Extended conjugated microporous polymers for photocatalytic hydrogen evolution from water

Conjugated microporous polymers (CMPs) have been used as photocatalysts for hydrogen production from water in the presence of a sacrificial electron donor. The relative importance of the linker geometry, the co-monomer linker length, and the degree of planarisation were studied with respect to the photocatalytic hydrogen evolution rate

Overexpressed Cavbeta3 inhibits N-type (Cav2.2) calcium channel currents through a hyperpolarizing shift of 'ultra-slow' and 'closed-state' inactivation

It has been shown that beta auxiliary subunits increase current amplitude in voltage-dependent calcium channels. In this study, however, we found a novel inhibitory effect of beta3 subunit on macroscopic Ba2+ currents through recombinant N- and R-type calcium channels expressed in Xenopus oocytes. Overexpressed beta3 (12.5 ng/cell cRNA) significantly suppressed N- and R-type, but not L-type, calcium channel currents at 'physiological' holding potentials (HPs) of -60 and -80 mV. At a HP of -80 mV, coinjection of various concentrations (0-12.5 ng) of the beta3 with Cav2.2alpha1 and alpha2delta enhanced the maximum conductance of expressed channels at lower beta3 concentrations but at higher concentrations (>2.5 ng/cell) caused a marked inhibition. The beta3-induced current suppression was reversed at a HP of -120 mV, suggesting that the inhibition was voltage dependent. A high concentration of Ba2+ (40 mM) as a charge carrier also largely diminished the effect of beta3 at -80 mV. Therefore, experimental conditions (HP, divalent cation concentration, and beta3 subunit concentration) approaching normal physiological conditions were critical to elucidate the full extent of this novel beta3 effect. Steady-state inactivation curves revealed that N-type channels exhibited 'closed-state' inactivation without beta3, and that beta3 caused an approximately 40-mV negative shift of the inactivation, producing a second component with an inactivation midpoint of approximately -85 mV. The inactivation of N-type channels in the presence of a high concentration (12.5 ng/cell) of beta3 developed slowly and the time-dependent inactivation curve was best fit by the sum of two exponential functions with time constants of 14 s and 8.8 min at -80 mV. Similar 'ultra-slow' inactivation was observed for N-type channels without beta3. Thus, beta3 can have a profound negative regulatory effect on N-type (and also R-type) calcium channels by causing a hyperpolarizing shift of the inactivation without affecting `ultra-slow' and `closed-state' inactivation properties

The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways.

Somatically acquired, activating mutations of GNAS, the gene encoding the stimulatory G-protein Gsalpha subunit, have been identified in kidney, thyroid, pituitary, leydig cell, adrenocortical and, more recently, in colorectal tumours, suggesting that mutations such as R201C may be oncogenic in these tissues. To study the role of GNAS in intestinal tumourigenesis, we placed GNAS R201C under the control of the A33-antigen promoter (Gpa33), which is almost exclusively expressed in the intestines. The GNAS R201C mutation has been shown to result in the constitutive activation of Gsalpha and adenylate cyclase and to lead to the autonomous synthesis of cyclic adenosine monophosphate (cAMP). Gpa33(tm1(GnasR201C)Wtsi/+) mice showed significantly elevated cAMP levels and a compensatory upregulation of cAMP-specific phosphodiesterases in the intestinal epithelium. GNAS R201C alone was not sufficient to induce tumourigenesis by 12 months, but there was a significant increase in adenoma formation when Gpa33(tm1(GnasR201C)Wtsi/+) mice were bred onto an Apc(Min/+) background. GNAS R201C expression was associated with elevated expression of Wnt and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK) pathway target genes, increased phosphorylation of ERK1/2 MAPK and increased immunostaining for the proliferation marker Ki67. Furthermore, the effects of GNAS R201C on the Wnt pathway were additive to the inactivation of Apc. Our data strongly suggest that activating mutations of GNAS cooperate with inactivation of APC and are likely to contribute to colorectal tumourigenesis

Chronic toxicity of an environmentally relevant and equitoxic ratio of five metals to two Antarctic marine microalgae shows complex mixture interactivity

