A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer's Disease.

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aß accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.

The Application of Nanoparticle-Based Imaging and Phototherapy for Female Reproductive Organs Diseases.

Various female reproductive disorders affect millions of women worldwide and bring many troubles to women's daily life. Let alone, gynecological cancer (such as ovarian cancer and cervical cancer) is a severe threat to most women's lives. Endometriosis, pelvic inflammatory disease, and other chronic diseases-induced pain have significantly harmed women's physical and mental health. Despite recent advances in the female reproductive field, the existing challenges are still enormous such as personalization of disease, difficulty in diagnosing early cancers, antibiotic resistance in infectious diseases, etc. To confront such challenges, nanoparticle-based imaging tools and phototherapies that offer minimally invasive detection and treatment of reproductive tract-associated pathologies are indispensable and innovative. Of late, several clinical trials have also been conducted using nanoparticles for the early detection of female reproductive tract infections and cancers, targeted drug delivery, and cellular therapeutics. However, these nanoparticle trials are still nascent due to the body's delicate and complex female reproductive system. The present review comprehensively focuses on emerging nanoparticle-based imaging and phototherapies applications, which hold enormous promise for improved early diagnosis and effective treatments of various female reproductive organ diseases.

A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies.

Purpose: This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies. Experimental Design: A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments included nuclear cytoplasmic localization of p27, XPO1 cargo proteins pre and post selinexor dosing and pharmacokinetic assessments were conducted at doses between 40 and 60 mg/m2. Results: In our Asian patient cohort, dosing at 40 mg/m2 given 2 out of 3 weeks, was the most tolerable for our patients. At this dose level, grade 3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), and anaemia (2%). Selinexor had a rapid oral absorption with median Tmax of 2 h and no PK accumulation after multiple doses of tested regimens. Complete responses were seen in two lymphoma patients. Partial responses were noted in three diffuse large B cell lymphomas, one Hodgkin's lymphoma and thymic carcinoma patient, respectively. Conclusion: Selinexor is tolerated by Asian patients at 40 mg/m2 twice a week given 2 out of 3 weeks. A 1-week drug holiday was needed as our patients could not tolerate the current approved continuous dosing regimens because of persistent grade 3 fatigue, anorexia and hyponatremia.

[Effects of heavy metal cadmium on Caulerpa lentillifera based on transcriptome analysis]. / 基于转录组分析重金属镉对长茎葡萄蕨藻的影响.

With the acceleration of industrialization, the toxic effect of heavy metal cadmium (Cd) pollution has become prominent. In order to explore the molecular mechanism of the physiological regulation of Caulerpa lentillifera under Cd stress, we analyzed the transcriptome of Cd-stressed (Hcd2+) algae tissues using RNA-Seq. A total of 702 differentially expressed genes (DEGs) were screened between the control and Hcd2+ groups, out of which 257 genes were up-regulated and 445 genes were down-regulated in the Hcd2+ group. We conducted functional annotation and enrichment analysis of the obtained DEGs. The results showed that various biological functions of C. lentillifera were affected under Cd2+stress, which eventually showed growth inhibition. Results of GO enrichment analysis showed that the production and removal of reactive oxygen species (ROS) in C. lentillifera were out of balance and caused oxidative damage such as DNA damage. Results of KEGG enrichment analysis showed that many photosynthesis-related pathways were inhibited, indicating that Cd2+ stress led to disorder of photosynthetic reaction of C. lentillifera.

Mechanical behaviour of inorganic solid-state batteries: can we model the ionic mobility in the electrolyte with Nernst-Einstein's relation?

