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SrCo1-xMgxV2O7 (x = 0–0.09) dielectrics were prepared via the solid state route and the effect of Mg substitution on the microwave dielectric properties of the ceramics was systematically investigated. In addition to the relative density and microstructure, the dielectric polarizability, packing fraction, lattice energy and bond valence also play a crucial role in controlling the dielectric properties of the ceramics at microwave frequencies. A high lattice energy representing a high structural stability leads to a low dielectric loss in the specimen. Fluctuated variation of the τf was highly related to the bond valence of the samples. Specimens with x = 0.07 at 660°C revealed the highest Q × f of 23,000 GHz along with an εr of 13.2 and a τf of – 95 ppm/°C and it is chemically compatible with the Al electrode, suggesting that the dielectric is highly promising for ULTCC applications.

Osteoarthritis (OA) is a chronic disease caused by the damage of articular cartilage. Kartogenin (KGN) is a well-recognized small molecule which could induce MSCs chondrogenesis and promote cartilage repair treatments. Nano-level micells could be a suitable drug carrier technology for the treatments. In this study, the acid-responsive methoxy poly(ethylene oxide)-hydrazone-poly(ε-caprolactone) copolymers, mPEG-Hz-b-PCL, were synthesized. The structure was characterized by 1H NMR. The evaluation of a designed kartogenin drug delivery system (DDS) of hydrazone-linkage-based pH responsive mPEG-Hz-b-PCL nanomicelles for treatment of osteoarthritis could be carried out.

In Ming Dynasty, the characteristic of social congregation among the Suzhou (蘇州) book collectors were extremely prevalent. The characteristic echoed withMing Dynasty’s “Wuzhong Wenyuan” (吳中文苑). The Suzhou book collectorshad significant influence on the regional collection culture at Suzhou during the Ming Dynasty, and even on the collection culture all over the country. Generally speaking, the social linkages between ancient book collectors can be categorized into four categories, namely through linkages via consanguinity (relationship by blood), affinity (relationship by marriage), same school of thoughts, or friendship. However, historical records on these four linkages are enormous and fragmented. Processing and analyzing such records is difficult. Therefore, this study attempts to utilize digital humanity technology by selecting the social community analysis software to conduct in-depth analysis on Suzhou book collectors in Ming Dynasty, aims to depict the four major social network models of the Suzhou book collectors, and to identify the heritage or connection through the difference periods. The study also aims to identify the core social groups among the Suzhou book collector communities in Ming Dynasty during different periods, and to provide answers questions such as the identity of core members in the social communities. The result may be different from the academic community previous perception, and can serve as a good clarification, and another good reference to the public.

Beijing in the Ming Dynasty was a national political, economic, cultural and transportation center, and the book market there was beyond comparison in scale. The rulers in the early Ming Dynasty especially attaches the great importance to the book cause, and the unprecedentedly prosperous economy of the cities after the middle period of the Ming Dynasty also created favorable conditions for the development of book practitioners. In addition, the prosperity of book carving industry in Ming Dynasty had made Beijin, where many important bookstores were concentrated at the time, form a book market naturally. Since many important, highly-educated book consumers throughout the country gathered there, a large number of book companies were attracted to form a large-scale industry. On the other hand, the thriving private book collection activity was also beneficial to the development of the book market. After mid-Ming Dynasty, in particular, the domestic economy extremely flourished so that the social atmosphere had changed and resulted in the great desire of book reading among regular people, which raised the demand for books. All of these conditions had invisibly created vast business opportunities as well as consumer groups, which enabled the book market of Ming Dynasty in Beijin to be well-adjusted to the trend and thrive.

Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed.

Several investigations have examined magnesia-based investments for pure titanium casting. However, the thermal expansion value was insufficient at low casting temperatures and high interfacial reactivity occurred at high casting temperatures. The purpose of this investigation was to modify a magnesia-based investment by adding a heat-resistant mold material, zirconia, in different ratios to produce a more accurate titanium casting. The thermal expansion value was measured using a new precise automatic laser recording machine and pure titanium was cast using an argon casting machine. The marginal accuracy was measured using a stereomicroscope and the interfacial reactivity of the titanium was evaluated using X-ray diffraction analysis. The results indicate that adding different amounts of zirconia to a magnesia-based investment can increase its thermal expansion value and decrease the interfacial reactivity of the titanium. Maximal thermal expansion in the zirconia-modified investments significantly increased by 5-6 weight % (wt%) and peaked at 1.62% expansion. Selevest with 5 wt% zirconia had the smallest mean marginal discrepancy, 21.70 μm at 750°C. Analysis of variance indicates significant differences in marginal discrepancy between zirconia-modified investments (p < 0.001). Adding zirconia can also decrease the interfacial reactivity of the titanium. The data indicated that proper amounts of zirconia (5-6 wt%) added to a magnesia-based investment can produce a more accurate and less interfacial reactive pure titanium casting.

