Investigating Permselectivity in PVDF Mixed Matrix Membranes Using Experimental Optimization, Machine Learning Segmentation, and Statistical Forecasting.

This research examines the correlation between interfacial characteristics and membrane distillation (MD) performance of copper oxide (Cu) nanoparticle-decorated electrospun carbon nanofibers (CNFs) polyvinylidene fluoride (PVDF) mixed matrix membranes. The membranes were fabricated by a bottom-up phase inversion method to incorporate a range of concentrations of CNF and Cu + CNF particles in the polymer matrix to tune the porosity, crystallinity, and wettability of the membranes. The resultant membranes were tested for their application in desalination by comparing the water vapor transport and salt rejection rates in the presence of Cu and CNF. Our results demonstrated a 64% increase in water vapor flux and a salt rejection rate of over 99.8% with just 1 wt % loading of Cu + CNF in the PVDF matrix. This was attributed to enhanced chemical heterogeneity, porosity, hydrophobicity, and crystallinity that was confirmed by electron microscopy, tensiometry, and scattering techniques. A machine learning segmentation model was trained on electron microscopy images to obtain the spatial distribution of pores in the membrane. An Autoregressive Integrated Moving Average with Explanatory Variable (ARIMAX) statistical time series model was trained on MD experimental data obtained for various membranes to forecast the membrane performance over an extended duration.

Lithium nitrate salt-assisted CO2 absorption for the formation of corrosion barrier layer on AZ91D magnesium alloy.

Mg alloy corrosion susceptibility is a major issue that limits its wide industrial application in transport, energy and medical sectors. A corrosion-resistant layer containing crystalline MgCO3 was formed on the surface of AZ91D Mg alloy by Li salt loading and thermal CO2 treatment. Compared to the uncoated AZ91D surface, the surface layer exhibited up to a ∼15-fold increase in corrosion resistance according to the electrochemical results in 3.5 wt% NaCl solution and ∼32% decrease in wear rate compared to untreated AZ91D. The improved corrosion resistance is attributed to the formation of a <10 µm thick dense layer containing Mg, O, C and Li with crystalline MgCO3 phases. The initial step was to form a porous MgO layer on the surface of AZ91D Mg alloy, followed by loading an alkali metal salt (i.e., LiNO3) onto the MgO surface. The porous MgO surface was then reconstructed into a dense insulation layer containing Mg carbonate through CO2 absorption facilitated by molten Li salt during thermal CO2 treatment at 350 °C. As a potential method to utilize excessive CO2 for beneficial outcomes, the formation of the carbonate-containing film introduced in this study opens a new pathway for protecting various existing Mg alloys for diverse industrial applications.

Amplifying Nanoparticle Reinforcement through Low Volume Topologically Controlled Chemical Coupling.

We present a streamlined method to covalently bond hydroxylated carbon nanotubes (CNOH) within a polyphenol matrix, all achieved through a direct, solvent-free process. Employing an extremely small concentration of CNOH (0.01% w/w) along with topologically contrasting linkers led to a maximum of 5-fold increase in modulus and a 25% enhancement in tensile strength compared to the unaltered matrix, an order of magnitude greater reinforcement (w/w) compared to state-of-the-art melt-processed nanocomposites. Through dynamic mechanical analysis, low field solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, we uncovered the profound influence of linker's conformational degrees of freedom on the segmental dynamics and therefore the material's properties.

Nanoscale Ion Transport Enhances Conductivity in Solid Polymer-Ceramic Lithium Electrolytes.

