Reciprocal coevolution of tumors and their microenvironments underlies disease progression, yet intrinsic limitations of patient-derived xenografts and simpler cell-based models present challenges towards a deeper understanding of these intercellular communication networks. To help overcome these barriers and complement existing models, we have developed a human microphysiological system (MPS) model of the human liver acinus, a common metastatic site, and have applied this system to estrogen receptor (ER)+ breast cancer. In addition to their hallmark constitutive (but ER-dependent) growth phenotype, different ESR1 missense mutations, prominently observed during estrogen deprivation therapy, confer distinct estrogen-enhanced growth and drug resistant phenotypes not evident under cell autonomous conditions. Under low molecular oxygen within the physiological range (~5-20%) of the normal liver acinus, the estrogen-enhanced growth phenotypes are lost, a dependency not observed in monoculture. In contrast, the constitutive growth phenotypes are invariant within this range of molecular oxygen suggesting that ESR1 mutations confer a growth advantage not only during estrogen deprivation but also at lower oxygen levels. We discuss the prospects and limitations of implementing human MPS, especially in conjunction with in situ single cell hyperplexed computational pathology platforms, to identify biomarkers mechanistically linked to disease progression that inform optimal therapeutic strategies for patients.

Pancreatic fistula is one of the most serious complications after pancreatoduodenectomy for treating any lesions at the pancreatic head. For years, surgeons have tried various methods to reduce its incidence.

Background: CAPON has two isoforms in human brain: long form of CAPON (CAPON-L) and short form of CAPON (CAPON-S). Recent studies have indicated the involvement of CAPON in tumor cell growth. We aimed to reveal the role of the two CAPON isoforms in the proliferation of glioma cells in this study. Materials and Methods: Lentivirus-mediated stable cell lines with CAPON-L or CAPON-S overexpression were established in U87 and U251 glioma cells. Cell counting kit-8 and colony formation assays were used to evaluate cell proliferation. Western blot analysis of cell cycle-related proteins and flow cytometry were performed to analyze cell cycle progression. Some important molecules of the AKT/mTOR pathway and P53 were also measured by Western blot analysis. Results: Overexpression of CAPON-L showed a significantly inhibitory role in U251 cells, while it exhibited a promoting role in U87 cells. Consistently, overexpressing CAPON-L impeded the cell cycle progression and down-regulated the expression levels of Cyclin D1, CDK4 and CDK6 in U251 cells, whereas it up-regulated the CDK6 level in U87 cells. The overexpression of CAPON-L significantly decreased the phosphorylation and/or total levels of AKT, mTOR and S6 in U251 cells, while it did not affect these signaling molecules in U87 cells, except for a significant increase in the phosphorylation of AKT at Thr-308 site. Transfecting constitutively active AKT (myr-AKT) partially reversed the decreased phosphorylation of AKT and S6 in the CAPON-L-overexpressing U251 cells. In addition, we found a significant decrease in the wild-type P53 level in the CAPON-L-overexpressing U87 cells. The overexpression of CAPON-S also inhibited cell proliferation, blocked cell cycle progression, and decreased the AKT/mTOR pathway activity in U251 cells. Conclusion: The effects of CAPON-L overexpression on glioma cell proliferation are dependent on the AKT/mTOR/P53 activity. The overexpression of CAPON inhibits U251 cell proliferation through the AKT/mTOR signaling pathway, while overexpressing CAPON-L promoted U87 cell proliferation, possibly through down-regulating the P53 level.

Lymphoma is one of the most common hematologic malignancy. Drug resistance is the main obstacle faced in lymphoma treatment. Cancer stem cells are considered as the source of tumor recurrence, metastasis and drug resistance. The β-Asarone, a low-toxicity compound from the traditional medical herb Acorus calamus, has been shown to act as an anti-cancer reagent in various cancer types. However, the anti-cancer activities of β-Asarone in lymphoma have not been shown.

The prevalence of atrial fibrillation (AF) is on the rise in the aging population with congenital heart disease (CHD). A few case series have described the feasibility and early outcomes associated with radiofrequency catheter ablation of AF centered on electrically isolating pulmonary veins (PV) in patients with CHD. In contrast, cryoballoon ablation has not previously been studied in this patient population despite its theoretical advantages, which include a favorable safety profile and shorter procedural time.

The complications with cytotoxic perfluorooctane (PFO) batches reported in 2015 were attributed to reactive underfluorinated impurities whose chemical identity and behavior still need to be clarified.

