The goal of the present study is to demonstrate 1H LF-NMR time relaxation measurements for efficient and rapid evaluation of Omega-3 polyunsaturated fatty acids (PUFA)-rich linseed oil (LSO) oxidative aging mechanisms, by monitoring primary chemical and structural changes occurring during thermal oxidative stress. The LF NMR monitors the different proton spin-spin coupling energy relaxation times, T2 within LSO molecular segments, from the initiation of free radical generation and hydroperoxide formation to the propagation of alkoxy radicals, and alpha, beta-unsaturated aldehydes formation, and a termination phase of crosslinked polymerization end products. The 1H LF NMR T2 values monitors both the covalent and secondary bonding interactions (e.g., electrostatic and hydrogen bonding) during the different oxidation phases. The present paper shows that LSO tail segments mobility in terms of T2 multi-exponential relaxation decays, generated by data reconstructing of 1H transversal relaxation components are providing a clear, sharp and informative understanding of LSO sample’s autoxidation aging processes. This is supported by high field band selective 1H NMR pulse excitation for hydroperoxide and aldehydes quantification of the same LSO samples at 25, 40, 60, 80, 100, and 120oC with pumped air for 168 h. Peroxide value, viscosity and self-diffusion, as well as fatty acids profile and by- products determined by GC-MS were also carried out, and correlated with the LSO tail T2 relaxation results. In conclusion the selective determination of LSO alkyl tail T2 energy relaxation time domain values was demonstrated as a rapid evaluation marker for following omega-3 PUFA-rich oils oxidative aging.

The sharp rise in anthropogenic activities and climate change have caused the extensive degradation of grasslands worldwide, jeopardising ecosystem function and threatening human well-being. Toxic weeds have been constantly spreading in recent decades; indeed, their occurrence is considered to provide an early sign of land degeneration. Policy makers and scientific researchers often focus on the negative effects of toxic weeds, such as how they inhibit forage growth, kill livestock and cause economic losses. However, toxic weeds can have several potentially positive ecological impacts on grasslands, such as promoting soil and water conservation, improving nutrient cycling and biodiversity conservation, and protecting pastures from excessive damage by livestock. We reviewed the literature to detail the adaptive mechanisms underlying toxic weeds and to provide new insight into their roles in degraded grassland ecosystems. The findings highlight that the establishment of toxic weeds may provide a self-protective strategy of degenerated pastures that does not require special interventions. Consequently, policy makers, managers and other personnel responsible for managing grasslands need to take appropriate actions to assess the long-term trade-offs between the development of animal husbandry and the maintenance of ecological services provided by grasslands.

Background and Purpose Intra-islet heparan sulfate (HS) plays an important role in the maintenance of the pancreatic islet function. The aim of this study was to investigate the effect mechanism of HS loss on the functioning of islets in diabetic mice. Experimental Approach The hypoglycemic effect of a heparanase inhibitor, OGT2115, was tested in streptozotocin-induced diabetic mice. The islets of pancreas sections were also stained to reveal their morphology. An insulinoma MIN6 cell line and primary isolated murine islets were used to investigate the effect of OGT2115 in vitro. Key Results Intra-islet HS was clearly lost in streptozotocin-induced diabetic mice due to the increased heparanase expression in damaged islets. OGT2115 prevented intra-islet HS loss to improve the glucose profile and insulin secretion in streptozotocin-treated mice. The apoptosis of pancreatic beta cells, the infiltration of mononuclear macrophages, CD4 and CD8 positive T-cells in islets was reduced by OGT2115 in streptozotocin-treated mice, but OGT2115 did not alter the direct streptozotocin-induced damage in vitro. The expression of heparanase was increased in high glucose-treated isolated islets but not in response to direct streptozotocin stimulation. Further experiments showed that high glucose stimuli could decrease the expression of peroxisome proliferator-activated receptor gamma (PPARγ) in cultured islets, thereby relieving the PPARγ-induced inhibition of heparanase gene expression. Conclusion and Implications Hyperglycemia could cause intra-islet HS loss by elevating the expression of heparanase, thereby aggravating inflammatory cell infiltration and islet damage. Inhibition of heparanase might provide benefit for pancreatic beta cell protection in type 1 diabetes.