Inorganic solid-state lithium-metal batteries could be the next-generation batteries owing to their non-flammability and higher specific energy density. Many research efforts have been devoted to improving the ionic conductivity of inorganic solid electrolytes. For a wide range of electrolytes including liquid and solid polymer electrolytes, an independent measurement or calculation of both electrolyte conductivity and diffusion coefficient is often time-consuming and challenging. As a result, Nernst-Einstein's relation has been used to relate the ionic conductivity to ionic diffusivity after the determination of either parameter. Although Nernst-Einstein's relation has been used for different electrolytes, we demonstrate in this perspective that this relation is not directly transferable to describe the ionic mobility for many inorganic solid electrolytes. The fundamental physics of Nernst-Einstein's relation shows that the relationship between the diffusion coefficient and electrolyte conductivity is derived for ionic mobility in a viscous or a gaseous medium. This postulation contradicts state-of-the-art experimental studies measuring the mechanical behaviour of inorganic solid electrolytes, which show that inorganic solid electrolytes are usually brittle rather than viscoelastic at ambient room temperature. The measurement of loss tangent is required to justify the use of Nernst-Einstein's relation. The outcome of such measurement has two implications. First, if the loss tangent of inorganic solid electrolytes is less than unity in the range of batteries operating temperatures, the impacts of using Nernst-Einstein's relation in modelling the ionic mobility should be quantified. Secondly, if the measured loss tangent is comparable to that of solid polymers and lithium metal, inorganic solid electrolytes may behave in a viscoelastic manner as opposed to the brittle behaviour usually suggested.

Lithium ion battery degradation: what you need to know.

The expansion of lithium-ion batteries from consumer electronics to larger-scale transport and energy storage applications has made understanding the many mechanisms responsible for battery degradation increasingly important. The literature in this complex topic has grown considerably; this perspective aims to distil current knowledge into a succinct form, as a reference and a guide to understanding battery degradation. Unlike other reviews, this work emphasises the coupling between the different mechanisms and the different physical and chemical approaches used to trigger, identify and monitor various mechanisms, as well as the various computational models that attempt to simulate these interactions. Degradation is separated into three levels: the actual mechanisms themselves, the observable consequences at cell level called modes and the operational effects such as capacity or power fade. Five principal and thirteen secondary mechanisms were found that are generally considered to be the cause of degradation during normal operation, which all give rise to five observable modes. A flowchart illustrates the different feedback loops that couple the various forms of degradation, whilst a table is presented to highlight the experimental conditions that are most likely to trigger specific degradation mechanisms. Together, they provide a powerful guide to designing experiments or models for investigating battery degradation.

Epithelial tissue geometry directs emergence of bioelectric field and pattern of proliferation.

Patterns of proliferation are templated by both gradients of mechanical stress as well as by gradients in membrane voltage (Vm), which is defined as the electric potential difference between the cytoplasm and the extracellular medium. Either gradient could regulate the emergence of the other, or they could arise independently and synergistically affect proliferation within a tissue. Here, we examined the relationship between endogenous patterns of mechanical stress and the generation of bioelectric gradients in mammary epithelial tissues. We observed that the mechanical stress gradients in the tissues presaged gradients in both proliferation and depolarization, consistent with previous reports correlating depolarization with proliferation. Furthermore, disrupting the Vm gradient blocked the emergence of patterned proliferation. We found that the bioelectric gradient formed downstream of mechanical stresses within the tissues and depended on connexin-43 (Cx43) hemichannels, which opened preferentially in cells located in regions of high mechanical stress. Activation of Cx43 hemichannels was necessary for nuclear localization of Yap/Taz and induction of proliferation. Together, these results suggest that mechanotransduction triggers the formation of bioelectric gradients across a tissue, which are further translated into transcriptional changes that template patterns of growth.

Experimental and numerical analysis to identify the performance limiting mechanisms in solid-state lithium cells under pulse operating conditions.

Solid-state lithium batteries could reduce the safety concern due to thermal runaway while improving the gravimetric and volumetric energy density beyond the existing practical limits of lithium-ion batteries. The successful commercialisation of solid-state lithium batteries depends on understanding and addressing the bottlenecks limiting the cell performance under realistic operational conditions such as dynamic current profiles of different pulse amplitudes. This study focuses on experimental analysis and continuum modelling of cell behaviour under pulse operating conditions, with most model parameters estimated from experimental measurements. By using a combined impedance and distribution of relaxation times analysis, we show that charge transfer at both interfaces occurs between the microseconds and milliseconds timescale. We also demonstrate that a simplified set of governing equations, rather than the conventional Poisson-Nernst-Planck equations, are sufficient to reproduce the experimentally observed behaviour during pulse discharge, pulse charging and dynamic pulse. Our simulation results suggest that solid diffusion in bulk LiCoO2 is the performance limiting mechanism under pulse operating conditions, with increasing voltage loss for lower states of charge. If bulk electrode forms the positive electrode, improvement in the ionic conductivity of the solid electrolyte beyond 10-4 S cm-1 yields marginal overall performance gains due to this solid diffusion limitation. Instead of further increasing the electrode thickness or improving the ionic conductivity on their own, we propose a holistic model-based approach to cell design, in order to achieve optimum performance for known operating conditions.