Poly(limonene carbonate) (PLC) has been highlighted as an attractive substitute to petroleum derived plastics, due to its utilisation of CO2 and bio-based limonene as feedstocks, offering an effective carbon capture and utilisation pathway. Our study investigates the techno-economic viability and environmental sustainability of a novel process to produce PLC from citrus waste derived limonene, coupled with an anaerobic digestion process to enable energy cogeneration and waste recovery maximisation. Computational process design was integrated with a life cycle assessment to identify the sustainability improvement opportunities. PLC production was found to be economically viable, assuming sufficient citrus waste is supplied to the process, and environmentally preferable to polystyrene (PS) in various impact categories including climate change. However, it exhibited greater environmental burdens than PS across other impact categories, although the environmental performance could be improved with a waste recovery system, at the cost of a process design shift towards energy generation. Finally, our study quantified the potential contribution of PLC to mitigating the escape of atmospheric CO2 concentration from the planetary boundary. We emphasise the importance of a holistic approach to process design and highlight the potential impacts of biopolymers, which is instrumental in solving environmental problems facing the plastic industry and building a sustainable circular economy.

Yeast adaptation to stress has been extensively studied. It involves large reprogramming of genome expression operated by many, more or less specific, transcription factors. Here, we review our current knowledge on the function of the eight Yap transcription factors (Yap1 to Yap8) in Saccharomyces cerevisiae, which were shown to be involved in various stress responses. More precisely, Yap1 is activated under oxidative stress, Yap2/Cad1 under cadmium, Yap4/Cin5 and Yap6 under osmotic shock, Yap5 under iron overload and Yap8/Arr1 by arsenic compounds. Yap3 and Yap7 seem to be involved in hydroquinone and nitrosative stresses, respectively. The data presented in this article illustrate how much knowledge on the function of these Yap transcription factors is advanced. The evolution of the Yap family and its roles in various pathogenic and non-pathogenic fungal species is discussed in the last section.

Thermoelectricity allows direct conversion between heat and electricity, providing alternatives for green energy technologies. Despite these advantages, for most materials the energy conversion efficiency is limited by the tendency for the electrical and thermal conductivity to be proportional to each other and the Seebeck coefficient to be small. Here we report counter examples, where the heavy fermion compounds YbTM 2Zn20 (TM = Co, Rh, Ir) exhibit enhanced thermoelectric performance including a large power factor (PF = 74 μW/cm-K2; TM = Ir) and a high figure of merit (ZT = 0.07; TM = Ir) at 35 K. The combination of the strongly hybridized electronic state originating from the Yb f-electrons and the novel structural features (large unit cell and possible soft phonon modes) leads to high power factors and small thermal conductivity values. This demonstrates that with further optimization these systems could provide a platform for the next generation of low temperature thermoelectric materials.

We present the results of experiments involving the isotopic fractionation by diffusion of K+ cations in methanol at 298 K along with supporting molecular dynamic simulations. The experiments, using glass Rayleigh fractionators filled with a methanol solution of KCl, constrain the ratio of the individual diffusivities of 41K and 39K (D 41K/D 39K) in methanol, and so the isotopic fractionation of K+ due to diffusion in methanol, to 0.9995 ± 0.0001. This isotopic fractionation is 25% of the fractionation resulting from K+ diffusion in water. This is consistent with published molecular dynamics simulations indicating greater hydrodynamic coupling between K+ ions and solvating methanol molecules compared to K+ ions and solvating water molecules.

Background: INTERBIO-21 st is Phase II of the INTERGROWTH-21 st Project, the population-based, research initiative involving nearly 70,000 mothers and babies worldwide coordinated by Oxford University and performed by a multidisciplinary network of more than 400 healthcare professionals and scientists from 35 institutions in 21 countries worldwide. Phase I, conducted 2008-2015, consisted of nine complementary studies designed to describe optimal human growth and neurodevelopment, based conceptually on the WHO prescriptive approach. The studies generated a set of international standards for monitoring growth and neurodevelopment, which complement the existing WHO Child Growth Standards. Phase II aims to improve the functional classification of the highly heterogenous preterm birth and fetal growth restriction syndromes through a better understanding of how environmental exposures, clinical conditions and nutrition influence patterns of human growth from conception to childhood, as well as specific neurodevelopmental domains and associated behaviors at 2 years of age. Methods: In the INTERBIO-21 st Newborn Case-Control Study, a major component of Phase II, our objective is to investigate the mechanisms potentially responsible for preterm birth and small for gestational age and their interactions, using deep phenotyping of clinical, growth and epidemiological data and associated nutritional, biochemical, omic and histological profiles. Here we describe the study sites, population characteristics, study design, methodology and standardization procedures for the collection of longitudinal clinical data and biological samples (maternal blood, umbilical cord blood, placental tissue, maternal feces and infant buccal swabs) for the study that was conducted between 2012 and 2018 in Brazil, Kenya, Pakistan, South Africa, Thailand and the UK. Discussion: Our study provides a unique resource for the planned analyses given the range of potentially disadvantageous exposures (including poor nutrition, pregnancy complications and infections) in geographically diverse populations worldwide. The study should enhance current medical knowledge and provide new insights into environmental influences on human growth and neurodevelopment.