The predictive design of flexible and solvent-free polymer electrolytes for solid-state batteries requires an understanding of the fundamental principles governing the ion transport. In this work, we establish a correlation among the composite structures, polymer segmental dynamics, and lithium ion (Li+) transport in a ceramic-polymer composite. Elucidating this structure-property relationship will allow tailoring of the Li+ conductivity by optimizing the macroscopic electrochemical stability of the electrolyte. The ion dissociation from the slow polymer segmental dynamics was found to be enhanced by controlling the morphology and functionality of the polymer/ceramic interface. The chemical structure of the Li+ salt in the composite electrolyte was correlated with the size of the ionic cluster domains, the conductivity mechanism, and the electrochemical stability of the electrolyte. Polyethylene oxide (PEO) filled with lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) or lithium bis(fluorosulfonyl) imide (LiFSI) salts was used as a matrix. A garnet electrolyte, aluminum substituted lithium lanthanum zirconium oxide (Al-LLZO) with a planar geometry, was used for the ceramic nanoparticle moieties. The dynamics of the strongly bound and highly mobile Li+ were investigated using dielectric relaxation spectroscopy. The incorporation of the Al-LLZO platelets increased the number density of more mobile Li+. The structure of the nanoscale ion-agglomeration was investigated by small-angle X-ray scattering, while molecular dynamics (MD) simulation studies were conducted to obtain the fundamental mechanism of the decorrelation of the Li+ in the LiTFSI and LiFSI salts from the long PEO chain.

Fanning the Flames of Endoplasmic Reticulum (ER) Stress: Can Sphingolipid Metabolism Be Targeted to Enhance ER Stress-Associated Immunogenic Cell Death in Cancer?

The three arms of the unfolded protein response (UPR) surveil the luminal environment of the endoplasmic reticulum (ER) and transmit information through the lipid bilayer to the cytoplasm to alert the cell of stress conditions within the ER lumen. That same lipid bilayer is the site of de novo synthesis of phospholipids and sphingolipids. Thus, it is no surprise that lipids are modulated by and are modulators of ER stress. Given that sphingolipids have both prosurvival and proapoptotic effects, they also exert opposing effects on life/death decisions in the face of prolonged ER stress detected by the UPR. In this review, we will focus on several recent studies that demonstrate how sphingolipids affect each arm of the UPR. We will also discuss the role of sphingolipids in the process of immunogenic cell death downstream of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiating factor 2α (eIF2α) arm of the UPR. Furthermore, we will discuss strategies to target the sphingolipid metabolic pathway that could potentially act synergistically with agents that induce ER stress as novel anticancer treatments. SIGNIFICANCE STATEMENT: This review provides the readers with a brief discussion of the sphingolipid metabolic pathway and the unfolded protein response. The primary focus of the review is the mechanism(s) by which sphingolipids modulate the endoplasmic reticulum (ER) stress response pathways and the critical role of sphingolipids in the process of immunogenic cell death associated with the ER stress response.

Tailoring Chemical Absorption-Precipitation to Lower the Regeneration Energy of a CO2 Capture Solvent.

Solvent-based CO2 capture consumes significant amounts of energy for solvent regeneration. To improve energy efficiency, this study investigates CO2 fixation in a solid form through solvation, followed by ionic self-assembly-aided precipitation. Based on the hypothesis that CO3 2- ions may bind with monovalent metal ions, we introduced Na+ into an aqueous hexane-1,6-diamine solution where CO2 forms carbamate and bicarbonate. Then, Na+ ions in the solvent act as a seed for ionic self-assembly with diamine carbamate to form an intermediate ionic complex. The recurring chemical reactions lead to the formation of an ionic solid from a mixture of organic carbamate/carbonate and inorganic sodium bicarbonate (NaHCO3 ), which can be easily removed from the aqueous solvent through sedimentation or centrifugation and heated to release the captured CO2 . Mild-temperature heating of the solids at 80-150 °C causes decomposition of the solid CO2 -diamine-Na molecular aggregates and discharge of CO2 . This sorbent regeneration process requires 6.5-8.6 GJ/t CO2 . It was also found that the organic carbamate/carbonate solid, without NaHCO3 , contains a significant amount of CO2 , up to 6.2 mmol CO2 /g-sorbent, requiring as low as 2.9-5.8 GJ/t CO2 . Molecular dynamic simulations support the hypothesis of using Na+ to form relatively less stable, yet sufficiently solid, complexes for the least energy-intensive recovery of diamine solvents compared to bivalent carbonate-forming ions.

The underwater soundscape of the North Sea.

