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Improvement of the performance of renewable energy harvesters is a crucial and complicated task. Among currently utilized renewable energy harvesters, parabolic solar collectors are some of the most promising and widely used apparatuses. However, researchers are still facing some issues regarding the optimization of PTC performance, including the enhancement of heat flux absorption by the absorber tubes. Among the proposed methods to overcome this drawback, the implementation of helical screw tape (HST) and nanofluids has proven to be most effective. In the present study, the CFD simulation of an absorber tube with HST is conducted. CuO/oil nanofluid with a nanoparticle volume fraction of 1 to 3% was chosen as the working fluid. The simulation is based on the realistic operational condition of a PTC absorber tube with corresponding nonuniform solar heat flux based on the local concentration ratio. The effects of the mass flow rate (Re), HST width and nanofluid volume fraction on pumping power and heat transfer are studied. Moreover, to combine the effect of both parameters, the performance evaluation criterion (PEC), a dimensionless variable, is calculated for all of the studied cases. Enhancement of the PEC parameter by the implementation of nanofluid and HST in comparison to base fluid passing through a plain tube is also determined and reported. According to the obtained results, with the implementation of the CuO/oil nanofluid, the PEC can be enhanced by 57.3–70.8, 68.7~86.4, and 83.4~105.9% for volume fractions of 1, 2, and 3%, respectively.

The increasing use of kidneys from donations after cardiac death (DCD) for renal transplantation is hindered by negative outcomes owing to organ injury after prolonged warm and cold ischemia-reperfusion. Recently, hydrogen sulfide (HWe tested a novel 30-day in vivo syngeneic murine model of DCD renal transplantation, in which the donor kidney was clamped for 30 minutes and stored for 18 hours in cold University of Wisconsin (UW) solution or UW with 150 μM sodium hydrogen sulfide (UW + NaHS) before transplantation. We also tested a 7-day in vivo porcine model of DCD renal autotransplantation, in which the left kidney was clamped for 60 minutes and preserved for 24 hours using hypothermic perfusion with UW or UW + 150 μM NaHS before autotransplantation. We collected blood and urine samples periodically, and collected kidney samples at the end point for histopathology and quantitative reverse transcription polymerase chain reaction.Rats that received HOur findings support the potential use of H

Our work presents a new process for the spatial atomic layer deposition (SALD) of SnO2 thin films from tin(ii) acetylacetonate and water, supported by a DFT study of different Sn metalorganic precursors.

Homopolymerization of butadiene (Bu) in 1,4-dioxane (Dox) was performed at 70 °C using molecular iodine (I2) in the presence of 4,4’-azobis(4-cyanovaleric acid) (ACVA), resulting in α-carboxyl ω-iodine heterotelechelic polybutadiene. Effect of Dox concentration, molar ratio of ACVA to I2 and initiator type on the Bu conversion was studied. Inhibition of the reaction by molecular I2 was observed until complete consumption of the I2 (induction period). Then, polymerization initiated by carboxyl- functionalized alkyl iodides in situ generated during induction period. ACVA decomposition rate constant (kd), induction time $$\left({t}_{ind}\right)$$ and $${k}_{p}^{2}/{k}_{t}$$ ratio were calculated using Bu conversion as a function of time data. A good agreement between the theoretical and experimental changes in the conversion versus time was observed, indicating accuracy of the kinetic parameters estimated in this work. Experimental $${t}_{ind}$$ was always less that theoretical one. It was attributed to reaction between Bu and I2, resulting in butadiene diiodide (I-Bu-I) compound. Formation of I-Bu-I species was further confirmed by 1H-NMR analysis of end functional groups (i.e. alkyl iodide and allyl iodide) of polybutadiene chains. Based on the 1H-NMR analysis, [I-Bu-I]/[I2]0 ratio was obtained for reaction B4 to be 0.235. It was found that among 1,2 and 1,4 additions, 1,2 addition of I2 to Bu is the dominant reaction. Exchange constant between the growing and dormant species (Cex) was estimated using GPC and conversion data to be in the range of 3.20–3.94. Then, $${M}_{n}$$ and $$D$$ evolution with conversion was investigated theoretically. Fraction of $$\alpha -$$ carboxyl, $$\omega-$$ iodide heterotelechelic PBu chains $$\left({f}_{HOOC-PBu-I}\right)$$ relative to all chains was estimated from 1H-NMR data to be 87% for reaction B4.