Mesenchymal proteases and tissue fluidity remodel the extracellular matrix during airway epithelial branching in the embryonic avian lung.

Reciprocal epithelial-mesenchymal signaling is essential for morphogenesis, including branching of the lung. In the mouse, mesenchymal cells differentiate into airway smooth muscle that wraps around epithelial branches, but this contractile tissue is absent from the early avian lung. Here, we have found that branching morphogenesis in the embryonic chicken lung requires extracellular matrix (ECM) remodeling driven by reciprocal interactions between the epithelium and mesenchyme. Before branching, the basement membrane wraps the airway epithelium as a spatially uniform sheath. After branch initiation, however, the basement membrane thins at branch tips; this remodeling requires mesenchymal expression of matrix metalloproteinase 2, which is necessary for branch extension but for not branch initiation. As branches extend, tenascin C (TNC) accumulates in the mesenchyme several cell diameters away from the epithelium. Despite its pattern of accumulation, TNC is expressed exclusively by epithelial cells. Branch extension coincides with deformation of adjacent mesenchymal cells, which correlates with an increase in mesenchymal fluidity at branch tips that may transport TNC away from the epithelium. These data reveal novel epithelial-mesenchymal interactions that direct ECM remodeling during airway branching morphogenesis.

Identification and characterization of antioxidant peptides from hydrolysate of blue-spotted stingray and their stability against thermal, pH and simulated gastrointestinal digestion treatments.

This study was conducted to identify and characterize antioxidant peptides from the alcalase hydrolysate of the blue-spotted stingray. Purification steps guided by ABTS cation radical (ABTS+) scavenging assay and de novo peptide sequencing produced two peptides, WAFAPA (661.3224 Da) and MYPGLA (650.3098 Da). WAFAPA (EC50 = 12.6 µM) had stronger antioxidant activity than glutathione (EC50 = 13.7 µM) and MYPGLA (EC50 = 19.8 µM). Synergism between WAFAPA and MYPGLA was detected. WAFAPA and MYPGLA surpassed carnosine in their ability to suppress H2O2-induced lipid oxidation. The peptides protected plasmid DNA and proteins from Fenton's reagent-induced oxidative damage. Thermal (25-100 °C) and pH 3-11 treatments did not alter antioxidant activity of the peptides. MYPGLA maintained its antioxidant activity after simulated gastrointestinal digestion, whereas WAFAPA showed a partial loss. The two peptides may have potential applications as functional food ingredients or nutraceuticals, whether used singly or in combination.

Extracellular Matrix Stiffness Exists in a Feedback Loop that Drives Tumor Progression.

Cells communicate constantly with their surrounding extracellular matrix (ECM) to maintain homeostasis, using both mechanical and chemical signals. In cancer, abnormal signaling leads to stiffening of the ECM. A stiff microenvironment affects many aspects of the cell, including internal molecular signaling as well as behaviors such as motility and proliferation. Thus, cells and ECM interact in a feedback loop to drive matrix deposition and cross-linking, which alter the mechanical properties of the tissue. Stiffer tissue enhances the invasive potential of a tumor and decreases therapeutic efficacy. This chapter describes how specific molecular effects caused by an abnormally stiff tissue drive macroscopic changes that help determine disease outcome. A complete understanding may foster the generation of new cancer therapies.

Substratum stiffness tunes proliferation downstream of Wnt3a in part by regulating integrin-linked kinase and frizzled-1.