Molecular chaperones are a set of conserved proteins that have evolved to assist the folding of many newly synthesized proteins by preventing their misfolding under conditions such as elevated temperatures, hypoxia, acidosis and nutrient deprivation. Molecular chaperones belong to the heat shock protein (HSP) family. They have been identified as important participants in immune functions including antigen presentation, immunostimulation and immunomodulation, and play crucial roles in metabolic rewiring and epigenetic circuits. Growing evidence has accumulated to indicate that metabolic pathways and their metabolites influence the function of immune cells and can alter transcriptional activity through epigenetic modification of (de)methylation and (de)acetylation. However, whether molecular chaperones can regulate metabolic programs to influence immune activity is still largely unclear. In this review, we discuss the available data on the biological function of molecular chaperones to immune responses during inflammation, with a specific focus on the interplay between molecular chaperones and metabolic pathways that drive immune cell fate and function.

Lung macrophages are substantially distinct from other tissue-resident macrophages. They act as frontier sentinels of the alveolar-blood interface and are constantly exposed to various pathogens. Additionally, they precisely regulate immune responses under homeostatic and pathological conditions to curtail tissue damage while containing respiratory infections. As a highly heterogeneous population, the phenotypes and functions of lung macrophages with differing developmental ontogenies are linked to both intrinsic and extrinsic metabolic processes. Importantly, targeting these metabolic pathways greatly impacts macrophage functions, which in turn leads to different disease outcomes in the lung. In this review, we will discuss underlying metabolic regulation of lung macrophage subsets and how metabolic circuits, together with epigenetic modifications, dictate lung macrophage function during bacterial infection. [ABSTRACT FROM AUTHOR]

C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α- conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4- expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4- eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile. [ABSTRACT FROM AUTHOR]

Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8–/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8–/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. [ABSTRACT FROM AUTHOR]

A novel technique and product for carpal tunnel microscopic surgical procedures using a modified medical device containing a head as a surgical scalpel under light guidance were designed and studied. The novel design of the medical device was developed and applied in a new carpal tunnel microscopic surgical procedure in place of the traditional carpal tunnel surgical procedure. Biological and clinical evaluations of carpal tunnel surgical procedure using the designed optically guided medical device were studied. For commercialized reasons, some guidance was considered, such as ISO 10993-1:2009(E), for the biological evaluation of the device. Furthermore, a clinical evaluation was carried out. The designed optically guided medical device could provide a powerful medical device for carpal tunnel syndrome and related applications. [ABSTRACT FROM AUTHOR]

A new fabrication process for designing nerve conduits with a porous ionic cross-linked alginate/chitosan composite for nervous regeneration could be prepared. New designed nerve conduits with a porous ionic cross-linked alginate/chitosan composite were developed for nervous regeneration. Nerve conduits (NCs) represent a promising alternative to conventional treatments for peripheral nerve repair. NCs composed of various polysaccharides such as sodium alginate were designed and prepared by lyophilization as potential matrices for tissue engineering. The use of a porous ionic cross-linked alginate/chitosan composite could provide penetration channels that would lead to the products' increasing penetration rate properties. Furthermore, the use of a porous ionic cross-linked alginate/chitosan composite also has a highly cross-linked structure, which would give the products relatively good mechanical properties. Furthermore, the drug could be incorporated into nerve conduits as a new drug-carrying system for nerve regeneration because of its porous and cross-linked structures. [ABSTRACT FROM AUTHOR]

