Enhanced Far-Field Thermal Radiation through a Polaritonic Waveguide.

We experimentally demonstrate the enhancement of the far-field thermal radiation between two nonabsorbent Si microplates coated with energy-absorbent silicon dioxide (SiO_{2}) nanolayers supporting the propagation of surface phonon polaritons. By measuring the radiative thermal conductance between two coated Si plates, we find that its values are twice those obtained without the SiO_{2} coating. This twofold increase results from the hybridization of polaritons with guided modes inside Si and is well predicted by fluctuational electrodynamics and an analytical model based on a two-dimensional density of polariton states. These findings could be applied to thermal management in microelectronics, silicon photonics, energy conversion, atmospheric sciences, and astrophysics.

Epithelium-derived cystatin SN inhibits house dust mite protease activity in allergic asthma.

BACKGROUND: Allergen source-derived proteases are a critical factor in the formation and development of asthma. The cysteine protease activity of house dust mite (HDM) disrupts the epithelial barrier function. The expression of cystatin SN (CST1) is elevated in asthma epithelium. CST1 inhibits the cysteine protease activity. We aimed to elucidate the role of epithelium-derived CST1 in the development of asthma caused by HDM. METHODS: CST1 protein levels in sputum supernatants and serum of patients with asthma and healthy volunteers were measured by ELISA. The ability of CST1 protein to suppress HDM-induced bronchial epithelial barrier function was examined in vitro. The effects of exogenous CST1 protein on abrogating HDM-induced epithelial barrier function and inflammation were examined in mice in vivo. RESULTS: CST1 protein levels were higher in sputum supernatants (142.4 ± 8.95 vs 38.87 ± 6.85 ng/mL, P < 0.0001) and serum (1129 ± 73.82 vs 703.1 ± 57.02 pg/mL, P = 0.0035) in patients with asthma than in healthy subjects. The levels were significantly higher in patients with not well- and very poorly controlled asthma than those with well-controlled asthma. Sputum and serum CST1 protein levels were negatively correlated with lung function in asthma. CST1 protein levels were significantly lower in the serum of HDM-specific IgE (sIgE)-positive asthmatics than in sIgE-negative asthmatics. The HDM-induced epithelial barrier function disruption was suppressed by recombinant human CST1 protein (rhCST1) in vitro and in vivo. CONCLUSION: Our data indicated that human CST1 protein suppresses asthma symptoms by protecting the asthmatic bronchial epithelial barrier through inhibiting allergenic protease activity. CST1 protein may serve as a potential biomarker for asthma control.

Effects of compound probiotics on intestinal barrier function and caecum microbiota composition of broilers.

Probiotics are beneficial microorganisms existing in nature and animals and can be used in livestock and poultry breeding. Here, 240 1-day-old Arbor Acre (AA) broilers were used to study the effects of compound probiotics (CP) on antioxidant capacity, intestinal barrier function and caecum microorganisms. 2‰, 3‰ or 4‰ CP were added to the basal diet. Blood, jejunum, caecum and caecum contents of broilers were collected on day 60, and the jejunum histopathological observation, oxidative stress state evaluation, intestinal barrier function mRNA level and caecum microflora composition were carried out. The results showed that CP significantly improved the growth performance of broilers in 1-30 days. Moreover, CP supplementation increased superoxide dismutase (SOD) activity, reduced malondialdehyde (MDA) and hydrogen peroxide (H2O2) contents in serum, and increased the mRNA levels of zona occludens 1 (ZO-1), claudin-1 and occludin in the jejunum of broilers. 3‰ CP observably increased the ratio of villus height to crypt depth, and the abundance of the genus Rikenellaceae_RC9_gut_group and Phascolarctobacterium, decreased the abundance of the genus Ruminococcaceae_UCG-014, together with regulation of several genes that are responsible for signaling pathways involved in carbohydrate metabolism, amino acid metabolism and endocrine and metabolic diseases. Taken together, the supplementation of CP could reduce oxidative stress levels, increase the mRNA expression levels of tight junction (TJ)-related genes and the colonization of beneficial bacteria in the caecum, which has a promoting effect on the growth performance in broilers.

Compound probiotics alleviate cadmium-induced intestinal dysfunction and microbiota disorders in broilers.