As awareness on the impact of anthropogenic underwater noise on marine life grows, underwater noise measurement programs are needed to determine the current status of marine areas and monitor long-term trends. The Joint Monitoring Programme for Ambient Noise in the North Sea (JOMOPANS) collaborative project was funded by the EU Interreg to collect a unique dataset of underwater noise levels at 19 sites across the North Sea, spanning many different countries and covering the period from 2019 to 2020. The ambient noise from this dataset has been characterised and compared - setting a benchmark for future measurements in the North Sea area. By identifying clusters with similar sound characteristics in three broadband frequency bands (25-160 Hz, 0.2-1.6 kHz, and 2-10 kHz), geographical areas that are similarly affected by sound have been identified. The measured underwater sound levels show a persistent and spatially uniform correlation with wind speed at high frequencies (above 1 kHz) and a correlation with the distance from ships at mid and high frequencies (between 40 Hz and 4 kHz). Correlation with ocean current velocity at low frequencies (up to 200 Hz), which are susceptible to nonacoustic contamination by flow noise, was also evaluated. These correlations were evaluated and simplified linear scaling laws for wind and current speeds were derived. The presented dataset provides a baseline for underwater noise measurements in the North Sea and shows that spatial variability of the dominant sound sources must be considered to predict the impact of noise reduction measures.

Highly Recyclable and Tough Elastic Vitrimers from a Defined Polydimethylsiloxane Network.

Despite intensive research on sustainable elastomers, achieving elastic vitrimers with significantly improved mechanical properties and recyclability remains a scientific challenge. Herein, inspired by the classical elasticity theory, we present a design principle for ultra-tough and highly recyclable elastic vitrimers with a defined network constructed by chemically crosslinking the pre-synthesized disulfide-containing polydimethylsiloxane (PDMS) chains with tetra-arm polyethylene glycol (PEG). The defined network is achieved by the reduced dangling short chains and the relatively uniform molecular weight of network strands. Such elastic vitrimers with the defined network, i.e., PDMS-disulfide-D, exhibit significantly improved mechanical performance than random analogous, previously reported PDMS vitrimers, and even commercial silicone-based thermosets. Moreover, unlike the vitrimers with random network that show obvious loss in mechanical properties after recycling, those with the defined network enable excellent thermal recyclability. The PDMS-disulfide-D also deliver comparable electrochemical signals if utilized as substrates for electromyography sensors after the recycling. The multiple relaxation processes are revealed via a unique physical approach. Multiple techniques are also applied to unravel the microscopic mechanism of the excellent mechanical performance and recyclability of such defined network.

Tuning Ionic Conductivity in Fluorite Gd-Doped CeO2-Bixbyite RE2O3 (RE = Y and Sm) Multilayer Thin Films by Controlling Interfacial Strain.

Interfacial strain in heteroepitaxial oxide thin films is a powerful tool for discovering properties and recognizing the potential of materials performance. Particularly, facilitating ion conduction by interfacial strain in oxide multilayer thin films has always been seen to be a highly promising route to this goal. However, the effect of interfacial strain on ion transport properties is still controversial due to the difficulty in deconvoluting the strain contribution from other interfacial phenomena, such as space charge effects. Here, we show that interfacial strain can effectively tune the ionic conductivity by successfully growing multilayer thin films composed of an ionic conductor Gd-doped CeO2 (GDC) and an insulator RE2O3 (RE = Y and Sm). In contrast to compressively strained GDC-Y2O3 multilayer films, tensile strained GDC-Sm2O3 multilayer films demonstrate the enhanced ionic conductivity of GDC, which is attributed to the increased concentration of oxygen vacancies. In addition, we demonstrate that increasing the number of interfaces has no impact on the further enhancement of the ionic conductivity in GDC-Sm2O3 multilayer films. Our findings demonstrate the unambiguous role of interfacial strain on ion conduction of oxides and provide insights into the rational design of fast ion conductors through interface engineering.

Characterization of Anticancer Effects of the Analogs of DJ4, a Novel Selective Inhibitor of ROCK and MRCK Kinases.