One of the main factors in the design of subways is the level of subway-induced vibrations. The ground borne vibrations are usually estimated by prediction models among which the FTA (Federal Transportation Association) general vibration assessment model is the most popular one. Although FTA approach/model is vastly used in the design and operation of underground railway systems, its reliability has not been sufficiently evaluated in the available literatures. This is addressed in this research. For this purpose, a comprehensive experimental investigation (both in the time and frequency domains) was conducted in three newly constructed subway lines in the Iranian underground railway (subway) network. The track and soil characteristics as well as ground borne vibrations were measured. The reliability and accuracy of the FTA model was assessed through comparisons of the experimental results obtained here with the FTA predictions. Contrary to the current belief, considerable underestimations of subway ground borne vibrations in the FTA model predictions were shown in this research. The results obtained indicate up to 20 dB differences between the experimental results and those of FTA predictions. Based on the field measurements obtained here and the theoretical background, the FTA model was improved/optimized, leading to increase the reliability of FTA model predictions in subway systems.

Cold preservation is the standard of care for renal grafts. However, research on alternatives like perfusion at higher temperatures and supplementing preservation solutions with hydrogen sulfide (H2S) has gained momentum. In this study, we investigated whether adding H2S donor AP39 to porcine blood during subnormothermic perfusion at 21 °C improves renal graft outcomes. Porcine kidneys were nephrectomized after 30 min of clamping the renal pedicles and treated to 4 h of static cold storage (SCS) on ice or ex vivo subnormothermic perfusion at 21 °C with autologous blood alone (SNT) or with AP39 (SNTAP). All kidneys were reperfused ex vivo with autologous blood at 37 °C for 4 h. Urine output, histopathology and RNAseq were used to evaluate the renal graft function, injury and gene expression profiles, respectively. The SNTAP group exhibited significantly higher urine output than other groups during preservation and reperfusion, along with significantly lower apoptotic injury compared to the SCS group. The SNTAP group also exhibited differential pro-survival gene expression patterns compared to the SCS (downregulation of pro-apoptotic genes) and SNT (downregulation of hypoxia response genes) groups. Subnormothermic perfusion at 21 °C with H2S-supplemented blood improves renal graft outcomes. Further research is needed to facilitate the clinical translation of this approach.

WOS:000573472800024 PubMed: 32871814 Background: Renal cell carcinoma (RCC) is the most common cancer of the kidney. The most common histotype is clear-cell (cc) RCC. Hydrogen sulfide (H2S) is an angiogenic and anti-apoptotic gasotransmitter that is elevated under pseudohypoxic conditions. H2S is endogenously produced by three enzymes: Cystathionine gamma-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MPST). Seeing as increased expression of these enzymes has been observed in other human cancer types, this study aimed to quantify H2S-producing enzyme expression in human RCC samples and evaluate whether it correlated with clinical outcomes. Patients and Methods: Eighty-eight human kidney tissue specimens, with healthy and cancerous tissue components, were immunohistochemically stained for CSE, CBS, and MPST. The mean pixel intensity of positively stained areas was quantified. A retrospective analysis was conducted to obtain patient demographics, rates of metastasis/recurrence, and prognostic characteristics. Statistical correlations between enzyme expressions and subsequent patient outcomes were evaluated. Results: There was significantly greater expression of CSE, CBS, and MPST in cc-RCC compared to paired healthy tissue (p

Cell death by hypoxia followed by reoxygenation (H/R) is responsible for tissue injury in multiple pathological conditions. Recent studies found that epigenetic reprogramming mediated by histone deacetylases (HDACs) is implicated in H/R-induced cell death. However, among 18 different isoforms comprising 4 classes (I-IV), the role of each HDAC in cell death is largely unknown. This study examined the role of HDAC8, which is the most distinct isoform of class I, in the hypoxia mimetic cobalt- and H/R-induced cytotoxicity of human proximal tubular HK-2 cells. Using the HDAC8-specific activator TM-2-51 (TM) and inhibitor PCI34051, we found that HDAC8 played a protective role in cytotoxicity. TM or overexpression of wild-type HDAC8, but not a deacetylase-defective HDAC8 mutant, prevented mitochondrial fission, loss of mitochondrial transmembrane potential and release of cytochrome C into the cytoplasm. TM suppressed expression of dynamin-related protein 1 (DRP1) which is a key factor required for mitochondrial fission. Suppression of DRP1 by HDAC8 was likely mediated by decreasing the level of acetylated histone H3 lysine 27 (a hallmark of active promoters) at the DRP1 promoter. Collectively, this study shows that HDAC8 inhibits cytotoxicity induced by cobalt and H/R, in part, through suppressing DRP1 expression and mitochondrial fission.