Cadmium (Cd), a common environmental pollutant, seriously threatens the health of intestine. This research aimed to investigate the effects of compound probiotics (CP) on intestinal dysfunction and cecal microbiota dysregulation induced by Cd in broilers. A total of 240 1-day-old Arbor Acre (AA) broilers were randomly assigned to four groups. After 120 days of feeding, the jejunum tissues and cecal contents were sampled for jejunum histopathological observation, the intestinal barrier and inflammatory factors related mRNA and proteins examinations, and intestinal microbiota analysis. The results showed that Cd could cause jejunal villus damage and inflammatory cells infiltration, down-regulate the mRNA levels of intestinal barrier related genes (ZO-1, ZO-2, ZO-3, Claudin1, Claudin3, Claudin4, Occludin, and E-cadherin) and inflammatory factor related genes (IL-1ß, IL-18, IFN-γ, NF-κB), and the protein levels of Claudin1, ZO-1, Occludin, but up-regulate the Claudin2, IL-2, IL-4 and IL-10 mRNA levels. However, the addition of CP could effectively improve these changes. In addition, 16S rRNA gene sequencing analysis showed that compared with the Cd group, supplementation CP increased the abundance of Lactobacillales, Clostridiales, Firmicutes, together with regulations on the pathways responsible for energy metabolism, translation and amino acid metabolism. In conclusion, CP could improve intestinal barrier damage and intestinal microbiota disturbance induced by Cd.

Epithelial expression and role of secreted STC1 on asthma airway hyperresponsiveness through calcium channel modulation.

BACKGROUND: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation, and airway remodeling. Airway hyperresponsiveness results from enhanced airway smooth muscle (ASM) contraction potentially under the control of an epithelium-derived relaxing factor (EpDRF). However, relatively rare is known about EpDRF. We aimed to elucidate the role of epithelium-derived stanniocalcin-1 (STC1) on AHR and ASM contraction. METHODS: Stanniocalcin-1 levels in the serum of asthmatic patients and healthy volunteers and in bronchoalveolar lavage fluid (BALF) from ovalbumin (OVA)-challenged mice were measured by ELISA. The effects of exogenous STC1 on AHR and on inflammation were examined in mice. IL-13 modulation of STC1 mRNA and protein levels was studied in human bronchial epithelial cell lines (16HBE). The function of STC1 on Ca2+ influx and ASM contraction was examined ex vivo. RESULTS: Serum STC1 was decreased in asthma (n = 93) compared with healthy volunteers (1071 ± 30.4 vs 1414 ± 75.1 pg/ml, p < 0.0001, n = 23) and correlated with asthma control (p = 0.0270), lung function (FEV1, p = 0.0130), and serum IL-13 levels (p = 0.0009). Treatment of ten asthmatic subjects with inhaled corticosteroids/long-acting beta2-agonists (ICS/LABA) for 1 year enhanced STC1 expression which correlated with improved asthma control (p = 0.022). STC1 was mainly expressed in bronchial epithelium and intranasal administration of recombinant human STC1 (rhSTC1) reduced AHR and inflammation in mice. IL-13 suppressed STC1 release from 16HBE, whereas rhSTC1 blocked store-operated Ca2+ entry (SOCE) by suppressing stromal interaction molecule 1 (STIM1) and further inhibited ASM cell contractility by suppressing Ca2+ -dependent myosin light chain (MLC) phosphorylation. CONCLUSION: Our data indicate that STC1 deficiency in asthmatic airways promotes STIM1 hyperactivity, enhanced ASM contraction, and AHR. STC1 may be a candidate EpDRF.

ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers: An Industrial Perspective from the IQ Consortium.

In October 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH began efforts to provide recommendations to harmonize guidances for biopharmaceutics classification system (BCS)-based biowaivers. Topics to be addressed included consideration of the dose used to classify solubility, tests, and criteria for establishing highly permeable, dissolution conditions, the influence of excipients, and aspects of product strength. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader R&D community. Its members have substantial expertise in all scientific domains associated with BCS-based waivers and drug product quality, as well as considerable experience in the application of BCS-based biowaivers. The ICH process recognizes that harmonization is achieved through the development of guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side. Thus, to facilitate these efforts and to encourage open and transparent discussion of other perspectives that may exist, IQ offers their perspective on these and related topics.

Ezrin, a Membrane Cytoskeleton Cross-Linker Protein, as a Marker of Epithelial Damage in Asthma.