Policymaking in order to increase the quality of medical journals needs having accurate data from their current status.

Waiting time in the hospital directly affects the quality of healthcare providing centers. One of the waiting times in hospital is the time spent waiting for receiving various consultations and visits requested by emergency medicine specialists from specialist services.

Copper indium sulfide quantum dots (CuInS2 QDs) were incorporated into a nanocrystalline TiO2 film by using spin coating-assisted successive ionic layer adsorption and reaction process to fabricate CuInS2 QD-sensitized TiO2 photoelectrodes for the solid-state quantum dot-sensitized solar cell (QDSSC) applications. The result shows that the photovoltaic performance of solar cell is extremely dependent on the number of cycles, which has an appreciable impact on the coverage ratio of CuInS2 on the surface of TiO2 and the density of surface defect states. In the following high-temperature annealing process, it is found that annealing TiO2/CuInS2 photoelectrode at a suitable temperature would be beneficial for decreasing the charge recombination and accelerating the charge transport. After annealing at 400 °C, a significantly enhanced photovoltaic properties of solid-state CuInS2 QDSSCs are obtained, achieving the power conversion efficiency (PCE) of 3.13%, along with an open-circuit voltage (VOC) of 0.68 V, a short-circuit photocurrent density (JSC) of 11.33 mA cm-2, and a fill factor (FF) of 0.41. The enhancement in the performance of solar cells is mainly ascribed to the suppression of charge recombination and the promotion of the electron transfer after annealing.

Fractalkine (CX3CL1) is a potent inflammatory mediator of the central nervous system, which is expressed by neurons and regulates microglial functions by binding to fractalkine receptor (CX3CR1). It has been demonstrated that neuroinflammation plays an important role in iron accumulation of the brain leading to neuronal cell death. The major regulator of iron homeostasis is the peptide hormone hepcidin. Hepcidin expression is triggered by inflammatory conditions, which may contribute to the neuronal iron accumulation. In the present study, we established a bilaminar co-culture system of differentiated SH-SY5Y cells and BV-2 microglia as a neuronal model to examine the effect of soluble fractalkine on iron homeostasis of microglia and SH-SY5Y cells. We determined the hepcidin expression of fractalkine-treated microglia which showed significant elevation. We examined the relation between increased hepcidin secretion, the known hepcidin regulators and the signalling pathways controlled by fractalkine receptor. Our data revealed that TMPRSS6 and alpha 1-antitrypsin levels decreased due to fractalkine treatment, as well as the activity of NFκB pathway and the tyrosine phosphorylation of STAT5 factor. Moreover, fractalkine-induced hepcidin production of microglia initiated ferroportin internalisation of SH-SY5Y cells, which contributed to iron accumulation of neurons. Our results demonstrate that soluble form of fractalkine regulates hepcidin expression of BV-2 cells through fractalkine-mediated CX3CR1 internalisation. Moreover, fractalkine indirectly contributes to the iron accumulation of SH-SY5Y cells by activating ferroportin internalisation and by triggering the expressions of divalent metal transporter-1, ferritin heavy chain and mitochondrial ferritin.

Hydroethidine is a fluorogenic probe that in the presence of the superoxide radical anion is oxidized to a red fluorescent product, 2-hydroxyethidium. In cells, hydroethidine is also oxidized to other products, including red fluorescent ethidium. Thus, selective monitoring of 2-hydroxyethidium is required for specific detection of the superoxide radical anion. Here, we provide protocols for HPLC- and LC-MS-based quantitation of 2-hydroxyethidium, among other oxidation products. Also, a protocol for continuous sampling for real-time monitoring of superoxide production using rapid HPLC measurements of 2-hydroxyethidium is described.

Aim: To investigate the function of Kdm2a in embryonic stem cells (ESCs). Materials & methods: Expression profile analysis after Kdm2a knockout. Analysis of Kdm2a, H3K4me3 and H3K27me3 ChIP-seq data in ESCs. qPCR analysis and ChIP-qPCR analysis of epigenetic changes after Kdm2a loss. Results:Kdm2a was dispensable for pluripotency maintenance in ESCs. Kdm2a genomic binding profile was positively correlated with that of H3K4me3, Zfx and Tet1. Kdm2a directly regulated germ cell genes in primordial germ cell-like cells. Kdm2a loss led to the reduced expression of endogenous retrovirus IAPEy and resulted in the gain of H3K36me2 and loss of H3K4me3 on IAPEy. Conclusion: Kdm2a regulates germ cell genes and endogenous retroviruses in ESCs possibly through demethylating H3K36me2 and influencing H3K4me3 deposition.