Direct access to a wide range of metal-free phthalocyanines and metallophthalocyanines in deep eutectic solvents (DESs), is reported. Substituted and unsubstituted phthalocyanines of Mn, Fe, Co, Ni, Cu, Zn, Pd, In, and Pt with various raw materials such as phthalonitriles, phthalimides, phthalic anhydrides and phthalic acids are successfully prepared in the DES based on choline chloride and urea in a very short reaction time with appropriate yields. It has been shown that DES as a green and rapidly degraded reaction medium in the environment plays a triple role as a solvent, organocatalyst, and reactant in this process. Moreover, the DES system could be separated and reused in four consecutive reaction runs with no considerable loss in catalytic activity.

Vanadium (V) and tungsten (VI) oxoperoxo complexes supported on Fe3O4 magnetic nanoparticles were synthesized and characterized. These compounds are assigned as catalyst 1 (C1: Fe3O4@Gly@r-Py@VO3) and catalyst 2 (C2: Fe3O4@Gly@r-Py@WO3), respectively, and were found to be efficient and reusable heterogeneous catalysts for the oxidation of alcohols and sulfides using H2O2.

The spleen is the major organ in which T cells are primed during infection with malaria parasites. However, little is known regarding the dynamics of the immune responses and their localization within the splenic tissue during malaria infection. We examined murine CD8+ T cell responses during infection with Plasmodium berghei using recombinant parasites expressing a model antigen ovalbumin (OVA) protein and compared the responses with those elicited by Listeria monocytogenes expressing the same antigen. OVA-specific CD8+ T cells were mainly activated in the white pulp of the spleen during malaria infection, as similarly observed during Listeria infection. However, the fates of these activated CD8+ T cells were distinct. During infection with malaria parasites, activated CD8+ T cells preferentially accumulated in the red pulp and/or marginal zone, where cytokine production of OVA-specific CD8+ T cells decreased, and the expression of multiple inhibitory receptors increased. These cells preferentially underwent apoptosis, suggesting that T cell exhaustion mainly occurred in the red pulp and/or marginal zone. However, during Listeria infection, OVA-specific CD8+ T cells only transiently expressed inhibitory receptors in the white pulp and maintained their ability to produce cytokines and become memory cells. These results highlighted the distinct fates of CD8+ T cells during infection with Plasmodium parasites and Listeria, and suggested that activation and exhaustion of specific CD8+ T cells occurred in distinct spleen compartments during infection with malaria parasites.

Antibiotics have been effective in treatment of infectious diseases, but resistance to these drugs has led to the severe consequences. In recent years, medicinal herbs have been used for the prevention and protection against infectious diseases. Thymol and carvacrol are active ingredients of family

Gallium-68 (68Ga) is a positron emitter for clinical positron emission tomography (PET) applications that can be produced by a 68Ge/68Ga generator without cyclotron. However, commercially available 68Ge/68Ga generator systems require multiple steps for the preparation of 68Ga radiopharmaceuticals and are sometimes plagued by metallic impurities in the 68Ga eluent. We developed a 68Ge/68Ga generator system using polysaccharide-based adsorbents and direct application of the generator-eluted 68Ga-citrate to PET imaging of tropical infectious diseases. N-Methylglucamine (MG) as a 68Ge-adsorbing unit (Sepha-MGs) was introduced to a series of Sephadex G-10, G-15, G-25, G-50, and G-75. In the batch method, over 97% of the 68Ge in the solution was adsorbed onto the Sepha-MG series within 15 min. In particular, 68Ge was effectively adsorbed on the Sepha(15)-MG packed columns and 70–80% of the 68Ga was eluted by 1 mL of 0.1 M trisodium citrate with low 68Ge contamination (

The resistive switching behaviors of AlOX/HfOX bilayer structures were investigated. Metal oxides were deposited by atomic layer deposition. Al and Pt were used as top and bottom electrodes, respectively. Compared with AlOX and HfOX monolayer structures, the bilayer structure showed lower set/reset voltages and more-uniform resistive switching properties. It also exhibited good data retention and endurance. The Al top electrode may gather oxygen ions from the oxide layer underneath and thereby create oxygen vacancies in the oxide layer. The uniform electrical property of the bilayer structure is attributed to confined formation/rupture of conductive filaments in the HfOX layer, whereas undissociated filaments in the AlOX layer nucleate rapid regeneration of filaments.