The Wnt/ß-catenin pathway controls a variety of cellular behaviors, aberrant activation of which are associated with tumor progression in several types of cancer. The same cellular behaviors are also affected by the mechanical properties of the extracellular matrix (ECM) substratum, which induces signaling through integrins and integrin-linked kinase (ILK). Here, we examined the role of substratum stiffness in the regulation of cell proliferation downstream of Wnt3a. We found that treatment with Wnt3a increased proliferation of cells cultured on stiff substrata, with compliances characteristic of breast tumors, but not of cells on soft substrata, with compliances comparable to that of normal mammary tissue. Depleting ILK rendered cells unresponsive to Wnt3a on both substrata. Ectopic expression of ILK permitted Wnt3a to induce proliferation of cells on both microenvironments, although proliferation on soft substrata remained lower than that on stiff substrata. We further showed that ILK regulates expression of the Wnt receptor frizzled-1 (Fzd1), suggesting the presence of a positive feedback loop between Wnt3a, ILK and Fzd1. These findings suggest that tissue mechanics regulates the cellular response to Wnt under physiological and pathological microenvironmental conditions.This article has an associated First Person interview with the first author of the paper.

Microfluidic chest cavities reveal that transmural pressure controls the rate of lung development.

Mechanical forces are increasingly recognized to regulate morphogenesis, but how this is accomplished in the context of the multiple tissue types present within a developing organ remains unclear. Here, we use bioengineered 'microfluidic chest cavities' to precisely control the mechanical environment of the fetal lung. We show that transmural pressure controls airway branching morphogenesis, the frequency of airway smooth muscle contraction, and the rate of developmental maturation of the lungs, as assessed by transcriptional analyses. Time-lapse imaging reveals that branching events are synchronized across distant locations within the lung, and are preceded by long-duration waves of airway smooth muscle contraction. Higher transmural pressure decreases the interval between systemic smooth muscle contractions and increases the rate of morphogenesis of the airway epithelium. These data reveal that the mechanical properties of the microenvironment instruct crosstalk between different tissues to control the development of the embryonic lung.

Isolation, chemical characterization, and immunomodulatory activity of naturally acetylated hemicelluloses from bamboo shavings.

Bamboo shavings, the outer or intermediate layer of bamboo stems, are the bulk of by-products produced in bamboo processing. In this study we investigated the isolation, chemical characterization, and immunostimulatory activity in vitro of the hemicelluloses from bamboo shavings. Shavings were first pretreated by steam explosion. The optimal pretreatment was found to be steam explosion at 2.2 MPa for 1 min. Following this pretreatment, the yield of hemicelluloses reached (2.05±0.22)% (based on the dry dewaxed raw materials), which was 5.7-fold higher than that of untreated samples. Bamboo-shavings hemicellulose (BSH) was then prepared by hot water extraction and ethanol precipitation from the steam-exploded shavings. Purification of BSH by anion-exchange chromatography of diethylaminoethanol (DEAE)-sepharose Fast Flow resulted in a neutral fraction (BSH-1, purity of 95.3%, yield of 1.06%) and an acidic fraction (BSH-2, purity of 92.5%, yield of 0.79%). The weight-average molecular weights (Mw) of BSH-1 and BSH-2 were 12 800 and 11 300 g/mol, respectively. Chemical and structural analyses by Fourier transform infrared spectroscopy (FT-IR), 1D (1H and 13C) and 2D (heteronuclear single quantum correlation (HSQC)) nuclear magnetic resonance (NMR) spectra revealed that BSH-1 was O-acetylated-arabinoxylan and BSH-2 was O-acetylated-(4-O-methylglucurono)-arabinoxylan. BSH-1 had a higher content of acetyl groups than BSH-2. For the immunomodulatory activity in vitro, BSH and BSH-2 significantly stimulated mouse splenocyte proliferation while BSH-1 had no effect; BSH, BSH-1, and BSH-2 markedly enhanced the phagocytosis activity and nitric oxide production of the murine macrophage RAW264.7 in a dose-dependent manner. Our results suggest that the water-extractable hemicelluloses from steam-exploded bamboo shavings are naturally acetylated and have immunostimulatory activity.

A 3D Culture Model to Study How Fluid Pressure and Flow Affect the Behavior of Aggregates of Epithelial Cells.

