Assessment of bio-availability of Cd, Pb, As and Tl via Gastric/Intestinal Digestion in Plants Collected From Different Kenyan Regions

In this study, total and bio-available levels of cadmium (Cd), Lead (Pb), arsenic (As) and Thallium (Tl) in 19 Kenya plants from two study sites (Manga and Borabu) were evaluated. ICP-MS technique was used to determine total Cd, Pb, As and Tl contents, while ultra-filtration and physiological extraction tests evaluated bio-accessibility of these elements. The plants had low concentrations; Cd (0.27±0.02 and 0.26±0.02), As (0.32±0.02 and 0.48±0.04), Tl (0.07± 0.02 and 0.06±0.01) and Pb (1.23±0.11 and 1.16±0.10) mg/kg in Manga and Borabu sites. However, sequential ultra-filtration showed more than 70% high molecular weight species (>10 kDa) predominated with Pb, Cd and Tl. The physiological based tests showed Cd, Pb, As and Tl extracted enzymatically were significantly higher (0.45±0.11, 0.46±0.12, 0.37±0.10 and 0.81±0.19µg/g) than aquatically extracted (0.32±0.07, 0.34±0.11, 0.26±0.08 and 0.50±0.27) µg/g, (p<0.05). Low bio-accessibility levels of these elements in medicinal plants justifies their use therapeutically.

Members of the GADD45 Protein Family Show Distinct Propensities to form Toxic Amyloid-Like Aggregates in Physiological Conditions

The three members (GADD45α, GADD45β, and GADD45γ) of the growth arrest and DNA damage-inducible 45 (GADD45) protein family are involved in a myriad of diversified cellular functions. With the aim of unravelling analogies and differences, we performed comparative biochemical and biophysical analyses on the three proteins. The characterization and quantification of their binding to the MKK7 kinase, a validated functional partner of GADD45β, indicate that GADD45α and GADD45γ are strong interactors of the kinase. Despite their remarkable sequence similarity, the three proteins present rather distinct biophysical properties. Indeed, while GADD45β and GADD45γ are marginally stable at physiological temperatures, GADD45α presents the Tm value expected for a protein isolated from a mesophilic organism. Surprisingly, GADD45α and GADD45β, when heated, form high-molecular weight species that exhibit features (ThT binding and intrinsic label-free UV/visible fluorescence) proper of amyloid-like aggregates. Cell viability studies demonstrate that they are endowed with a remarkable toxicity against SHSY-5Y and HepG2 cells. The very uncommon property of GADD45β to form cytotoxic species in near-physiological conditions represents a puzzling finding with potential functional implications. Finally, the low stability and/or the propensity to form toxic species of GADD45 proteins constitute important features that should be considered in interpreting their many functions.

Dithienopyrrole-based Organic Electroactive Materials and Their Photovoltaic Aspects

4H-dithieno[3,2-b:2',3'-d]pyrrole has recently become a useful building block in the synthesis of donor-acceptor molecules with practical application in various organic technologies. The DTP molecule itself consists of a pyrrole ring with two fused thiophenes providing an alternative for the related dithieno[3,2-b:2′,3′-d]thiophene. Most notably, the significance of DTP-based low- and high-molecular weight species has increased in recent years since, upon proper processing, they allow to improve the performance of many fields of organic electronics. This review is a trial of a brief report on recent advances in modern DTP chemistry with examples of their applications, mostly in the area of organic photovoltaics. The scope of this manuscript was to present the structure-property relationships that had been found together with the development of DTP-based materials.

Exoplanet secondary atmosphere loss and revival

The next step on the path toward another Earth is to find atmospheres similar to those of Earth and Venus—high–molecular-weight (secondary) atmospheres—on rocky exoplanets. Many rocky exoplanets are born with thick (>10 kbar) H2-dominated atmospheres but subsequently lose their H2; this process has no known Solar System analog. We study the consequences of early loss of a thick H2atmosphere for subsequent occurrence of a high–molecular-weight atmosphere using a simple model of atmosphere evolution (including atmosphere loss to space, magma ocean crystallization, and volcanic outgassing). We also calculate atmosphere survival for rocky worlds that start with no H2. Our results imply that most rocky exoplanets orbiting closer to their star than the habitable zone that were formed with thick H2-dominated atmospheres lack high–molecular-weight atmospheres today. During early magma ocean crystallization, high–molecular-weight species usually do not form long-lived high–molecular-weight atmospheres; instead, they are lost to space alongside H2. This early volatile depletion also makes it more difficult for later volcanic outgassing to revive the atmosphere. However, atmospheres should persist on worlds that start with abundant volatiles (for example, water worlds). Our results imply that in order to find high–molecular-weight atmospheres on warm exoplanets orbiting M-stars, we should target worlds that formed H2-poor, that have anomalously large radii, or that orbit less active stars.