PURPOSE OF REVIEW The current review aims to examine recent evidence about improvements, therapeutics and novel approaches for renal graft preservation along with presenting a pragmatic outlook on their potential for clinical translation. RECENT FINDINGS Modifying established cold preservation methods (4 °C) with oxygenation, gene therapies and gasotransmitters such as hydrogen sulfide has been shown to improve renal graft outcomes with minimum modifications to current protocols. These strategies have also shown promise in the context of normothermic preservation (34-37 °C), which circumvents the damage caused by cold preservation. Although normothermic machine perfusion (NMP) is being evaluated in clinical trials, it is limited by high cost, the use of blood and the lack of standardized protocols. Recent studies confirmed that preservation at subnormothermic temperatures (∼20 °C) is effective with approved preservation solutions and, in conjunction with exogenous hydrogen sulfide therapy, this approach may expedite a static preservation alternative to NMP. SUMMARY Progress has been made in investigating improvements and alternatives to cold preservation. Promising therapeutic strategies have also been studied in the context of cold, subnormothermic and normothermic preservation. Further research is needed to optimize clinical renal graft preservation.

Hydrogen sulfide (H2S) is the latest member of the gasotransmitter family and known to play essential roles in cancer pathophysiology. H2S is produced endogenously and can be administered exogenously. Recent studies showed that H2S in cancers has both pro- and antitumor roles. Understanding the difference in the expression and localization of tissue-specific H2S-producing enzymes in healthy and cancer tissues allows us to develop tools for cancer diagnosis and treatment. Urological malignancies are some of the most common cancers in both men and women, and their early detection is vital since advanced cancers are recurrent, metastatic, and often resistant to treatment. This review summarizes the roles of H2S in cancer and looks at current studies investigating H2S activity and expression of H2S-producing enzymes in urinary cancers. We specifically focused on urothelial carcinoma, renal cell carcinoma, and prostate cancer, as they form the majority of newly diagnosed urinary cancers. Recent studies show that besides the physiological activity of H2S in cancer cells, there are patterns between the development and prognosis of urinary cancers and the expression of H2S-producing enzymes and indirectly the H2S levels. Though controversial and not completely understood, studying the expression of H2S-producing enzymes in cancer tissue may represent an avenue for novel diagnostic and therapeutic strategies for addressing urological malignancies.

Renal transplantation is the preferred treatment for end-stage renal disease. Currently, there is a large gap between the supply and demand for transplantable kidneys. The use of sub-optimal grafts obtained via donation after cardiac death (DCD) is on the rise. While static cold storage (SCS) in University of Wisconsin (UW) solution on ice (4 degrees C) is the clinical standard of care for renal graft preservation, cold storage has been associated with negative graft outcomes. The alternative, normothermic machine perfusion, involves mechanical perfusion of the organ at physiological or normothermic temperature (37 degrees C) and this technique is expensive, complicated and globally inaccessible. As such, simpler alternatives are of interest. Preliminary results revealed that UW solution is more protective at 21 degrees C than 37 degrees C and subnormothermic preservation is of interest because it may facilitate the use of existing solutions while preventing cold injury. We have previously shown that SCS in UW solution supplemented with mitochondria-targeted H2S donor AP39 improves renal graft outcomes. As such, it was hypothesized subnormothermic preservation at 21 degrees C with AP39 will also improve renal outcomes. Using an in vitro model of hypoxia and reoxygenation, we found that treating porcine tubular epithelial cells with UW + 5 mu M AP39 during 18 h hypoxia at 21 degrees C significantly increased renal tubular epithelial cell viability after 24 h of reoxygenation at 37 degrees C compared to UW alone. Also, AP39-supplemented UW solution was significantly more cytoprotective during hypoxia at 21 degrees C than hypoxia at 37 degrees C, regardless of AP39 concentration. Using an ex vivo DCD organ preservation model, we found that DCD porcine kidneys stored for 24 h in UW + 200 nM AP39 at 21 degrees C showed significantly lower tissue necrosis than DCD porcine kidneys preserved using SCS in UW solution, the clinical standard of care. Overall, our findings suggest that exogenous H2S supplementation improves the viability of the gold standard organ preservation solution, UW solution, for subnormothermic preservation at 21 degrees C.