Myricetin (Myr) is a naturally occurring flavonoid exhibiting diverse biological and pharmacological properties, but its characteristics such as water insolubility, poor aqueous stability, and poor bioavailability limit its clinical application, including in ophthalmology. To increase its clinical application in ophthalmology, Myr was designed to be encapsulated in a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG) polymeric micelles to increases its aqueous solubility, stability, and corneal permeability to promote its efficacy in eye disease treatments. Thus, the Myr micelle ophthalmic solution was prepared and characterized encapsulation efficiency (EE), micelle size, and zeta potential. The chemical stability of Myr and the short-term storage stability of the Myr micelle ophthalmic solution were evaluated, followed by in vitro cytotoxicity and in vivo ocular irritation; in vitro cellular uptake and in vivo corneal permeation; and in vitro antioxidant activity and in vivo anti-inflammatory efficacy were also further evaluated. Myr could be incorporated into micelles with high EE. PVCL-PVA-PEG micelles significantly enhanced Myr's aqueous solubility and chemical stability. The Myr micelle ophthalmic solution also showed high storage stability. In rabbits, the Myr micelle ophthalmic solution displayed good in vitro cellular tolerance. Remarkable improvements in in vitro cellular uptake and in vivo corneal permeation were also observed in the Myr micelle ophthalmic solution, and significant improvements in the in vitro antioxidant activity and in vivo anti-inflammatory efficacy were also obtained. Overall, these results supported that the Myr micelle ophthalmic solution could be a promising nanomedicine for ocular tissues.

Redirection of immune cells to efficiently eliminate tumor cells holds great promise. Natural killer cells (NK), macrophages, or T cells are specifically engaged with target cells expressing markers after infection or neoplastic transformation, resulting in their activation and subsequent killing of those targets. Multiple strategies to redirect immunity have been developed in the past two decades, but they have technical hurdles or cause undesirable side-effects, as exemplified by the T cell-based chimeric antigen receptor approaches (CAR-T therapies) or bispecific T cell engager platforms. Our first-in-class bispecific antibody redirecting innate immune cells to tumors (AFM13, a CD30/CD16A-specific innate immune cell engager) has shown signs of clinical efficacy in CD30-positive lymphomas and the potential to be safely administered, indicating a wider therapeutic window compared to T cell engaging therapies. AFM13 is the most advanced candidate from our fit-for-purpose redirected optimized cell killing (ROCK®) antibody platform, which comprises a plethora of CD16A-binding innate immune cell engagers with unique properties. Here, we discuss aspects of this modular platform, including the advantages of innate immune cell engagement over classical monoclonal antibodies and other engager concepts. We also present details on its potential to engineer a fit-for-purpose innate immune cell engager format that can be equipped with unique CD16A domains, modules that influence pharmacokinetic properties and molecular architectures that influence the activation of immune effectors, as well as tumor targeting. The ROCK® platform is aimed at the activation of innate immunity for the effective lysis of tumor cells and holds the promise of overcoming limitations of other approaches that redirect immune cells by widening the therapeutic window.

Speech perception in complex sound fields can greatly benefit from different unmasking cues to segregate the target from interfering voices. This study investigated the role of three unmasking cues (spatial separation, gender differences, and masker time reversal) on speech intelligibility and perceived listening effort in normal-hearing listeners. Speech intelligibility and categorically scaled listening effort were measured for a female target talker masked by two competing talkers with no unmasking cues or one to three unmasking cues. In addition to natural stimuli, all measurements were also conducted with glimpsed speech-which was created by removing the time-frequency tiles of the speech mixture in which the maskers dominated the mixture-to estimate the relative amounts of informational and energetic masking as well as the effort associated with source segregation. The results showed that all unmasking cues as well as glimpsing improved intelligibility and reduced listening effort and that providing more than one cue was beneficial in overcoming informational masking. The reduction in listening effort due to glimpsing corresponded to increases in signal-to-noise ratio of 8 to 18 dB, indicating that a significant amount of listening effort was devoted to segregating the target from the maskers. Furthermore, the benefit in listening effort for all unmasking cues extended well into the range of positive signal-to-noise ratios at which speech intelligibility was at ceiling, suggesting that listening effort is a useful tool for evaluating speech-on-speech masking conditions at typical conversational levels.