Treatment with JQ1, a BET bromodomain inhibitor, is selectively detrimental to R6/2 Huntington’s disease mice

Transcriptional and epigenetic alterations occur early in Huntington’s disease (HD), and treatment with epigenetic modulators is beneficial in several HD animal models. The drug JQ1, which inhibits histone acetyl-lysine reader bromodomains, has shown promise for multiple cancers and neurodegenerative disease. We tested whether JQ1 could improve behavioral phenotypes in the R6/2 mouse model of HD and modulate HD-associated changes in transcription and epigenomics. R6/2 and non-transgenic (NT) mice were treated with JQ1 daily from 5 to 11 weeks of age and behavioral phenotypes evaluated over this period. Following the trial, cortex and striatum were isolated and subjected to mRNA-seq and ChIP-seq for the histone marks H3K4me3 and H3K27ac. Initially, JQ1 enhanced motor performance in NT mice. In R6/2 mice, however, JQ1 had no effect on rotarod or grip strength but exacerbated weight loss and worsened performance on the pole test. JQ1-induced gene expression changes in NT mice were distinct from those in R6/2 and primarily involved protein translation and bioenergetics pathways. Dysregulation of HD-related pathways in striatum was exacerbated by JQ1 in R6/2 mice, but not in NTs, and JQ1 caused a corresponding increase in the formation of a mutant huntingtin protein-dependent high molecular weight species associated with pathogenesis. This study suggests that drugs predicted to be beneficial based on their mode of action and effects in wild-type or in other neurodegenerative disease models may have an altered impact in the HD context. These observations have important implications in the development of epigenetic modulators as therapies for HD.

GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior

Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted Atg7 in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to Atg7 deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor–associated protein-like 2 (GABARAPL2) to differentially form high–molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABAA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation.

Emergence of Function and Selection from Recursively Programmed Polymerisation Reactions in Mineral Environments

<b>Living systems are characterised by an ability to sustain chemical reaction networks far-from-equilibrium. It is likely that life first arose through a process of continual disruption of equilibrium states in recursive reaction networks, driven by periodic environmental changes allowing the emergence of a memory. Herein, we report the emergence of proto-enzymatic function from recursive polymerisation reactions using amino acids and glycolic acid over four wet-dry cycles. Reactions are kept out of equilibrium by diluting products 9:1 in fresh starting solution at the end of each recursive cycle, and the development of complex high molecular weight species is explored using a new metric, the Mass Index, which allows the complexity of the system to be explored as a function of cycle. This process is carried out on a range of different mineral environments. We explore the hypothesis that disrupting equilibrium <i>via</i> recursive cycling imposes a selection pressure and subsequent boundary conditions on products, which may otherwise be prone to uncontrolled combinatorial explosion. After just four reaction cycles, product mixtures from recursive reactions exhibit greater catalytic activity and truncation of product space towards higher molecular weight species compared to non-recursive controls. </b>

Emergence of Function and Selection from Recursively Programmed Polymerisation Reactions in Mineral Environments

<b>Living systems are characterised by an ability to sustain chemical reaction networks far-from-equilibrium. It is likely that life first arose through a process of continual disruption of equilibrium states in recursive reaction networks, driven by periodic environmental changes allowing the emergence of a memory. Herein, we report the emergence of proto-enzymatic function from recursive polymerisation reactions using amino acids and glycolic acid over four wet-dry cycles. Reactions are kept out of equilibrium by diluting products 9:1 in fresh starting solution at the end of each recursive cycle, and the development of complex high molecular weight species is explored using a new metric, the Mass Index, which allows the complexity of the system to be explored as a function of cycle. This process is carried out on a range of different mineral environments. We explore the hypothesis that disrupting equilibrium <i>via</i> recursive cycling imposes a selection pressure and subsequent boundary conditions on products, which may otherwise be prone to uncontrolled combinatorial explosion. After just four reaction cycles, product mixtures from recursive reactions exhibit greater catalytic activity and truncation of product space towards higher molecular weight species compared to non-recursive controls. </b>