The Rho associated coiled-coil containing protein kinase (ROCK1 and ROCK2) and myotonic dystrophy-related Cdc-42 binding kinases (MRCKα and MRCKß) are critical regulators of cell proliferation and cell plasticity, a process intimately involved in cancer cell migration and invasion. Previously, we reported the discovery of a novel small molecule (DJ4) selective multi-kinase inhibitor of ROCK1/2 and MRCKα/ß. Herein, we further characterized the anti-proliferative and apoptotic effects of DJ4 in non-small cell lung cancer and triple-negative breast cancer cells. To further optimize the ROCK/MRCK inhibitory potency of DJ4, we generated a library of 27 analogs. Among the various structural modifications, we identified four additional active analogs with enhanced ROCK/MRCK inhibitory potency. The anti-proliferative and cell cycle inhibitory effects of the active analogs were examined in non-small cell lung cancer, breast cancer, and melanoma cell lines. The anti-proliferative effectiveness of DJ4 and the active analogs was further demonstrated against a wide array of cancer cell types using the NCI-60 human cancer cell line panel. Lastly, these new analogs were tested for anti-migratory effects in highly invasive MDA-MB-231 breast cancer cells. Together, our results demonstrate that selective inhibitors of ROCK1/2 (DJE4, DJ-Allyl) inhibited cell proliferation and induced cell cycle arrest at G2/M but were less effective in cell death induction compared with dual ROCK1/2 and MRCKα/ß (DJ4 and DJ110).

Anti-polyelectrolyte and polyelectrolyte effects on conformations of polyzwitterionic chains in dilute aqueous solutions.

Polyzwitterions (PZs) are considered as model synthetic analogs of intrinsically disordered proteins. Based on this analogy, PZs in dilute aqueous solutions are expected to attain either globular (i.e. molten, compact) or random coil conformations. Addition of salt is expected to open these conformations. To the best of our knowledge, these hypotheses about conformations of PZs have never been verified. In this study, we test these hypotheses by studying effects of added salt [potassium bromide (KBr)] on gyration and hydrodynamic radii of poly(sulfobetaine methacrylate) in dilute aqueous solutions using dynamic light scattering and small-angle X-ray scattering, respectively. Effects of zwitteration are revealed by direct comparisons of the PZs with the polymers of the same backbone but containing (1) no explicit charges on side groups such as poly(2-dimethylaminoethyl methacrylate)s and (2) explicit cationic side groups with tertiary amino bromide pendants. Zeta-potential measurements, transmission electron microscopy, and ab initio molecular dynamics simulations reveal that the PZs acquire net positive charge in near salt-free conditions due to protonation but retain coiled conformations. Added KBr leads to nonmonotonic changes exhibiting an increase followed by a decrease in radius of gyration (and hydrodynamic radius), which are called antipolyelectrolyte and polyelectrolyte effects, respectively. Charge regulation and screening of charge-charge interactions are discussed in relation to the antipolyelectrolyte and polyelectrolyte effects, respectively, which highlight the importance of salt in affecting net charge and conformations of PZs.

Effects of Salt on Phase Behavior and Rheological Properties of Alginate-Chitosan Polyelectrolyte Complexes.

Oppositely charged polyelectrolytes often form polyelectrolyte complexes (PECs) due to the association through electrostatic interactions. Obtaining PECs using natural, biocompatible polyelectrolytes is of interest in the food, pharmaceutical, and biomedical industries. In this work, PECs were prepared from two biopolymers, positively charged chitosan and negatively charged alginate. We investigate the changes in the structure and properties of PECs by adding sodium chloride (salt doping) to the system. The shear modulus of PECs can be tuned from ∼10 to 104 Pa by changing the salt concentration. The addition of salt led to a decrease in the water content of the complex phase with increasing shear modulus. However, at a very high salt concentration, the shear modulus of the complex phase decreased but did not lead to the liquid coacervate formation, typical of synthetic polyelectrolytes. This difference in phase behavior has likely been attributed to the hydrophobicity of chitosan and long semiflexible alginate and chitosan chains that restrict the conformational changes. Large amplitude oscillatory shear experiments captured nonlinear responses of PECs. The compositions of the PECs, determined as a function of salt concentration, signify the preferential partitioning of salt into the complex phase. Small-angle X-ray scattering of the salt-doped PECs indicates that the Kuhn length and radius of the alginate-chitosan associated structure qualitatively agree with the captured phase behavior and rheological data. This study provides insights into the structure-property as a function of salt concentration of natural polymer-based PECs necessary for developing functional materials from natural polyelectrolytes.