RATIONALE: Bronchial epithelial cell damage occurs in patients with bronchial asthma. Ezrin, a membrane-cytoskeleton protein, maintains cellular morphology and intercellular adhesion and protects the barrier function of epithelial cells. OBJECTIVES: To study the role of ezrin in bronchial epithelial cells injury and correlate its expression with asthma severity. METHODS: Levels of ezrin were measured in exhaled breath condensate (EBC) and serum in patients with asthma and BAL fluid (BALF) from a mouse model of asthma by ELISA. The regulation of IL-13 on ezrin protein levels was studied in primary bronchial epithelial cells. Ezrin knockdown using shRNA was studied in human bronchial epithelial 16HBE cells. MEASUREMENTS AND MAIN RESULTS: Ezrin levels were decreased in asthmatic EBC (92.7 ± 34.99 vs. 150.5 ± 10.22 pg/ml, P < 0.0001) and serum (700.7 ± 55.59 vs. 279.2 ± 25.83 pg/ml, P < 0.0001) compared with normal subjects. Levels were much lower in uncontrolled (P < 0.001) and partly controlled patients (P < 0.01) compared with well-controlled subjects. EBC and serum ezrin levels correlated with lung function in patients with asthma and serum ezrin levels were negatively correlated with serum IL-13 and periostin. IL-13-induced downregulation of ezrin expression in primary bronchial epithelial cells was significantly attenuated by the Janus tyrosine kinase 2 inhibitor, TG101348. Ezrin knockdown changed 16HBE cell morphology, enlarged intercellular spaces, and increased their permeability. Ezrin expression was decreased in the lung tissue and BALF of "asthmatic" mice and negatively correlated with BALF IL-13 level. CONCLUSIONS: Ezrin downregulation is associated with IL-13-induced epithelial damage and might be a potential biomarker of asthma control.

Configurable swellability of hydrogel microstructure for structural-color-based imaging concealment/encryption.

Optical information concealment/encryption technologies are of great importance to structural color applications. Although a series of responsive materials have been developed for dynamic structural color, the shortcomings of the high-quality synthesis process, the complex controlling method, and the low-resolution capability limit their practical use. Herein, we proposed a novel strategy of humidity-driven structural-color-based imaging concealment/encryption by utilizing metal-hydrogel-metal (MHM) nanocavities with configurable swellablity response to humidity change. With varied exposure doses, multi-stage MHM nanocavities with swellable hydrogel interlayers are achieved, generating dynamic structural color covering the visible spectrum. We revealed that the swelling ratio of hydrogel microstructures can be gradually adjusted between 1.05 and 2.08 by varying the exposure dose. We demonstrated that a hydrogel-based structural color image can be concealed with humidity changes by configurating swellable and non-swellable hydrogel pixels together. Furthermore, we developed the double exposure method in which the first exposure can generate pixel arrays for the deceptive image and the second exposure can locally suppress the swellablity of certain pixels. This method can highlight hidden images in a moist state, demonstrating a powerful strategy for high-density optical information encryption.

Impact of nanopillars on phonon dispersion and thermal conductivity of silicon membranes.

The performance of silicon-based thermoelectric energy generators is limited by the high thermal conductivity of silicon. Theoretical works have long proposed reducing the thermal conductivity by resonant phonon modes in nanopillars placed on the surface of silicon films. However, these predictions have never been confirmed due to the difficulty in the nanofabrication and measurements of such nanoscale systems. In this work, we report on the fabrication and measurements of silicon films with nanopillars as small as 12 nm in diameter. Our Brillouin light scattering spectroscopy experiments revealed that nanopillars indeed host resonant phonon modes. Yet, our thermal measurements using the micro time-domain thermoreflectance technique showed only a statistically insignificant difference between the thermal properties of silicon membranes with and without nanopillars. Results of this work contrast with the predictions of a substantial reduction in the thermal conductivity due to nanopillars and suggest refining the simulations to account for realistic experimental conditions.

Selenium alleviates cadmium-induced mitophagy through FUNDC1-mediated mitochondrial quality control pathway in the lungs of sheep.

Cadmium (Cd) is a poisonous metal element that causes mitochondrial dysfunction. Selenium (Se) can reduce the damage of Cd to various organs of animals, but the protective mechanism of Se in Cd-induced lung injury has not been fully elucidated. For purpose of further illustrating the specific mechanism of Se alleviated Cd-triggered pulmonary toxicity, 48 sheep were divided into 4 groups, of which the sheep in the treatment group were taken 1 mg/kg body weight (BW) of Cd, 0.34 mg/kg BW of Se, and 0.34 mg Se + 1 mg/kg BW of Cd by intragastric administration for 50 d, respectively. The results indicated that Cd caused inflammatory cell infiltration and alveolar wall thickening, which facilitated mitochondrial vacuolation and formation of mitophagosomes in lung tissues. Simultaneously, Cd treatment impaired the antioxidant capacity of sheep lung tissue. Additionally, Cd treatment down-regulated the expression levels of mitochondrial biogenesis and mitochondrial fusion, but up-regulated the levels of mitochondrial fission and mitophagy mediated by FUNDC1. Moreover, the immunofluorescence co-localization puncta of LC3B/COX IV, LC3B/FUNDC1 were increased after Cd treatment. Nevertheless, co-treatment with Se improved effectively the above variation caused by Cd exposure. In summary, Se could mitigate Cd-generated mitophagy through FUNDC1-mediated mitochondrial quality control pathway in the lungs of sheep.