Cells are surrounded by mechanical stimuli in their microenvironment. It is important to determine how cells respond to the mechanical information that surrounds them in order to understand both development and disease progression, as well as to be able to predict cell behavior in response to physical stimuli. Here we describe a protocol to determine the effects of interstitial fluid flow on the migratory behavior of an aggregate of epithelial cells in a three-dimensional (3D) culture model. This protocol includes detailed methods for the fabrication of a 3D cell culture chamber with hydrostatic pressure control, the culture of epithelial cells as an aggregate in a collagen gel, and the analysis of collective cell behavior in response to pressure-driven flow.

Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells.

Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277-87. ©2016 AACR.

Localized Smooth Muscle Differentiation Is Essential for Epithelial Bifurcation during Branching Morphogenesis of the Mammalian Lung.

The airway epithelium develops into a tree-like structure via branching morphogenesis. Here, we show a critical role for localized differentiation of airway smooth muscle during epithelial bifurcation in the embryonic mouse lung. We found that during terminal bifurcation, changes in the geometry of nascent buds coincided with patterned smooth muscle differentiation. Evaluating spatiotemporal dynamics of α-smooth muscle actin (αSMA) in reporter mice revealed that αSMA-expressing cells appear at the basal surface of the future epithelial cleft prior to bifurcation and then increase in density as they wrap around the bifurcating bud. Disrupting this stereotyped pattern of smooth muscle differentiation prevents terminal bifurcation. Our results reveal stereotyped differentiation of airway smooth muscle adjacent to nascent epithelial buds and suggest that localized smooth muscle wrapping at the cleft site is required for terminal bifurcation during airway branching morphogenesis.

Initial validation of the Yin-Yang Assessment Questionnaire for persons with diabetes mellitus.

AIM: To initially test for the content validity, comprehensibility, test-retest reliability and internal consistency reliability of the Yin-Yang Assessment Questionnaire (YY-AQ). METHODS: The process of initial validity and reliability test covered: (1) content validation from the findings of 18 multiple-case studies, validated Yin- and Yang-deficiency assessment questionnaires, relevant literatures and registered Chinese medicine practitioners; (2) comprehension with the levels of comprehensibility for each item categorized on a 3-point scale (not comprehensible; moderately comprehensible; highly comprehensible). A minimum of three respondents selecting for each item of moderately or highly comprehensible were regarded as comprehensive; (3) test-retest reliability conducted with a 2-wk interval. The intraclass correlation coefficients (ICCs) and their 95%CIs were calculated using a two-way random effects model. Wilcoxon Signed Rank test for related samples was adopted to compare the medians of test-retest scores. An ICC value of 0.85 or higher together with P > 0.05, was considered acceptable; and (4) internal consistency of the total items was measured and evaluated by Cronbach's coefficient alpha (α). A Cronbach's α of 0.7 or higher was considered to represent good internal consistency. RESULTS: Eighteen Yin-deficiency and 14 Yang-deficiency presentation items were finalized from content validation. Five participants with type 2 diabetes mellitus (T2DM) performed the comprehensibility and test-retest reliability tests. Comprehensibility score level of each presentation item was found to be moderate or high in three out of the five participants. Test-retest reliability showed that the single measure ICC of the total Yin-deficiency presentation items was 0.99 (95%CI: 0.89-0.99) and the median scores on the first and 14(th) days were 17 (IQR 6.5-27) and 21 (IQR 6-29) (P = 0.144) respectively. The single measure ICC of the total Yang-deficiency presentation items was 0.88 (95%CI: 0.79-0.99) and the median scores on the first and 14(th) days were 10 (IQR 6-18) and 14 (IQR 7-23) (P = 0.144) respectively. The results of a descriptive correlation study on 140 survey participants with T2DM using the YY-AQ showed that internal consistency of the total Yin-deficiency and Yang-deficiency presentation items was satisfactory, with Cronbach's α of 0.79 and 0.78 respectively. CONCLUSION: The YY-AQ will be tested further for comprehensibility, test-retest and internal consistency reliabilities, scoring system validity, construct validity, convergent and discriminant validities, responsiveness and predictive validity.

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVß8-TGFß signaling in the brain.

Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVß8 activates angiosuppressive TGFß gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVß8 in the brain or downstream TGFß1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb(ret/ret) mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.