Solution homo- and copolymerization of butadiene (Bu) and acrylonitrile (AN) in 1,4-dioxane (Dox) was carried out in the presence of molecular iodine (I2) and 4,4′-azobis (4-cyanovaleric acid) (ACVA), both acting as an in situ generator of carboxyl-functionalized alkyl iodide as a chain transfer agent (CTA), to synthesize α-carboxyl ω-iodine heterotelechelic polymer architectures. Effect of various variables including solvent concentration and type, ACVA to I2 molar ratio and reaction temperature (60 and 70 °C) on the overall conversion versus time data was investigated. It was found that before complete consumption by initiator-derived radicals during the induction period, molecular I2 inhibits the reaction. Polymerization period was then started in the presence of an in situ generated CTA. From conversion versus time data, rate constant of initiator decomposition (kd), induction time ( t i n d ) and overall average rate constant of k ‾ p 2 / k ‾ t were estimated and compared with those reported for conventional free-radical homo- and copolymerization of Bu and AN. A good agreement between the theoretical and experimental variations in the conversion versus time was also observed, indicating accuracy of the kinetic constants calculated in the present work. Comparison of the theoretical and experimental induction times revealed that molecular I2 reacts with Bu, resulting in butadiene diiodide species ( I − B u − I ) which can act along with carboxyl-functionalized alkyl iodide as CTAs. Formation of I − B u − I was also confirmed by 1H NMR analysis. Also, fraction of I2 consumed by Bu (i.e. [ I − B u − I ] / [ I 2 ] 0 ) was estimated from kinetic data at hand. [ I − B u − I ] / [ I 2 ] 0 value as high as 20.8% was observed in the case of Bu homopolymerization and decreased by increasing the AN content in the initial feed. In the case of AN homopolymerization, no consumption of I2 by AN was observed.

Oxoperoxo tungsten(VI) complex immobilized on Schiff base-modified Fe3O4 super paramagnetic nanoparticles were synthesized and appropriately characterized using FT-IR, XRD, SEM, TEM, EDX, BET, and VSM analysis. The synthesized nanoparticles efficiently catalyzed oxidation of benzylic alcohols with H2O2 as oxidant in high yields, with high to excellent selectivity. The catalyst can be recovered using an external magnetic field and recycled for subsequent oxidation reactions without any appreciable loss of efficiency. The simple preparation, high activity, excellent selectivity, and simple recoverability of the catalyst are advantageous.

The host-parasite relationship is one of the main themes of modern parasitology. Recent revolutions in science, including the development of various fluorescent proteins/probes and two-photon microscopy, have made it possible to directly visualize and study the mechanisms underlying the interaction between the host and pathogen. Here, we describe our method of preparing and setting-up the liver for our experimental approach of using intravital imaging to examine the interaction between Plasmodium berghei ANKA and antigen-specific CD8+ T cells during the liver-stage of the infection in four dimensions. Since the liver is positioned near the diaphragm, neutralization of respiratory movements is critical during the imaging process. In addition, blood circulation and temperature can be affected by the surgical exposure due to the anatomy and tissue structure of the liver. To control respiration, we recommend anesthesia with isoflurane inhalation at 1% during the surgery. In addition, our protocol introduces a cushion of gauze around the liver to avoid external pressure on the liver during intravital imaging using an inverted microscope, which makes it possible to image the liver tissue for long periods with minimal reduction in the blood circulation and with minimal displacement and tissue damage. The key point of this method is to reduce respiratory movements and external pressure on the liver tissue during intravital imaging.

CD4(+) T cells play critical roles in protection against the blood stage of malarial infection; however, their uncontrolled activation can be harmful to the host. In this study, in which rodent models of Plasmodium parasites were used, the expression of inhibitory receptors on activated CD4(+) T cells and their cytokine production was compared with their expression in a bacterial and another protozoan infection. CD4(+) T cells from mice infected with P. yoelii 17XL, P yoelii 17XNL, P. chabaudi, P. vinckei and P. berghei expressed the inhibitory receptors, PD-1 and LAG-3, as early as 6 days after infection, whereas those from either Listeria monocytogenes- or Leishmania major-infected mice did not. In response to T-cell receptor stimulation, CD4(+) T cells from mice infected with all the pathogens under study produced high concentrations of IFN-γ. IL-2 production was reduced in mice infected with Plasmodium species, but not in those infected with Listeria or Leishmania. In vitro blockade of the interaction between PD-1 and its ligands resulted in increased IFN-γ production in response to Plasmodium antigens, implying that PD-1 expressed on activated CD4(+) T cells actively inhibits T cell immune responses. Studies using Myd88(-/-), Trif(-/-) and Irf3(-/-) mice showed that induction of these CD4(+) T cells and their ability to produce cytokines is largely independent of TLR signaling. These studies suggest that expression of the inhibitory receptors PD-1 and LAG-3 on CD4(+) T cells and their reduced IL-2 production are common characteristic features of Plasmodium infection.