Observation of phonon Poiseuille flow in isotopically purified graphite ribbons.

In recent times, the unique collective transport physics of phonon hydrodynamics motivates theoreticians and experimentalists to explore it in micro- and nanoscale and at elevated temperatures. Graphitic materials have been predicted to facilitate hydrodynamic heat transport with their intrinsically strong normal scattering. However, owing to the experimental difficulties and vague theoretical understanding, the observation of phonon Poiseuille flow in graphitic systems remains challenging. In this study, based on a microscale experimental platform and the pertinent occurrence criterion in anisotropic solids, we demonstrate the existence of the phonon Poiseuille flow in a 5.5 µm-wide, suspended and isotopically purified graphite ribbon up to a temperature of 90 K. Our observation is well supported by our theoretical model based on a kinetic theory with fully first-principles inputs. Thus, this study paves the way for deeper insight into phonon hydrodynamics and cutting-edge heat manipulating applications.

Near-isotropic polariton heat transport along a polar anisotropic nanofilm.

The heat transport of surface phonon-polaritons propagating along a polar uniaxial anisotropic nanofilm is studied for different orientations of its optical axis, film thicknesses, and temperatures. For an hBN nanofilm, it is shown that i) the propagation of polaritons can be described in terms of even and odd modes that generalize the transverse magnetic and transverse electrical ones that typically appear in isotropic films. ii) The frequency spectrum of polaritons can efficiently be tuned with the angle between the film optical axis and their propagation direction. iii) The polariton thermal conductivity takes higher values for a thinner or hotter nanofilm. iv) The even and odd modes have a remarkable contribution to the total polariton thermal conductivity, which takes a value higher than 5.6 Wm-1K-1 for a 25-nm-thick nanofilm at 500 K. The obtained results thus uncover some key features of the propagation and heat transport of polaritons in uniaxial nanofilms.

Protonated cross-linkable nanocomposite coatings with outstanding underwater superoleophobic and anti-viscous oil-fouling properties for crude oil/water separation.

Superhydrophilic/underwater superoleophobic coatings that effectively prevent viscous oil contamination have been of considerable interest for the great potential in oil spill remediation and oilfield wastewater treatment. In the present work, a protonated cross-linkable nanocomposite coating with robust underwater superoleophobicity and intensified hydration capability is proposed through the synthesis of active polymeric nanocomplex (PNC), cross-linking reaction between PNC and hydrophilic chitosan (CS), and final protonation to further improve water affinity. Benefiting from the hierarchical structure and strong hydration capability induced by electrostatic interactions and hydrogen bondings, the nanocomposite coating coated textile exhibits excellent superhydrophilicity (within 0.28 s with water contact angle reaching 0°), underwater superoleophobicity (underwater crude oil contact angle at 160°), and ultralow oil adhesion even to highly viscous silicone oil. Moreover, the nanocomposite coating presents a robust chemical resistance, mechanical tolerance, and storage stability. Simultaneously, the nanocomposite coating adapts well to various porous substrates (e.g., stainless steel mesh and Ni sponge) with great anti-oil-fouling and self-cleaning performances. Importantly, the coating coated textile is successfully applied in crude oil/water separation with excellent efficiency and repeatability. The findings conceivably stand out as a new methodology to fabricate superhydrophilic/underwater superoleophobic materials with outstanding anti-viscous oil-fouling property for practically treating oily wastewater.

A Pancancer Study of PIEZO1 as a Prognosis and Immune Biomarker of Human Tumors.