Caused by acute radiation skin reaction and injury, receiving radiotherapy treatment process is often performed side-effects on cancer patients. The clinical manifestations of skin irritation, itching, peeling, pigmentation, ulcer bleeding and other symptoms, in addition to causing patient discomfort and affecting quality of life, may increase the risk of local or systemic infection, and lead to interruption of radiation therapy. At present, for acute radiation dermatitis, there is no uniform treatment, and the various methods are evaluated variously. In this study, the authors focus on broken pearls using room temperature super extraction system, the water extraction process of wet-grinding method, nano-scale pearl, along with a large number of high purity natural amino acid extracts in the water. The room-temperature super-extraction system (RTSES) can be extracted from a relatively high-volume of pearl extract. We use pearl extract as the main component of experimental material, and the blending of pearl extract and poly (γ-glutamic acid) is used to form biodegradable composite hydrogels. This study aims to evaluate the use of RTSES to extract the major active components of pearl and enhance their anti-inflammation and anti-apoptosis effects. The possible effect of pearl extract on inducing apoptosis in human keratinocyte cells (HaCaT) under the exposure of low dose UVB has been investigated. Various concentrations of pearl extracts have been used to study the effect of low dosage UVB on HaCaT cells. The results show that pearl extract has no toxic effect on HaCaT cells. Combining the pearl extract and poly (γ-glutamic acid) hydrogels with UVB irradiation would decrease the inflammation and apoptosis of HaCaT cells. The commercial pearl extract has the potential to inhibit radiation dermatitis occurring within keratinocyte cells. [ABSTRACT FROM AUTHOR]

The small intestinal submucosa (SIS) is an acellular collagen-based matrix, primarily composed of fibrillar collagens (types I, II, and V). They enhance healing due to a minimal immune response. A good degradation rate is the degradation of materials equal to the rate of remodeling in the host. The SIS should apply a good degradation rate and cytocompatibility. In this study, a series of SIS with different degradation rates is obtained by treatment with Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Morphology, composition, degradable ratio, mechanical properties and cytocompatibility of the SIS are evaluated. We determined a 20µm thickness and 60µm pore size of the native SIS. The degradable ratio of the native SIS was approximately 90% in the presence of 0.25 mg/ml collagenase for 24 hours. The storage modulus of the native SIS was 388MPa. The degradable ratio of the SIS decreased to 6% and the storage modulus increased to 777 MPa after being treated with 30mM EDC for 24 hours. In cytocompatibility assay, cell numbers on the native SIS were similar as on the treated SIS due to the non-toxicity of the EDC treatment process. This SIS exhibited collagenase resistance, stronger mechanical strength and good cytocompatibility after the EDC treatment concluded. The cross-linked SIS could be utilized as a potential cell carrier for tissue engineering application. [ABSTRACT FROM AUTHOR]

A series of designed drug-release systems were prepared and established for clear moisture healing. These systems were designed to have an interpenetrating polymer network (IPN) structure, which contained a breathable polyurethane film, hydrocolloidlayer, and polyacrylate adhesive layer. Breathable polyurethane film (2000 g/m²/24 hr) with high moisture permeability was employed as a base for new drug-release systems or wound dressings. All drug-release systems having a polyurethane film-backed hydrocolloid acrylated adhesive layer showed an increase of water uptakes with increasing time. After 114 hours, high water uptakes of drug-release systems with 20% hydrocolloid components were observed in the values of 160, 1100, and 1870% for different additional hydrocolloid components of carboxymethylcellulose, sodium alginate, and carbomer U10, respectively. New drug-release systems of polyurethane film-backed hydrocolloid/adhesive layers could be designed and established for wound care managements. [ABSTRACT FROM AUTHOR]

Hydroxypropyl methylcellulose (HPMC) was employed in this study to design controllable drug release systems because of its non-toxic nature, swelling properties. New interpenetrating polymer networks (IPN) of HPMC / tri-isocyanate crosslinked polyurethane (TCPU) could be prepared on the surfaces of IPN materials. To design "Novel Drug-carrying Matrix Systems", incorporation of novel structure is important to the possible formation of drug-carrying spaces within the material, which was achieved by using Tris (6-isocyanatohexyl) isocyanurate with three soft hexyl arms in this study. A series of novel drug-carrying matrix systems prepared by crosslinking reaction could be candidates for an excellent and smart potential material. When the polymeric networks were established on the surfaces of resulting materials, the developed hydrophilic interpenetrating polymeric structures of HPMC/ polyurethane could provide good wettability to the wound dressings, particularly for moisture healing application. The materials containing HPMC/polyurethane networks using 1% cross-linking agent showed a water uptake value of 5.1% after one hour, which has great potential for use as wound dressings for moisture healing. Furthermore, a new drug delivery system of hydrophilic IPN was successfully designed and established. [ABSTRACT FROM AUTHOR]