Background and purpose: Chronic alcohol intake provoked unfavorable geometric and functional changes in the heart along with altered autophagy. Parkin, a cytosolic E3 ubiquitin ligase encoded by PARK2 gene, governs mitochondrial homeostasis and mitophagy although its role in alcoholic cardiomyopathy remains unclear. Experimental approach: This study was designed to examine the role of Parkin in alcohol-induced cardiomyopathy. Adult male wild-type (WT) and PARKIN2 knockout (Parkin-/-) mice were placed on alcohol (4%) or control diet for 8 weeks. Echocardiographic and cardiomyocyte mechanical properties, myocardial and mitochondrial morphology, autophagy and mitophagy were evaluated. GFP-LC3 puncta was employed to assess autophagosome formation. Key results: Our results revealed that alcohol intake led to unfavorable geometric and contractile changes (enlarged left ventricular chamber; decreased fractional shortening, ejection fraction, peak shortening and velocity of shortening/relengthening, prolonged relengthening duration), enlarged cardiomyocyte size and interstitial fibrosis, as well as mitochondrial swelling with cristae disarrangement and mitochondrial depolarization, the effects of which were exacerbated by Parkin deficiency. Alcohol consumption promoted autophagy and PINK1-Parkin-mediated mitophagy, the effects of which were cancelled off by Parkin knockout. Co-immunoprecipitation noted a tight interaction between Parkin and Ambra1 (autophagy and beclin1 regulator 1). In vitro study using neonatal rat cardiomyocytes revealed that Parkin transfection ameliorated ethanol-induced changes in autophagy. However, Ambra1 silencing negated Parkin-induced protection against ethanol-induced autophagy. Conclusions and implications: Taken together, these data suggest an integral role for Parkin in the face of alcoholic challenge possibly through its interaction with Ambra1 to promote autophagy and maintain mitochondrial homeostasis.

Peptide-based cancer therapy has been of great interest due to the unique advantages of peptides, such as the low molecular weight, the ability to specifically target tumor cells, easy availability and low toxicity in normal tissues. Therefore, identify and synthesize novel peptides could provide a promising choice to patients with cancer. The antitumor second generation peptide CIGB-552 has been developed as a candidate to cancer treatment. Proteomic and genomic studies have identified the intracellular protein COMMD1 as the specific target of CIGB-552. This peptide penetrates inside tumor cells to induce the proteasomal degradation of RelA, causing the termination of NF-kB signaling. The antitumor activity of CIGB-552 has been validated in vitro in different human cancer cell lines, as well as in vivo in syngeneic and xenograft tumor mouse models and in cancer-bearing dogs. The aim of this review is to present and discuss the experimental data about CIGB-552, its mechanism of action and its therapeutic potential in human chronic diseases. This peptide is already in phase I of clinical trials as antineoplastic drug, but also has possible application to other inflammatory and metabolic conditions.

It is a pleasure and an honour to welcome you to the first edition of Applied AI Letters.  Getting to this point has been a combination of many people's hard work and we are very excited to move into the next stage, sharing our vision for Applied AI Letters with you.  Why did we start Applied AI Letters?When we consider the lifecycle of a successful idea, we can identify some unique stages. We have put these together in Figure 1.  Initially, a challenge should be identified, and it is often (although not always) the case that there is some idea of the impact solving this challenge should have.  If this challenge ignites the scientific spirit, research then begins post haste.  Hopefully, at some point a research breakthrough is made, allowing a first in kind or first in class solution to the challenge.  Solving a challenge is not the end of the story though, with the approach then being generalised, allowing its application to new and more impactful areas.  Finally, the idea becomes so ingrained in the scientific and technological psyche that its use is no longer questioned, but expected; we call this the commoditisation stage.  This way of thinking has been adopted in many places, such as the technology adoption curve, and the TRL levels used by, for example, NASA and the EU.\cite{hder2017}

Despite its inherent costs, sexual reproduction is ubiquitous in nature, and the mechanisms to protect it from a competitive displacement by asexuality remain unclear. Popular mutation-based explanations, like the Muller's ratchet and the Kondrashov's hatchet, assume that purifying selection may not halt the accumulation of deleterious mutations in the non-recombining genomes, ultimately leading to their degeneration. However, empirical evidence is scarce and it remains particularly unclear whether mutational degradation proceeds fast enough to ensure the decay of clonal organisms and to prevent them from outcompeting their sexual counterparts. To test this hypothesis, we jointly analyzed the exome sequences and the fitness-related phenotypic traits of the sexually-reproducing fish species and their clonal hybrids, whose evolutionary ages ranged from F1 generations to 300 ky. As expected, mutations tended to accumulate in the clonal genomes in a time-dependent manner. However, contrary to the predictions, we found no trend towards increased non-synonymity of mutations acquired by clones, nor higher radicality of their amino-acid substitutions. Moreover, there was no evidence for fitness degeneration in the old clones compared to that in the younger ones. In summary, although a purifying selection may still be relaxed in the asexual genomes, our data indicate that its efficiency is not drastically decreased. Even the oldest investigated clone was found to be too young to suffer fitness consequences from a mutation accumulation. This suggests that mechanisms other than mutation accumulation may be needed to explain the competitive advantage of sex in the short term.