In this study, we investigated the effect of Ni and Ta doping on resistive switching behaviors of solution-processed HfOX-based resistive switching memory (RRAM) devices. The observations are discussed in terms of oxygen vacancies according to doping concentration. The initial resistance and forming voltages are influenced by doping concentration due to the reduction of formation energy of oxygen vacancies, whereby a higher concentration of dopant results in a lower forming voltage and initial resistance of RRAM devices. In addition, the Ni dopant has a significant effect on forming processes in HfOX-based RRAM devices. It is observed that 10% of Ni doping can lead to forming-free behaviors. This study demonstrates the facile control of resistive switching behaviors by doping processes during the preparation of solutions and suggests that proper doping is an easy method that can lead to modulation of RRAM properties for future nonvolatile memory applications.

INTRODUCTION: Patients suffering from chronic kidney disease (CKD) experience a number of associated comorbidities, including anemia. Relative deficiency in renal erythropoietin (EPO) production is thought to be a primary cause of anemia. Interestingly, CKD patients display low levels of hydrogen sulfide (H2S), an endogenously derived renal oxygen sensor. Previous in vitro experiments have revealed that H2S-deficient renal cell lines produce less EPO than wild-type renal cell lines during hypoxia.METHODS: We postulated that H2S might be a primary mediator of EPO synthesis during hypoxia, which was tested using an in vivo murine model of whole-body hypoxia and in clinical samples obtained from CKD patients.RESULTS: Following a 72-hour period of hypoxia (11% O2), partial H2S knockout mice (lacking the H2S biosynthetic enzyme cystathionine γ-lyase [CSE]) displayed lower levels of hemoglobin, EPO and cystathionine-β-synthase (CBS) (another H2S biosynthetic enzyme) compared to wild-type mice, all of which was rescued by exogenous H2S supplementation. We also found that anemic CKD patients requiring exogenous EPO exhibited lower urinary thiosulfate levels compared to non-anemic CKD patients of similar CKD classification.CONCLUSIONS: Together, our results confirm an interplay between the actions of H2S during hypoxia and EPO production.

Introduction Depletion therapy in high immunologic risk (HR) patients by antithymocyte globulin (rATG) induces lymphopenia and subsequent compartmental repopulation of T-cell subsets. rATG is also given to patients receiving kidneys from donations after cardiac death (DCDs) to mitigate innate immune activation associated with the DCD process. Methods We compared the T-cell response with rATG in both HR and DCD kidney recipients. We examined the reconstitution of T-cell subsets after rATG treatment in HR and DCD recipients (n = 19 per group) by multicolor flow cytometry. Results Following treatment, there was a rapid drop in the frequency of T cells in both groups, which persisted over 28 days. HR patients had an early surge in the frequency of CD4+ naive, effector-memory, and regulatory T cells. Although we found a significant proliferation of the T cells in both groups, the DCD cohort had a blunted response as well as reduced CD4+ T-cell immune-reactivity compare with the HR group. Conclusions Our data suggest that there is a lack of significant homeostatic proliferative response in DCD recipients following rATG, and CD4+ T cells may be less reactive in the DCD group than previously thought, indicating that rATG treatment may not have to be considered a first-line induction therapy in DCD recipients.

Renal transplantation is the preferred treatment for end-stage renal disease. Currently, there is a large gap between the supply and demand for transplantable kidneys. The use of sub-optimal grafts obtained via donation after cardiac death (DCD) is on the rise. While static cold storage (SCS) in University of Wisconsin (UW) solution on ice (4°C) is the clinical standard of care for renal graft preservation, cold storage has been associated with negative graft outcomes. The alternative, normothermic machine perfusion, involves mechanical perfusion of the organ at physiological or normothermic temperature (37°C) and this technique is expensive, complicated and globally inaccessible. As such, simpler alternatives are of interest. Preliminary results revealed that UW solution is more protective at 21°C than 37°C and subnormothermic preservation is of interest because it may facilitate the use of existing solutions while preventing cold injury. We have previously shown that SCS in UW solution supplemented with mitochondria-targeted H

CD8+ T cells are the major effector cells that protect against malaria liverstage infection, forming clusters around Plasmodium-infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8+ T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8+ T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8+ T cells specific for an unrelated antigen, respectively. While antigen-specific CD8+ T cells were essential for cluster formation, both antigen-specific and nonspecific CD8+ T cells joined the clusters. However, nonspecific CD8+ T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8+ T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8+ T cells interact with CD11c+ cells around infected hepatocytes. The depletion of CD11c+ cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c+ dendritic cells and presumably macrophages in the formation of CD8+ T cell clusters around Plasmodium-infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8+ T cells, specific and unrelated activated CD8+ T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8+ T cells seem to play a limited role in protective immunity against Plasmodium parasites., Infection and Immunity, 86(4), 00717-17; 2018