Photocarrier-induced persistent structural polarization in soft-lattice lead halide perovskites.

The success of the lead halide perovskites in diverse optoelectronics has motivated considerable interest in their fundamental photocarrier dynamics. Here we report the discovery of photocarrier-induced persistent structural polarization and local ferroelectricity in lead halide perovskites. Photoconductance studies of thin-film single-crystal CsPbBr3 at 10 K reveal long-lasting persistent photoconductance with an ultralong photocarrier lifetime beyond 106 s. X-ray diffraction studies reveal that photocarrier-induced structural polarization is present up to a critical freezing temperature. Photocapacitance studies at cryogenic temperatures further demonstrate a systematic local phase transition from linear dielectric to paraelectric and relaxor ferroelectric under increasing illumination. Our theoretical investigations highlight the critical role of photocarrier-phonon coupling and large polaron formation in driving the local relaxor ferroelectric phase transition. Our findings show that this photocarrier-induced persistent structural polarization enables the formation of ferroelectric nanodomains at low temperature, which suppress carrier recombination and offer the possibility of exploring intriguing carrier-phonon interplay and the rich polaron photophysics.

Structure-Dynamics Interrelation Governing Charge Transport in Cosolvated Acetonitrile/LiTFSI Solutions.

Concentrated ionic solutions present a potential improvement for liquid electrolytes. However, their conductivity is limited by high viscosities, which can be attenuated via cosolvation. This study employs a series of experiments and molecular dynamics simulations to investigate how different cosolvents influence the local structure and charge transport in concentrated lithium bis(trifluoromethane-sulfonyl)imide (LiTFSI)/acetonitrile solutions. Regardless of whether the cosolvent's dielectric constant is low (for toluene and dichloromethane), moderate (acetone), or high (methanol and water), they preserve the structural and dynamical features of the cosolvent-free precursor. However, the dissimilar effects of each case must be individually interpreted. Toluene and dichloromethane reduce the conductivity by narrowing the distribution of Li+-TFSI- interactions and increasing the activation energies for ionic motions. Methanol and water broaden the distributions of Li+-TFSI- interactions, replace acetonitrile in the Li+ solvation, and favor short-range Li+-Li+ interactions. Still, these cosolvents strongly interact with TFSI-, leading to conductivities lower than that predicted by the Nernst-Einstein relation. Finally, acetone preserves the ion-ion interactions from the cosolvent-free solution but forms large solvation complexes by joining acetonitrile in the Li+ solvation. We demonstrate that cosolvation affects conductivity beyond simply changing viscosity and provide fairly unexplored molecular-scale perspectives regarding structure/transport phenomena relation in concentrated ionic solutions.

Leadership of AAAP scientists and journals in animal science: achievements, limitations, and challenges.

The Asian-Australasian Association of Animal Production Societies (AAAP), the only international scientific organization in animal science representing Asia and Pacific region, showed a remarkable development since its inception in 1980. The number of member countries increased from 8 to 19 while 19 congresses were held in 11 different member countries. The AAAP also helped creating the official journal, Asian-Australasian Journal of Animal Sciences in 1988 with the title being changed to Animal Bioscience in 2021. It is an open access journal indexed by most global databases and has become one of the most respected global journals in animal science. Through scientific meetings and journal publication, the AAAP has made a tremendous contribution to the advancement of animal science and industry throughout its member countries over the last 40 years. This paper summarizes the advances in animal science in the Asia-Pacific region, together with the roles of the AAAP scientists and journals in developing animal science.

Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation.