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest to understanding pulmonary vascular homeostasis and developing new treatments for pulmonary hypertension. In particular, it would be helpful to discover the key molecules in the integrated vascular response to hypoxia to inform potential drug targets. One strategy is to take advantage of experiments of nature; specifically, to understand the molecular basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. This is the motivation for genetic studies in populations and animals adapted to life at high altitudes. To date, these studies highlight the importance of hypoxia-inducible factor 2α (HIF-2α), encoded by EPAS1, and prolyl hydroxylase domain-containing protein 2 (PHD), encoded by EGLN1, and support efforts to pharmacologically manipulate HIF-2 activity as a treatment for pulmonary hypertension.

Fluorescent pseudomonads represent one of the largest groups of bacteria inhabiting the surfaces of plants, but their genetic composition in planta is poorly understood. Here, we examined the population structure and diversity of fluorescent pseudomonads isolated from sugar beet grown at two geographic locations (Oxford, UK and Auckland, New Zealand). To seek evidence for niche adaptation, bacteria were sampled from three types of leaves (immature, mature and senescent) and then characterized using a combination of genotypic and phenotypic analysis. We first performed multilocus sequence analysis (MLSA) of three housekeeping genes (gapA, gltA, acnB) in a total of 152 isolates (96 from Oxford, 56 from Auckland). The concatenated sequences were grouped into 81 sequence types and 22 distinct operational taxonomic units (OTUs). Significant levels of recombination were detected, particularly for the Oxford isolates (rate of recombination to mutation (r/m) = 5.23 for the whole population). Subsequent ancestral analysis performed in STRUCTURE found evidence of six ancestral populations, and their distributions significantly differed between Oxford and Auckland strains. Next, the ability to grow on 95 carbon sources was assessed using the BiologTM GN2 microtiter plates. A distance matrix was generated from the raw growth data (A660) and subjected to multidimensional scaling (MDS) analysis. There was a significant correlation between the substrate utilization profiles and MLSA genotypes. Both phenotypic and genotypic analyses indicated presence of a geographic structure for strains from Oxford and Auckland. Significant differences were genotypically detected between strains isolated from immature versus mature/senescent leaves. The fluorescent pseudomonads thus showed an ecotypic population structure, suggestive of adaptation to both geographical and local plant environments.

We report on the development of a new model of alveolar air-tissue interface consisting of an array of suspended hexagonal monolayers of gelatin nanofibers supported by microframes and a microfluidic device for the patch integration. The suspended monolayers are deformed to a central displacement of 40-80 μm at the air-liquid interface by application of air pressure in the range of 200-1000 Pa. With respect to the diameter of the monolayers that is 500 μm, this displacement corresponds to a linear strain of 2-10% in agreement with the physiological strain range in the lung alveoli. The culture of A549 cells on the monolayers for an incubation time 1-3 days showed viability in the model. We exerted a periodic strain of 5% at a frequency of 0.2 Hz during 1 hour to the cells. We found that the cells were strongly coupled to the nanofibers, but the strain reduced the coupling and induced remodeling of the actin cytoskeleton, which led to a better tissue formation. Our model can serve as a versatile tool in lung investigations such as in inhalation toxicology and therapy.

Abstract: Searching for energetic materials with balanced detonation performance and sensitivity is the enduring ambition in the evolution of high energy density materials (HEDMs). The coplanar molecular structure of energetic compound has a powerful impact on performance. Herein, the novel compounds of bis(nitrotriazoles) tetrazine (BNTT) was designed and investigated by density functional theory(DFT) method. However, the coplanar BNTT’s oxides would a highlight of molecular design with good balance between superior performance with acceptable sensitivities. Results show that all these designed compounds possess high densities, positive heats of formation, remarkable detonation performance, and acceptable impact sensitivity. In particular, B1-3 possess higher density (ρ=1.97g·cm-3) and exhibits the better balance between detonation performance (Q=1779.83 cal·g-1, D=9.48km·s-1, P=42.01GPa) and sensitivity (h50%=28cm) than RDX. The theoretical study offer that all novel compounds possess acceptable sensitivity. It may be seen as the potential candidates of HEDMs.

