprey, and discuss supplements and alternatives to pesticides and their wider effect, as well as the effects of new invasive species. To prevent the extirpation of native sea lamprey populations, or the re-expansion of non-native populations, we conclude with a call for new and ongoing dialogue and collaboration among all sea lamprey biologists and managers across the native and non-native range

Dynamical aspects of mean field plane rotators and the Kuramoto model

The Kuramoto model has been introduced in order to describe synchronization phenomena observed in groups of cells, individuals, circuits, etc... We look at the Kuramoto model with white noise forces: in mathematical terms it is a set of N oscillators, each driven by an independent Brownian motion with a constant drift, that is each oscillator has its own frequency, which, in general, changes from one oscillator to another (these frequencies are usually taken to be random and they may be viewed as a quenched disorder). The interactions between oscillators are of long range type (mean field). We review some results on the Kuramoto model from a statistical mechanics standpoint: we give in particular necessary and sufficient conditions for reversibility and we point out a formal analogy, in the N to infinity limit, with local mean field models with conservative dynamics (an analogy that is exploited to identify in particular a Lyapunov functional in the reversible set-up). We then focus on the reversible Kuramoto model with sinusoidal interactions in the N to infinity limit and analyze the stability of the non-trivial stationary profiles arising when the interaction parameter K is larger than its critical value K_c. We provide an analysis of the linear operator describing the time evolution in a neighborhood of the synchronized profile: we exhibit a Hilbert space in which this operator has a self-adjoint extension and we establish, as our main result, a spectral gap inequality for every K>K_c.Comment: 18 pages, 1 figur

A subset of malignant mesothelioma tumors retain osteogenic potential

Malignant mesothelioma (MM) is an aggressive serosal tumor associated with asbestos exposure. We previously demonstrated that mesothelial cells differentiate into cells of different mesenchymal lineages and hypothesize that osseous tissue observed in a subset of MM patients is due to local differentiation of MM cells. In this study, the capacity of human and mouse MM cells to differentiate into osteoblast-like cells was determined in vitro using a functional model of bone nodule formation and in vivo using an established model of MM. Human and murine MM cell lines cultured in osteogenic medium expressed alkaline phosphatase and formed mineralized bone-like nodules. Several human and mouse MM cell lines also expressed a number of osteoblast phenotype markers, including runt-related transcription factor 2 (RUNX2), osteopontin, osteonectin and bone sialoprotein mRNA and protein. Histological analysis of murine MM tumors identified areas of ossification within the tumor, similar to those observed in human MM biopsies. These data demonstrate the ability of MM to differentiate into another mesenchymal cell type and suggest that MM cells may contribute to the formation of the heterologous elements observed in MM tumors

Detecting autoreactive B cells in the peripheral blood of people with type 1 diabetes using ELISpot

Type 1 diabetes mellitus (T1D) is an autoimmune disorder where T lymphocytes damage the islet beta cells but B lymphocytes also play an important role. Although changes in peripheral B cell phenotype have been observed, little is known about the B cells that secrete the autoantibodies. We developed a sensitive B cell enzyme-linked immunospot assay (ELISpot assay) to detect individual B cell antibody responses to glutamic acid decarboxylase (GAD) and islet antigen-2 (IA-2). We found that even healthy donors have B cells that secrete antibodies in response to GAD and IA-2 in the ELISpot. There was increased B cell reactivity to autoantigens in the peripheral blood of individuals with newly-diagnosed, but not long-standing, type 1 diabetes. However, no correlation with serum autoantibody levels was found, indicating that additional factors such as antigen affinity or exposure to antigens in vivo are required for antibody secretion, and that even healthy donors have potentially autoreactive B cells

Hsp70 oligomerization is mediated by an interaction between the interdomain linker and the substrate-binding domain

Oligomerization in the heat shock protein (Hsp) 70 family has been extensively documented both in vitro and in vivo, although the mechanism, the identity of the specific protein regions involved and the physiological relevance of this process are still unclear. We have studied the oligomeric properties of a series of human Hsp70 variants by means of nanoelectrospray ionization mass spectrometry, optical spectroscopy and quantitative size exclusion chromatography. Our results show that Hsp70 oligomerization takes place through a specific interaction between the interdomain linker of one molecule and the substrate-binding domain of a different molecule, generating dimers and higher-order oligomers. We have found that substrate binding shifts the oligomerization equilibrium towards the accumulation of functional monomeric protein, probably by sequestering the helical lid sub-domain needed to stabilize the chaperone: substrate complex. Taken together, these findings suggest a possible role of chaperone oligomerization as a mechanism for regulating the availability of the active monomeric form of the chaperone and for the control of substrate binding and release

Lagrangian Description of the Variational Equations

A variant of the usual Lagrangian scheme is developed which describes both the equations of motion and the variational equations of a system. The required (prolonged) Lagrangian is defined in an extended configuration space comprising both the original configurations of the system and all the virtual displacements joining any two integral curves. Our main result establishes that both the Euler-Lagrange equations and the corresponding variational equations of the original system can be viewed as the Lagrangian vector field associated with the first prolongation of the original LagrangianAfter discussing certain features of the formulation, we introduce the so-called inherited constants of the motion and relate them to the Noether constants of the extended system