Aims/hypothesis: Interferon regulatory factor (IRF)4 plays a critical role in lymphoid development and the regulation of immune responses. Genetic deletion of IRF4 has been shown to suppress autoimmune disease in several mouse models, but its role in autoimmune diabetes in NOD mice remains unknown. Methods: To address the role of IRF4 in the pathogenesis of autoimmune diabetes in NOD mice, we generated IRF4-knockout NOD mice and investigated the impact of the genetic deletion of IRF4 on diabetes, insulitis and insulin autoantibody; the effector function of T cells in vivo and in vitro; and the proportion of dendritic cell subsets. Results: Heterozygous IRF4-deficient NOD mice maintained the number and phenotype of T cells at levels similar to NOD mice. However, diabetes and autoantibody production were completely suppressed in both heterozygous and homozygous IRF4-deficient NOD mice. The level of insulitis was strongly suppressed in both heterozygous and homozygous IRF4-deficient mice, with minimal insulitis observed in heterozygous mice. An adoptive transfer study revealed that IRF4 deficiency conferred disease resistance in a gene-dose-dependent manner in recipient NOD/severe combined immunodeficiency mice. Furthermore, the proportion of migratory dendritic cells in lymph nodes was reduced in heterozygous and homozygous IRF4-deficient NOD mice in an IRF4 dose-dependent manner. These results suggest that the levels of IRF4 in T cells and dendritic cells are important for the pathogenesis of diabetes in NOD mice. Conclusions/interpretation: Haploinsufficiency of IRF4 halted disease development in NOD mice. Our findings suggest that an IRF4-targeted strategy might be useful for modulating autoimmunity in type 1 diabetes., Diabetologia, 58(11), pp.2606-2614; 2015

CD8+ T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around Plasmodium-infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8+ T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8+ T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8+ T cells specific for an unrelated antigen, respectively. While antigen-specific CD8+ T cells were essential for cluster formation, both antigen-specific and nonspecific CD8+ T cells joined the clusters. However, nonspecific CD8+ T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8+ T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8+ T cells interact with CD11c+ cells around infected hepatocytes. The depletion of CD11c+ cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c+ dendritic cells and presumably macrophages in the formation of CD8+ T cell clusters around Plasmodium-infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8+ T cells, specific and unrelated activated CD8+ T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8+ T cells seem to play a limited role in protective immunity against Plasmodium parasites.

Interferon regulatory factor 4 (IRF4) has critical roles in immune cell differentiation and function and is indispensable for clonal expansion and effector function in T cells. Here, we demonstrate that the AKT pathway is impaired in murine CD8+ T cells lacking IRF4. The expression of phosphatase and tensin homolog (PTEN), a negative regulator of the AKT pathway, was elevated in Irf4?/? CD8+ T cells. Inhibition of PTEN partially rescued downstream events, suggesting that PTEN constitutes a checkpoint in the IRF4-mediated regulation of cell signaling. Despite the clonal expansion defect, in the absence of IRF4, memory-like CD8+ T cells could be generated and maintained, although unable to expand in recall responses. The homeostatic proliferation of naive Irf4?/? CD8+ T cells was impaired, whereas their number eventually reached a level similar to that of wild-type CD8+ T cells. Conversely, memory-like Irf4?/? CD8+ T cells underwent homeostatic proliferation in a manner similar to that of wild-type memory CD8+ T cells. These results suggest that IRF4 regulates the clonal expansion of CD8+ T cells at least in part via the AKT signaling pathway. Moreover, IRF4 regulates the homeostatic proliferation of naive CD8+ T cells, whereas the maintenance of memory CD8+ T cells is IRF4-independent., European Journal of Immunology, 48(8), pp.1319-1328; 2018

Gallium-68 (68Ga) is a positron emitter for clinical positron emission tomography (PET) applications that can be produced by a 68Ge/68Ga generator without cyclotron. However, commercially available 68Ge/68Ga generator systems require multiple steps for the preparation of 68Ga radiopharmaceuticals and are sometimes plagued by metallic impurities in the 68Ga eluent. We developed a 68Ge/68Ga generator system using polysaccharide-based adsorbents and direct application of the generator-eluted 68Ga-citrate to PET imaging of tropical infectious diseases. N-Methylglucamine (MG) as a 68Ge-adsorbing unit (Sepha-MGs) was introduced to a series of Sephadex G-10, G-15, G-25, G-50, and G-75. In the batch method, over 97% of the 68Ge in the solution was adsorbed onto the Sepha-MG series within 15 min. In particular, 68Ge was effectively adsorbed on the Sepha(15)-MG packed columns and 70–80% of the 68Ga was eluted by 1 mL of 0.1 M trisodium citrate with low 68Ge contamination (