Mini- commentary on BJOG-19-1190.R1: Cardio-metabolic risk factors among young infertile women: a systematic review and meta-analysis

European starlings (Sturnus vulgaris) represent one of the most widespread and problematic avian invasive species in the world. Understanding their unique population history and current population dynamics can contribute to conservation efforts and clarify how evolutionary processes play out over short timescales. European starlings were introduced to Central Park, New York in 1890, and from a founding group of about 100 birds, they have expanded across North America with a current population of approximately 200 million. There were also multiple introductions in Australia in the mid-19th century, and at least one introduction in South Africa in the late 19th century. Independent introductions on these three continents provide a robust system to investigate invasion genetics. In this study, we compare mitochondrial diversity in European starlings from North America, Australia and South Africa, and a portion of the native range in the United Kingdom. Of the three invasive ranges, the North American population shows the highest haplotype diversity and evidence of both sudden demographic and spatial expansion. Comparatively, the Australian population shows the lowest haplotype diversity, but also shows evidence for sudden demographic and spatial expansion. South Africa is intermediate to the other invasive populations in genetic diversity but does not show evidence of demographic expansion. In previous studies, population genetic structure was found in Australia, but not in South Africa. Here we find no evidence of population structure in North America. Although all invasive populations share haplotypes with the native range, only one haplotype is shared between invasive populations. This suggests these three invasive populations represent independent subsamples of the native range. The structure of the haplotype network implies that the native range sampling does not comprehensively characterize the genetic diversity there. This study represents the most geographically widespread analysis of European starling population genetics to date.

Though the pathogenesis of acute myeloid leukemia (AML) is still unknown, accumulating evidence has revealed that immune response plays a vital part in the pathogenesis. Here, we investigated the involvement of 24 single-nucleotide polymorphisms (SNPs) of immuno-related genes, including cytokines (IL2, IL4, IL9, IL-12A, IL-22, IFNG, and TGFB1), transcriptional regulatory genes (TBX21, STAT1, STAT3, STAT5B, STAT6, GATA3, FOXP3, and IRF4), and others (IL2RA IL6R NFKBIA), in 269 AML inpatients and 200 healthy controls. Furthermore, we analyzed the relationship between the SNPs and clinical characteristics. Immuno-related SNP genotyping was performed on the Sequenom MassARRAY iPLEX platform. All the SNPs in healthy controls were consistent with Hardy–Weinberg equilibrium. All final p values were adjusted by Bonferroni multiple testing. Our results showed that IL-22 (rs2227491) was significantly associated with the white blood cell (WBC) counts. STAT5B (rs6503691) showed a close relationship with the recurrent genetic abnormalities in patients with AML. We verified the negatively independent effect of age and risk of cytogenetics on overall survival (OS). More importantly, the GG genotype of IL-12A (rs6887695) showed a negative impact on AML prognosis independently. Furthermore, the relative expression of IL-12 was decreased in GG genotype, no matter under codominant or recessive model. However, no correlation was observed between the SNPs mentioned above and disease susceptibility, risk stratification, and survival. Our findings suggest that immuno-related gene polymorphisms are associated with prognosis in AML, which may perform as novel inspection targets for AML patients.

Gully erosion is a significant source of fine suspended sediment (<63µm) and associated nutrient pollution to freshwater and marine waterways. Researchers, government agencies, and monitoring groups are currently using monitoring methods designed for streams and rivers (e.g., autosamplers, rising stage samplers, and turbidity loggers) to evaluate suspended sediment in gullies. This is potentially problematic because gullies have unique hydrological and operational challenges that differ to those of streams and rivers. Here we present a laboratory and field-based assessment of the performance of common suspended sediment monitoring techniques applied to gullies. We also evaluate a recently-described method; the pumped active suspended sediment (PASS) sampler, which has been modified for monitoring suspended sediment in gully systems. Discrete autosampling provided data at high temporal resolution, but had considerable uncertainty associated with the poor collection efficiency (25 ± 10%) of heavier sediment particles (i.e., sand). Rising stage sampling, while robust and cost-effective, suffered from large amounts of condensation under field conditions (25-35% of sampler volume), thereby diluting sample concentrations and introducing additional measurement uncertainty. The turbidity logger exhibited low uncertainty (< 10%) when calibrated with suspended sediment concentration data from physically collected samples, however, this calibration approach needs to be performed on a site-specific basis to overcome the error associated with the impact of different particle size distributions on the turbidity measurement. The modified PASS sampler proved to be a reliable and representative measurement method for gully sediment water quality, however, the time-integrated nature of the method limits its temporal resolution compared to the other monitoring methods. We recommend monitoring suspended sediment in alluvial gully systems using a combination of complementary techniques (e.g., PASS and RS samplers) to account for the limitations associated with individual methods.

