We apply the Bielecki metric on the space C([a, b]), to analyze the different types of stabilities of non-linear fractional integral equation corresponding to fractional boundary value problems. Sufficient conditions are obtained to prove stability results for fractional non-linear Volterra and Fredholm integral equations, given by Ulam, Hyer and Rassias. We extend the respective stability results to the fractional integral equations where the domain of integration is an unbounded interval. We provide numerical examples which asserts our stability results.

We establish nonexistence of nontrivial solutions (including sign-changing ones) for some partial differential inequalities of elliptic and parabolic type containing nonlinear terms that depend on the positive and negative part of the sought function in different ways. Systems of elliptic inequalities with similar structure are also considered. The proofs are based on the test function method.

Although species delimitation can be highly contentious, the development of reliable methods to accurately ascertain species boundaries is an imperative step in cataloguing and describing Earth’s quickly disappearing biodiversity. Spider species delimitation remains largely based on morphological characters; however, many mygalomorph spider populations are morphologically indistinguishable from each other yet have considerable molecular divergence. The focus of our study, Antrodiaetus unicolor species complex which contains two sympatric species, exhibits this pattern of relative morphological stasis with considerable genetic divergence across its distribution. A past study using two molecular markers, COI and 28S, revealed that A. unicolor is paraphyletic with respect to A. microunicolor. To better investigate species boundaries in the complex, we implement the cohesion species concept and employ multiple lines of evidence for testing genetic exchangeability and ecological interchangeability. Our integrative approach includes extensively sampling homologous loci across the genome using a RADseq approach (3RAD), assessing population structure across their geographic range using multiple genetic clustering analyses that include STRUCTURE, PCA, and a recently developed unsupervised machine learning approach (Variational Autoencoder). We evaluate ecological similarity by using large-scale ecological data for niche-based distribution modeling. Based on our analyses, we conclude that this complex has at least one additional species as well as confirm species delimitations based on previous less comprehensive approaches. Our study demonstrates the efficacy of genomic-scale data for recognizing cryptic species, suggesting that species delimitation with one data type, whether one mitochondrial gene or morphology, may underestimate true species diversity in morphologically homogenous taxa with low vagility.

In this paper we investigate the size of a bi-dimensional fragmentation process. A rectangle of dimensions x and y is considered, it is split into four sub-rectangles with some probability that depends on x and y, we iterate until the stop of the process. The total number of the all the obtained rectangles at the end of the process satisfies some equality in distribution which is resolved , using some tools on integral equations, via the contraction method.

Crowd-based hydrological observations can supplement existing monitoring networks and allow data collection in regions where otherwise no data would be available. In the citizen science project CrowdWater, repeated water level observations using a virtual staff gauge approach result in time series of water level classes. To investigate the quality of these observations, we compared the water level class data for a number of locations where water levels were also measured and assessed when these observations were submitted. We analysed data for nine locations where citizen scientists reported multiple observations using a smartphone app and stream level data were also available. At twelve other locations, signposts were set up to ask citizens to record observations on a form that could be left in a letterbox. The results indicate that the quality of the data collected with the app was higher than for the forms. A possible explanation is that for each app location, most contributions were made by a single person, whereas at the locations of the forms almost every observation was made by a new contributor. On average, more contributions were made between May and September than during the other months. Observations were submitted for a range of flow conditions, with a higher fraction of high flow observations for the data collected with the app. Overall, the results are encouraging for citizen science approaches in hydrology and demonstrate that the smartphone application with its virtual staff gauge is a promising approach for crowd-based water level class observations.

Backgroud: A long-term hepatic inflammatory response is a risk factor for liver cancer initiation and progression. Interleukin (IL)-35 is the newest member of the IL-12 cytokine family, and has been reported to play an essential role in the immunosuppressive liver microenvironment. Herein we focus on the expression profiles of IL-35 in hepatocellular carcinoma (HCC) and the effect on local immune status. Methods: HCC transcriptome array data were downloaded from Gene Expression Omnibus. The bioinformatics analysis was performed by the BRB array tools and online Ingenuity Pathway Analysis software. The serum IL-35 level was detected by AimPlet bead-based immunoassay. In situ IL-35 expression detection was performed by immunohistochemical staining and western blot. Results: Our results showed that there were large amounts of IL-35 expressed in HCC serum and tumor tissues. IL-35 expression affects the transcript of thousands of genes, most of which correlated with T-cell immunity. This study proved that enhancement of regulatory T cells (Tregs) and impairment of cytolytic T cells are prominent effects of IL-35. Conclusions: Elevated IL-35 played critical roles in HCC patients through affecting the balance between Tregs and cytotoxic T cells. Dissection of the precise targets and the underlying molecular mechanisms will lead to alternative treatments for HCC patients.

We develop a novel approach to trophic metacommunities which allows us to explore how progressive habitat loss affects food webs. Our method combines classic metapopulation models on fragmented landscapes with a Bayesian network representation of trophic interactions for calculating local extinction rates. This means we can repurpose known results from classic metapopulation theory for trophic metacommunities, such as ranking the habitat patches of the landscape with respect to their importance to the persistence of the metacommunity as a whole. We use this to study the effects of habitat loss, both on model communities and the plant-mammal Serengeti food web dataset as a case study. Combining straightforward parameterizability with computational efficiency, our method permits the analysis of species-rich food webs over large landscapes, with hundreds or even thousands of species and habitat patches, while still retaining much of the flexibility of explicit dynamical models.

Tissue constructs of physiologically relevant scale require a vascular system to maintain cell viability. However, in vitro vascularization of engineered tissues is still a major challenge. Successful approaches are based on a feeder layer (FL) to support vascularization. Here, we investigated whether the supporting effect on the self-assembled formation of vascular-like structures by microvascular endothelial cells (mvECs) originates from the FL itself or from its extracellular matrix (ECM). Therefore, we compared the influence of ECM, either derived from adipose-derived stem cells (ASCs) or adipogenic differentiated ASCs, with the classical approaches based on a cellular FL. All cell-derived ECM (cdECM) substrates enable mvEC growth with high viability. Vascular-like structure formation was visualized by immunofluorescence staining of endothelial surface protein CD 31 and can be observed on all cdECM and FL substrates but not on control substrate collagen I. On adipogenic differentiated ECM longer and higher branched structures can be found compared to stem cell cdECM. An increased concentration of pro-angiogenic factors can be found in cdECM substrates and FL approaches compared to controls. Finally, expression of proteins associated with tube formation (E-selectin and thrombomodulin) was confirmed. These results highlight cdECM as promising biomaterial for in vitro vascularization in adipose tissue engineering.

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.