PIEZO1, a mechanosensitive ion channel protein, has been identified in the correlation between several cancers. However, the systematic pancancer study of PIEZO1 still lacks. We examined PIEZO1 across thirty-three types of cancers to explore its role in prognosis and immunological function for the first time. Based on the open databases TCGA, GTEx and CPTAC, PIEZO1 has been demonstrated to be differentially expressed in most cancers compared to adjacent normal tissues. The distinct correlation between PIEZO1 and prognosis of tumor patients was explored by GEPIA2. Genetic alteration of PIEZO1 in the TCGA tumors showed that mutation is the alteration which is linked to OS, DSS, DFS and PFS in some tumors. Alterations of protein phosphorylation levels were detected in some cancers based on the CPTAC dataset. PIEZO1 expression was linked with immune cell infiltration, such as endothelial cell and cancer-associated fibroblast. Finally, KEGG and GO enrichment analyses were applied to investigate the molecular mechanism of PIEZO1. Our first pancancer analysis illustrated the roles of PIEZO1 in different types of tumors.

Langerin-expressing dendritic cells in pulmonary immune-related diseases.

Dendritic cells (DCs) are "frontline" immune cells dedicated to antigen presentation. They serve as an important bridge connecting innate and adaptive immunity, and express various receptors for antigen capture. DCs are divided into various subclasses according to their differential expression of cell surface receptors and different subclasses of DCs exhibit specific immunological characteristics. Exploring the common features of each sub-category has became the focus of many studies. There are certain amounts of DCs expressing langerin in airways and peripheral lungs while the precise mechanism by which langerin+ DCs drive pulmonary disease is unclear. Langerin-expressing DCs can be further subdivided into numerous subtypes based on the co-expressed receptors, but here, we identify commonalities across these subtypes that point to the major role of langerin. Better understanding is required to clarify key disease pathways and determine potential new therapeutic approaches.

Molybdenum and Cadmium Co-induce Mitochondrial Quality Control Disorder via FUNDC1-Mediated Mitophagy in Sheep Kidney.

Molybdenum (Mo), fundamental trace mineral for animals and plants, but undue Mo damages animal health. Cadmium (Cd) is a toxic heavy metal that exists in the environment. Nevertheless, the mechanism of Mo and Cd on mitochondrial quality control are still indistinct. The objective of this research was to explore the effects of mitophagy on mitochondrial quality control via the FUNDC1-mediated by Mo and Cd in sheep kidney. Forty-eight 2-month-old sheep were stochastically divided into four groups, as shown below: control group, Mo [45 mg/kg body weight (BW)] group, Cd (1 mg/kg BW) group and Mo (45 mg/kg BW)+Cd (1 mg/kg BW) group, with 50 days feed technique. The results showed that Mo or/and Cd attract an unbalance of trace minerals and vacuoles and granular degeneration of renal tubular epithelial cells, and increase the number of mitophagosomes and vacuole-mitochondria and LC3 puncta and MDA and H2O2 contents, and decrease ATP content in the kidney. Moreover, Mo or/and Cd treatment could upregulate the mRNA levels of FUNDC1, LC3A, LC3B, PGAM5, DRP1, FIS1 and MFF, and the protein levels of FUNDC1, p-FUNDC1, LC3II/LC3I, DRP1, MFF and FIS1, downregulate the mRNA levels of MFN1, MFN2, OPA1, PGC-1α, SIRT1, SIRT3, FOXO1 and FOXO3, and the protein levels of MFN1, MFN2, OPA1 and PGC-1α. Notably, variations of above-mentioned factors in Mo and Cd group were more obvious than in Mo or Cd groups. Taken together, these results displayed that Mo and Cd co-treatment might induce mitochondrial quality control disorder via FUNDC1-mediated mitophagy in sheep kidney.

Performance of a Mid-Infrared Sensor for Simultaneous Trace Detection of Atmospheric CO and N2O Based on PSO-KELM.

In this article, a field deployable sensor was developed using a self-developed 4.58-µm continuous wave quantum cascade laser (CW-QCL) for the simultaneous detection of carbon monoxide (CO) and nitrous oxide (N2O), both of which have strong fundamental absorption bands in this waveband. The sensor is based on tunable diode laser absorption spectroscopy (TDLAS) technology, which combined a multi-pass gas cell (MPGC) with a 41 m optical path length to achieve high-precision detection. Meanwhile, the particle swarm optimization-kernel extreme learning machine (PSO-KELM) algorithm was applied for CO and N2O concentration prediction. In addition, the self-designed board-level QCL driver circuit and harmonic signal demodulation circuit reduce the sensor cost and size. A series of validation experiments were conducted to verify the sensor performance, and experiments showed that the concentration prediction results of the PSO-KELM algorithm are better than those of the commonly used back propagation (BP) neural networks and partial least regression (PLS), with the smallest root mean square error (RMSE) and linear correlation coefficient closest to 1, which improves the detection precision of the sensor. The limit of detection (LoD) was assessed to be 0.25 parts per billion (ppb) for CO and 0.27 ppb for N2O at the averaging time of 24 and 38 s. Field deployment of the sensor was reported for simultaneous detection of CO and N2O in the air.