A characteristic of memory T (TM) cells is their ability to mount faster and stronger responses to reinfection than naïve T (TN) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 TM cells have more mitochondrial mass than CD8 TN cells and, that upon activation, the resulting secondary effector T (TE) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, TM cells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than TN cells, suggesting that greater mitochondrial mass in TM cells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both TN and TM cells. We also found that fatty acid oxidation is needed for TM cells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in TM cells. Our results demonstrate that greater mitochondrial mass endows TM cells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection. [ABSTRACT FROM AUTHOR]

The vitellarium is a highly proliferative organ, producing cells which are incorporated along with a fertilized ovum into the schistosome egg. Vitellarial growth fails to occur in virgin female schistosomes in single sex (female-only) infections, and involution of this tissue, which is accompanied by physical shrinkage of the entire worm, occurs when mature females sexually regress upon removal from their male partners. We have found that upon removal from their hosts into tissue culture, female parasites regress whether they are mated or not, but that cessation of egg production and a decline in expression of the vitelline gene p14 is delayed by mating. We used BrdU labeling to investigate whether there was a loss of proliferation in the vittelarium that might account for regression and found that the proliferation rate declined equally in paired and singled females once placed into culture. However, TUNEL staining and Caspase 3 activity measurements indicate that the loss of vitrellarial cellularity associated with regression is associated with profound apoptotic vitelline cell death, which is not apparent in the vitellaria of paired females immediately ex vivo, and which develops in vitro regardless of whether males are present or not. Furthermore, primordial vitellaria in virgin females have a high frequency of apoptotic cells but are characterized by a proliferation rate that is indistinguishable from that in fully developed vitellaria in mature paired females. Taken together, our data suggest that the vitelline proliferation rate is independent of pairing status. In contrast, the survival of vitelline cells, and therefore the development of the vitellarium, is highly male-dependent. Both processes are negatively affected by removal from the host regardless of whether male worms are present or not, and are unsustainable using standard tissue culture approaches. [ABSTRACT FROM AUTHOR]

This study was aimed to develop the new transdermal formulation to improve the permeability of buprenorphine. The apparent partition coefficients of buprenorphine were measured using the buffers at pH 1.2 to 10.0 as aqueous phase. The solubility of buprenorphine was 12.97 μg/mL in the 0.1 M phosphate buffer at pH 6.8. The influences of vehicles at different pH, adhesives, and permeation enhancers on the penetration of buprenorphine through nude mouse skin were investigated using the static Franz diffusion cells. The permeation parameter Jss of buprenorphine increased along with the reduction of the pH of receptor fluid, and the vehicle at pH 6.8 was used in the following skin permeation studies. The pressure sensitive adhesives (PSA) including polyisobutylene (PIB), polystyrene-block-polyisoprene-block-polystyrene (SIS), and acrylic adhesives were evaluated. The permeability of buprenorphine was higher in the PIB or SIS adhesives than that in the acrylic adhesives under the condition without enhancer. When combined the enhancers with propylene glycol (PG) to improve the penetration of buprenorphine, the permeation-cnhancing effects of enhancers were in the following order: lauric acid > linolenic acid > menthol > oleic acid > N-methyl-2-pyrrolidone (NMP) > laurocapram > glabridin. Finally, a matrix-type transdermal delivery system for buprenorphine was formulated using acrylic adhesive, PG, and lauric acid. The -parameter was 2.68 ± 0.20 μg/cm²/h and buprenorphine permeated across the nude mouse skin was 31.68%. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells. [ABSTRACT FROM AUTHOR]

Summary: T helper type 2 (Th2) cytokine-activated M2 macrophages contribute to inflammation resolution and wound healing. This study shows that IL-4-primed macrophages exhibit a stronger response to lipopolysaccharide stimulation while maintaining M2 signature gene expression. Metabolic divergence between canonical M2 and non-canonical proinflammatory-prone M2 (M2INF) macrophages occurs after the IL-4Rα/Stat6 axis. Glycolysis supports Hif-1α stabilization and proinflammatory phenotype of M2INF macrophages. Inhibiting glycolysis blunts Hif-1α accumulation and M2INF phenotype. Wdr5-dependent H3K4me3 mediates the long-lasting effect of IL-4, with Wdr5 knockdown inhibiting M2INF macrophages. Our results also show that the induction of M2INF macrophages by IL-4 intraperitoneal injection and transferring of M2INF macrophages confer a survival advantage against bacterial infection in vivo. In conclusion, our findings highlight the previously neglected non-canonical role of M2INF macrophages and broaden our understanding of IL-4-mediated physiological changes. These results have immediate implications for how Th2-skewed infections could redirect disease progression in response to pathogen infection.