We recently identified the sphingosine kinases (SphK1/2) as key intracellular regulators of immunogenic cell death (ICD) in colorectal cancer (CRC) cells. To better understand the mechanism by which SphK inhibition enhances ICD, we focused on the intracellular signaling pathways leading to cell surface exposure of calreticulin (ectoCRT). Herein, we demonstrate that ABT-263 and AZD-5991, inhibitors of Bcl-2/Bcl-XL and Mcl-1, respectively, induce the production of ectoCRT, indicative of ICD. Inhibition of SphK1 significantly enhanced ABT/AZD-induced ectoCRT production, in a caspase 8-dependent manner. Mechanistically, we demonstrate that ABT/AZD-induced Bak/Bax activation stimulates pro-survival SphK1/sphingosine-1-phosphate (S1P) signaling, which attenuates ectoCRT production. Additionally, we identified a regulatory role for ceramide synthase 6 (CerS6)/C16:0 ceramide in transporting of ectoCRT to the cell surface. Together, these results indicate that the sphingolipid metabolic regulators of the sphingolipid rheostat, S1P and C16:0 ceramide, influence survival/death decisions of CRC cells in response to ICD-inducing chemotherapeutic agents. Importantly, SphK1, which produces S1P, is a stress-responsive pro-survival lipid kinase that suppresses ICD. While ceramide, produced by the inhibition of SphK1 is required for production of the cell surface marker of ICD, ectoCRT. Thus, inhibition of SphK1 represents a means to enhance the therapeutic efficacy of ICD-inducing agents.

Ionic Conductivity Enhancement of Polymer Electrolytes by Directed Crystallization.

We report that hot stretching of poly(ethylene oxide) (PEO)-based solid polymer electrolytes (SPEs) can lead to a preferred orientation of PEO crystalline lamellae, thereby reducing the tortuosity of the ion-conduction pathway along the thickness direction of the SPE film, causing improved ionic conductivity. The hot stretching method is implemented by stretching SPE films above the melting point of PEO in an inert environment followed by crystallization at room temperature while maintaining the applied strain. The effect of hot stretching on the crystalline orientation, crystallinity, morphology, and ion transport in PEO with two types of salts, lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and lithium triflate (LiCF3SO3), is investigated in detail. Wide-angle X-ray scattering (WAXS) and small-angle X-ray scattering (SAXS) show that the orientation of PEO crystalline lamellae induces the formation of a short ion-conduction pathway along the through-plane direction of the SPE films, leading to 1.4- to 3.5-fold enhancement in the through-plane ionic conductivity.

Extending the viability of human precision-cut intestinal slice model for drug metabolism studies.

Human Precision-cut intestinal slices (hPCIS) are used to study intestinal physiology, pathophysiology, drug efficacy, toxicology, kinetics, and metabolism. However, the use of this ex vivo model is restricted to approximately a 24 h timeframe because of declining viability of the hPCIS during traditional culture. We hypothesized that we could extend the hPCIS viability by using organoid medium. Therefore, we cultured hPCIS for up to 72 h in organoid media [expansion medium (Emed) and differentiation medium (Dmed)]. After incubation, we assessed culture-induced changes on viability markers, specific cell type markers and we assessed the metabolic activity of enterocytes by measuring midazolam metabolite formation. We show that the adenosine triphosphate (ATP)/protein ratio of Emed-cultured hPCIS and morphology of both Emed- and Dmed-cultured hPCIS was improved compared to WME-cultured hPCIS. Emed-cultured hPCIS showed an increased expression of proliferation and stem cell markers, whereas Dmed-cultured hPCIS showed an increased expression of proliferation and enterocyte markers, along with increased midazolam metabolism. Using the Emed, the viability of hPCIS could be extended for up to 72 h, and proliferating stem cells remained preserved. Using Dmed, hPCS also remained viable for up to 72 h, and specifically rescued the metabolizing enterocytes during culture. In conclusion, by using two different organoid culture media, we could extend the hPCIS viability for up to 72 h of incubation and specifically steer stem cells or enterocytes towards their original function, metabolism, and proliferation, potentially allowing pharmacokinetic and toxicology studies beyond the 24 h timeframe.

Inhibition of Sphingosine Kinase Activity Enhances Immunogenic Cell Surface Exposure of Calreticulin Induced by the Synthetic Cannabinoid 5-epi-CP-55,940.