Phase transition in V-doped cobalt hydroxide for a superior alkaline hydrogen evolution reaction.

Herein, V-doped cobalt hydroxides grown on carbon cloth (V-Co(OH)2/CC) were prepared via hydrothermal method. The incorporation of V can trigger phase transition and tune the local electronic structure of Co(OH)2, thereby improving the intrinsic alkaline HER activity. We find that the V-Co(OH)2 dominated by ß-Co(OH)2 exhibits excellent HER activity with only 83 mV overpotential at a current density of 10 mA cm-2, which outperforms most reported hydroxide-based catalysts and even surpasses the commercial Pt/C at large current density (>160 mA cm-2).

Selenium alleviates cadmium-induced aging via mitochondrial quality control in the livers of sheep.

Cadmium (Cd) is a heavy metal with toxicity that induces mitochondrial dysfunction and aging, and selenium (Se) can alleviate its toxicity. However, the underlying mechanism of Se alleviating Cd-induced aging in sheep livers deserves further study. This study was to explore the protective mechanism of Se on the Cd-induced aging in the livers of sheep. A total of forty-eight sheep weighing about 10 kg were randomly divided into four groups: control group, Se group [0.34 mg Se·kg-1·body weight (BW)], Cd group (1 mg Cd·kg-1·BW), and Se + Cd group (0.34 mg Se·kg-1·BW +1 mg Cd·kg-1·BW). The results showed that Cd caused vacuolization, granule denaturation, and mitochondrial vacuolization in hepatocytes. Furthermore, the levels of catalase (CAT), total superoxide dismutase (T-SOD), glutathione (GSH) and adenosine triphosphate (ATP) in liver mitochondria were down-regulated, but the levels of hydrogen peroxide (H2O2) and malonaldehyde (MDA) were up-regulated under Cd treatment. Besides, the cyclin-dependent kinase inhibitor 1 (P21) immunohistochemistry positive signal and the puncta of immunofluorescence co-locations of E3 ubiquitin ligase Parkin (Parkin)/ cytochrome c oxidase IV (COX IV) and light chain 3B (LC3B)/COX IV were increased under Cd stress. Moreover, Cd exposure decreased the levels of mitochondrial biogenesis and fusion related factors and minichromosome maintenance protein 2 (MCM2), but increased the levels of mitochondrial fission, mitophagy, and cell aging related factors. However, the variations mentioned above caused by Cd were effectively ameliorated by Se co-treatment. In conclusion, Se might alleviate Cd-induced aging via regulating mitochondrial quality control in sheep livers.

Using absorption simulation and gastric pH modulated dog model for formulation development to overcome achlorhydria effect.

Impaired absorption of weakly basic drugs in patients with reduced gastric acidity can lead to loss of efficacy of the therapeutic agent. Hence, a robust formulation which can provide adequate exposure in achlorhydric patients is imperative to achieve the desired efficacy. In this report, formulation development of a weakly basic Merck compound A is described. Compound A shows lower solubility at higher pH and thus is prone to reduced exposure under conditions of achlorhydria, as the compound's solubility increases only in environments of less than pH 2. Several formulations with or without an acidifier were developed and characterized by in vitro dissolution and in gastric pH modified dog model to assess their bioperformance in high gastric pH conditions. To predict the bioperformance of these formulations in humans, a dissolution based absorption model was developed and validated against the observed PPI-interaction data in the clinic and the gastric pH-adjusted dog data. An additional absorption model was developed to allow for incorporation of the dog PK data to provide translation of preclinical to clinical exposure. Based on the in vitro dissolution, in silico absorption modeling and preclinical in vivo data, a citric acid-based formulation (F2) was selected for a human pharmacokinetic study. This study showed that exposures from F2 were not meaningfully different in the presence of proton pump inhibitor (PPI) as compared to non-PPI, thus confirming that the F2 formulation was successful in overcoming the achlorhydria effect. These efforts also highlighted that the complementary use of in vitro/in silico/in vivo (IVISIV) tools may be a helpful strategy in the development of formulations to overcome the achlorhydria effect and achieve adequate exposure in patients with high gastric pH.