Lung macrophages are substantially distinct from other tissue-resident macrophages. They act as frontier sentinels of the alveolar-blood interface and are constantly exposed to various pathogens. Additionally, they precisely regulate immune responses under homeostatic and pathological conditions to curtail tissue damage while containing respiratory infections. As a highly heterogeneous population, the phenotypes and functions of lung macrophages with differing developmental ontogenies are linked to both intrinsic and extrinsic metabolic processes. Importantly, targeting these metabolic pathways greatly impacts macrophage functions, which in turn leads to different disease outcomes in the lung. In this review, we will discuss underlying metabolic regulation of lung macrophage subsets and how metabolic circuits, together with epigenetic modifications, dictate lung macrophage function during bacterial infection.

The transcription factor BHLHE40 is an emerging regulator of the immune system. Recent studies suggest that BHLHE40 regulates type 2 immunity, but this has not been demonstrated in vivo. We found that BHLHE40 is required in T cells for a protective TH2 cell response in mice infected with the helminth Heligmosomoides polygyrus bakeri. H. polygyrus elicited changes in gene and cytokine expression by lamina propria CD4+ T cells, many of which were BHLHE40 dependent, including production of the common b (CSF2RB) chain family cytokines GM-CSF and IL-5. In contrast to deficiency in GM-CSF or IL-5 alone, loss of both GM-CSF and IL-5 signaling impaired protection against H. polygyrus. Overall, we show that BHLHE40 regulates the TH2 cell transcriptional program during helminth infection to support normal expression of Csf2, Il5, and other genes required for protection and reveal unexpected redundancy of common β chain-dependent cytokines previously thought to possess substantially divergent functions. [ABSTRACT FROM AUTHOR]

Immune activation is now understood to be fundamentally linked to intrinsic and/or extrinsic metabolic processes which are essential for immune cells to survive, proliferate, and perform their effector functions. Moreover, disruption or dysregulation of these pathways can result in detrimental outcomes and underly a number of pathologies in both communicable and non-communicable diseases. In this review, we discuss how the metabolism of carbohydrates and amino acids in particular can modulate innate immunity and how perturbations in these pathways can result in failure of these immune cells to properly function or induce unfavorable phenotypes.

Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.

Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8-/-mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8-/-M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis.

Small nucleolar RNAs (snoRNAs) are non-coding RNAs that form ribonucleoproteins to guide covalent modifications of ribosomal and small nuclear RNAs in the nucleus. Recent studies have also uncovered additional non-canonical roles for snoRNAs. However, the physiological contributions of these small RNAs are largely unknown. Here, we selectively deleted four snoRNAs encoded within the introns of the ribosomal protein L13a (Rpl13a) locus in a mouse model. Loss of Rpl13a snoRNAs altered mitochondrial metabolism and lowered reactive oxygen species tone, leading to increased glucose-stimulated insulin secretion from pancreatic islets and enhanced systemic glucose tolerance. Islets from mice lacking Rpl13a snoRNAs demonstrated blunted oxidative stress responses. Furthermore, these mice were protected against diabetogenic stimuli that cause oxidative stress damage to islets. Our study illuminates a previously unrecognized role for snoRNAs in metabolic regulation. [ABSTRACT FROM AUTHOR]

Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations.

Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A "chokepoint reaction" is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery of new anthelmintic drugs with broad-spectrum efficacy.

Schistosomes, parasitic flatworms that cause the neglected tropical disease schistosomiasis, have been considered to have an entirely carbohydrate based metabolism, with glycolysis playing a dominant role in the adult parasites. However, we have discovered a close link between mitochondrial oxygen consumption by female schistosomes and their ability to produce eggs. We show that oxygen consumption rates (OCR) and egg production are significantly diminished by pharmacologic inhibition of carnitine palmitoyl transferase 1 (CPT1), which catalyzes a rate limiting step in fatty acid β-oxidation (FAO) and by genetic loss of function of acyl CoA synthetase, which complexes with CPT1 and activates long chain FA for use in FAO, and of acyl CoA dehydrogenase, which catalyzes the first step in FAO within mitochondria. Declines in OCR and egg production correlate with changes in a network of lipid droplets within cells in a specialized reproductive organ, the vitellarium. Our data point to the importance of regulated lipid stores and FAO for the compartmentalized process of egg production in schistosomes.