Abstract: Sensitivity to bitter tastes provides animals with an important means of interacting with their environment and thus, influences their dietary preferences. Genetic variants encoding functionally distinct receptor types contribute to variation in bitter taste sensitivity. Our previous study showed that two nonsynonymous sites, A52V and Q296H, in the TAS2R20 gene are directionally selected in giant pandas from the Qinling Mountains, which are speculated to be the causative base-pair changes of Qinling pandas for the higher preference for bamboo leaves in comparison with other pandas. Here, we used functional expression in engineered cells to identify agonists of pTAS2R20 (i.e. giant panda’s TAS2R20) and interrogated the differences in perception in the in vitro responses of pTAS2R20 variants to the agonists. Our results show that pTAS2R20 is specifically activated by quercitrin and that pTAS2R20 variants exhibit differences in the sensitivity of their response to the agonist. Compared to pTAS2R20 in pandas from other areas, the receptor variant with A52V and Q296H, which is most commonly found in Qinling pandas, confers a significantly decreased sensitivity to quercitrin. We subsequently quantified the quercitrin content of the leaves of bamboo distributed in the Qinling Mountains, which was found to be significantly higher than that of the leaves of bamboo from panda habitats in other areas. Our results suggest that the decreased sensitivity to quercitrin in Qinling pandas results in higher-quercitrin-containing bamboo leaves to be tasting less bitter to them and thus, influences their dietary preference. This study illustrates the genetic adaptation of Qinling pandas to their environments and provides a fine example of the functional effects of directional selection in the giant panda.

Many current animal models of heart failure are hampered by intrinsic methodological complexities, while other models yield only a subtle cardiac phenotype even after prolonged in vivo treatments. A new “chemogenetic” animal model of heart failure recapitulates a critical characteristic shared by many disease states that lead to heart failure in humans: an increase in redox stress in the heart. This “chemogenetic” approach exploits a recombinant yeast enzyme that can be dynamically and specifically activated in vivo to generate the reactive oxygen species (ROS) hydrogen peroxide (H2O2) in cardiac myocytes. Redox stress can be rapidly, selectively, and reversibly manipulated by chemogenetic generation of ROS in cardiac myocytes, yielding a new model of dilated cardiomyopathy. Treatment of animals with the angiotensin receptor blocker valsartan promotes recovery of ventricular function and resolution of adverse cardiac remodeling. This Mini-Review discusses in vivo chemogenetic approaches to manipulate and analyze oxidative stress in the heart.

Rationale: Conventional models of cultural humility - even those extending analysis beyond the dyad of healthcare provider-patient to include concentric social influences such as families, communities and institutions that make the clinical relationship possible - aren’t conceptually or methodologically calibrated to accommodate shifts occurring in contemporary biomedical cultures. More complex models are required that are attuned to how advances in biomedical, communications and information technologies are increasingly transforming the very cultural and material conditions of health care and its delivery structures, and thus how power manifests in clinical encounters. Methodological Intervention: In this paper, we offer a two-pronged intervention in the cultural humility literature. At a first level of analysis, we suggest the need to broaden understandings of culture and associated workings of power to accommodate the effects of biomedicine’s technologising turn. A second level of intervention invites experimentation to broaden the availability of methodological tools to analyse and assess the multidimensionality of technologies and their agentic effects in healthcare encounters. Drawing from new materialism theories, practices of care are approached “diffractively” as contingent and dynamic material-discursive events. Our neo-materialist framework for cultural humility expands analytical sight-lines beyond hierarchical relationships and dichotomies privileging humans (practitioner and/or patient) as sole actants in the clinical exchange. Attended to are the ongoing dynamics of practices entangling big-data driven knowledges and interventions, pharmacological technologies and material instruments and devices, diseases, and the bodies/subjectivities of health care providers and patients. We investigate the implications for clinical assessment if a cultural humility framework is methodologically attuned to the clinical encounter as a discontinuous, discursive-material process producing multiple, contextually emergent data moments and objects for analysis. Engaging evaluative inquiry diffractively allows for a different ethical practice of care, one that attends to the forms of patient and health provider accountability and responsibility emerging in the clinical encounter.