© 2018 Metal contaminants are rarely present in the environment individually, yet environmental quality guidelines are derived from single-metal toxicity data. Few metal mixture studies have investigated more than binary mixtures and many are at unrealistically high effect concentrations to freshwater organisms. This study investigates the toxicity of five metals (Cd, Cu, Ni, Pb, and Zn) to the Antarctic marine microalgae Phaeocystis antarctica and Cryothecomonas armigera. Two mixtures were tested: (i) an equitoxic mixture of contaminants present at their single-metal EC10 concentrations, and (ii) an environmental mixture based on the ratio metal concentrations in a contaminated Antarctic marine bay. Observed toxicity, as chronic population growth rate inhibition, was compared to Independent Action (IA) and Concentration Addition (CA) predictions parameterised to use EC10 values. This allowed for the inclusion of metals with low toxicities. The biomarkers chlorophyll a fluorescence, cell size and complexity, and intracellular lipid concentrations were assessed to investigate possible mechanisms behind metal-mixture interactions. Both microalgae had similar responses to the equitoxic mixture: non-interactive by IA and antagonistic by CA. Toxicity from the environmental mixture was antagonistic by IA to P. antarctica; however, to C. armigera it was concentration-dependent with antagonism at low toxicities and synergism at high toxicities by both IA and CA. Differences in dissolved organic carbon production and detoxification mechanisms may be responsible for these responses and warrants further investigation. This study shows that mixture toxicity interactions can be ratio, species, and concentration dependent. The responses of the microalgae to different mixture ratios highlight the need to assess toxicity at environmentally realistic metal ratios. Parameterising IA and CA reference models to use EC10s allowed for the inclusion of metals at low effect concentrations, which may otherwise be ignored. Reference mixture models are generally suitable for predicting chronic toxicity of metals to these marine microalgae at environmentally realistic ratios and concentrations. Toxic metal-mixture interactions were found to be concentration, ratio, and species dependent in exposures to two Antarctic marine microalgae

How are adjacent spinal levels affected by vertebral fracture and by vertebroplasty? A biomechanical study on cadaveric spines

Background Context Spinal injuries and surgery may have important effects on neighboring spinal levels, but previous investigations of adjacent-level biomechanics have produced conflicting results. We use “stress profilometry” and noncontact strain measurements to investigate thoroughly this long-standing problem. Purpose This study aimed to determine how vertebral fracture and vertebroplasty affect compressive load-sharing and vertebral deformations at adjacent spinal levels. Study Design We conducted mechanical experiments on cadaver spines. Methods Twenty-eight cadaveric spine specimens, comprising three thoracolumbar vertebrae and the intervening discs and ligaments, were dissected from fourteen cadavers aged 67–92 years. A needle-mounted pressure transducer was used to measure the distribution of compressive stress across the anteroposterior diameter of both intervertebral discs. “Stress profiles” were analyzed to quantify intradiscal pressure (IDP) and concentrations of compressive stress in the anterior and posterior annulus. Summation of stresses over discrete areas yielded the compressive force acting on the anterior and posterior halves of each vertebral body, and the compressive force resisted by the neural arch. Creep deformations of vertebral bodies under load were measured using an optical MacReflex system. All measurements were repeated following compressive injury to one of the three vertebrae, and again after the injury had been treated by vertebroplasty. The study was funded by a grant from Action Medical Research, UK ($143,230). Authors of this study have no conflicts of interest to disclose. Results Injury usually involved endplate fracture, often combined with deformation of the anterior cortex, so that the affected vertebral body developed slight anterior wedging. Injury reduced IDP at the affected level, to an average 47% of pre-fracture values (p<.001), and transferred compressive load-bearing from nucleus to annulus, and also from disc to neural arch. Similar but reduced effects were seen at adjacent (non-fractured) levels, where mean IDP was reduced to 73% of baseline values (p<.001). Vertebroplasty partially reversed these changes, increasing mean IDP to 76% and 81% of baseline values at fractured and adjacent levels, respectively. Injury also increased creep deformation of the vertebral body under load, especially in the anterior region where a 14-fold increase was observed at the fractured level and a threefold increase was observed at the adjacent level. Vertebroplasty also reversed these changes, reducing deformation of the anterior vertebral body (compared with post-fracture values) by 62% at the fractured level, and by 52% at the adjacent level. Conclusions Vertebral fracture adversely affects compressive load-sharing and increases vertebral deformations at both fractured and adjacent levels. All effects can be partially reversed by vertebroplasty

Targeted action to increase inclusion at the Wellcome Sanger Institute

\ua9 2024, Ahmed et al.The Sanger Excellence Fellowship has been established to increase the representation of researchers with Black-heritage backgrounds at a leading research centre in the UK