IRF4 is a transcription factor from the IRF factor family that plays pivotal roles in the differentiation and function of T and B lymphocytes. Although IRF4 is also expressed in dendritic cells (DCs) and macrophages, its roles in these cells in vivo are not clearly understood. In this study, conditional knockout mice that lack IRF4 in DCs or macrophages were generated and infected with Leishmania major. Mice lacking DC expression of IRF4 showed reduced footpad swelling compared with C57BL/6 mice, whereas those lacking IRF4 in macrophages did not. Mice with IRF4-deficient DCs also showed reduced parasite burden, and their CD4+ T cells produced higher levels of IFN-γ in response to L. major Ag. In the draining lymph nodes, the proportion of activated CD4+ T cells in these mice was similar to that in the control, but the proportion of IFN-γ–producing cells was increased, suggesting a Th1 bias in the immune response. Moreover, the numbers of migrating Langerhans cells and other migratory DCs in the draining lymph nodes were reduced both before and postinfection in mice with IRF4 defects in DCs, but higher levels of IL-12 were observed in IRF4-deficient DCs. These results imply that IRF4 expression in DCs inhibits their ability to produce IL-12 while promoting their migratory behavior, thus regulating CD4+ T cell responses against local infection with L. major.

We previously showed that treatment of mice with the Flt3 ligand (Flt3L) prevents development of lethal experimental cerebral malaria and inhibits parasitemia during Plasmodium berghei ANKA (PbA) infection. In this study, we investigated the mechanisms underlying the reduction of parasitemia in Flt3L-treated mice. Studies using gene knockout mice and antibody treatment indicated that the anti-parasitemia effect of Flt3L was mediated by innate immune system and was dependent on MyD88, IFN-γ, IL-12 and natural killer (NK) cells. The number of NK cells and their ability to produce IFN-γ was enhanced in Flt3L-treated mice. Phagocytic activity of splenocytes was increased in Flt3L-treated mice after PbA infection when compared with that in untreated mice, and this activity was mainly mediated by the accumulation of F4/80(mid) CD11b(+) cells in the spleen. In both MyD88(-/-) and IFN-γ(-/-) mice, the proportion of F4/80(mid) CD11b(+) cells was not increased in the spleen of Flt3L-treated mice after infection. These correlations suggest that NK cells produce IFN-γ in Flt3L-treated mice, and accumulation of F4/80(mid) CD11b(+) cells in the spleen is promoted by an IFN-γ -dependent manner, culminating in the inhibition of parasitemia. These findings imply that Flt3L promotes effective innate immunity against malaria infection mediated by interplay among varieties of innate immune cells.

The spleen is the major organ in which T cells are primed during infection with malaria parasites. However, little is known regarding the dynamics of the immune responses and their localization within the splenic tissue during malaria infection. We examined murine CD8

CD4(+) T cells play critical roles in protection against the blood stage of malarial infection; however, their uncontrolled activation can be harmful to the host. In this study, in which rodent models of Plasmodium parasites were used, the expression of inhibitory receptors on activated CD4(+) T cells and their cytokine production was compared with their expression in a bacterial and another protozoan infection. CD4(+) T cells from mice infected with P. yoelii 17XL, P yoelii 17XNL, P. chabaudi, P. vinckei and P. berghei expressed the inhibitory receptors, PD-1 and LAG-3, as early as 6 days after infection, whereas those from either Listeria monocytogenes- or Leishmania major-infected mice did not. In response to T-cell receptor stimulation, CD4(+) T cells from mice infected with all the pathogens under study produced high concentrations of IFN-γ. IL-2 production was reduced in mice infected with Plasmodium species, but not in those infected with Listeria or Leishmania. In vitro blockade of the interaction between PD-1 and its ligands resulted in increased IFN-γ production in response to Plasmodium antigens, implying that PD-1 expressed on activated CD4(+) T cells actively inhibits T cell immune responses. Studies using Myd88(-/-), Trif(-/-) and Irf3(-/-) mice showed that induction of these CD4(+) T cells and their ability to produce cytokines is largely independent of TLR signaling. These studies suggest that expression of the inhibitory receptors PD-1 and LAG-3 on CD4(+) T cells and their reduced IL-2 production are common characteristic features of Plasmodium infection.