Background: Endogenous and synthetic cannabinoids have been shown to induce cancer cell death through the accumulation of the sphingolipid, ceramide (Cer). Recently, we have demonstrated that Cer accumulation enhances the induction of immunogenic cell death (ICD). Objectives: The primary objective of this study was to demonstrate that (±) 5-epi CP 55,940 (5-epi), a by-product of the chemical synthesis of the synthetic cannabinoid CP 55,940, induces ICD in colorectal cancer (CRC) cells, and that modulation of the sphingolipid metabolic pathway through inhibition of the sphingosine kinases (SphKs) enhances these effects. Methods: A cell culture model system of human CRC cell lines was employed to measure the cell surface and intracellular production of markers of ICD. The effects of 5-epi, alone and in combination with SphK inhibitors, on production of Cer through the de novo sphingolipid synthesis pathway were measured by Liquid Chromatography - Tandem Mass Spectrometry (LC/MS/MS)-based sphingolipidomic analysis. Cell surface exposure of calreticulin (ectoCRT), a hallmark of ICD, was measured by flow cytometry. Examination of the effects of 5-epi, alone and in combination with SphK inhibitors, on the intracellular signaling pathway associated with ICD was conducted by immunoblot analysis of human CRC cell lines. Results: Sphingolipidomic analysis indicated that 5-epi induces the de novo sphingolipid synthetic pathway. 5-epi dose dependently induces cell surface exposure of ectoCRT, and inhibition of Cer metabolism through inhibition of the SphKs significantly enhances 5-epi-induced ectoCRT exposure in multiple CRC cell lines. 5-epi induces and SphK inhibition enhances activation of the cell death signaling pathway associated with ICD. Conclusions: This study is the first demonstration that cannabinoids can induce the cell surface expression of ectoCRT, and potentially induce ICD. Moreover, this study reinforces our previous observation of a role for Cer accumulation in the induction of ICD and extends this observation to the cannabinoids, agents not typically associated with ICD. Inhibition of SphKs enhanced the 5-epi-induced signaling pathways leading to ICD and production of ectoCRT. Overexpression of SphK1 has previously been associated with chemotherapy resistance. Thus, targeting the SphKs has the potential to reverse chemotherapy resistance and simultaneously enhance the antitumor immune response through enhancement of ICD induction.

Mental and physical health of international humanitarian aid workers on short-term assignments: Findings from a prospective cohort study.

Research findings show humanitarian work impacts one's health. We conducted a prospective observational study among 618 international humanitarian aid workers (iHAWs)' recruited from 76 countries to investigate health changes and ill-health risk factors after mostly short-term (<1 year) medical emergency assignments. The aid workers were assigned to 27 countries. Data collected between 2017 and 2020. We also compared a gold-standard clinical interview with self-report questionnaires to assess whether self-report scores overestimate the prevalence of clinical anxiety, depression and PTSD. Analyses consisted of repeated measures ANOVAs and adjusted odds ratios, using pre-assignment (T1), post-assignment (T2) and two-month follow-up data (T3). Humanitarian workers experienced on average, 2.6 experienced and witnessed potential traumatic events, and 4.8 male and 5.6 female assignment-related stressors. Self-report health indicators demonstrated a significant increase in emotional exhaustion, loss of vitality, decreased social functioning and emotional well-being between T1 and T2, all of which improved between T2 and T3. PTSD, depression, experienced role limitations, physical functioning, pain, and general health - remained stable. Anxiety levels decreased significantly between T1 and T2. The presence of DSM-5 disorders anxiety (6.6 %), depression (1.3 %) and PTSD (0.3 %) was low compared to norm populations, except for alcohol-use disorder (13 %). None of the reported T2 risk factors was significant at T3. Compared to the clinical interview, self-report cut-off thresholds inflated the presence of a potential anxiety disorder (3×), PTSD (8×) and depression (25×). Humanitarian work is highly stressful but most iHAWs remained healthy. Looking into how iHAWs stay healthy may be a more useful way forward.