Infection and inflammation stimulate expansion of a CD74+ Paneth cell subset to regulate disease progression.

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.

Human Plasmacytoid Dendritic Cells Express C-Type Lectin Receptors and Attach and Respond to Aspergillus fumigatus.

Plasmacytoid dendritic cells (pDCs) have been implicated as having a role in antifungal immunity, but mechanisms of their interaction with fungi and the resulting cellular responses are not well understood. In this study, we identify the direct and indirect biological response of human pDCs to the fungal pathogen Aspergillus fumigatus and characterize the expression and regulation of antifungal receptors on the pDC surface. Results indicate pDCs do not phagocytose Aspergillus conidia, but instead bind hyphal surfaces and undergo activation and maturation via the upregulation of costimulatory and maturation markers. Measuring the expression of C-type lectin receptors dectin-1, dectin-2, dectin-3, and mannose receptor on human pDCs revealed intermediate expression of each receptor compared with monocytes. The specific dectin-1 agonist curdlan induced pDC activation and maturation in a cell-intrinsic and cell-extrinsic manner. The indirect activation of pDCs by curdlan was much stronger than direct stimulation and was mediated through cytokine production by other PBMCs. Overall, our data indicate pDCs express various C-type lectin receptors, recognize and respond to Aspergillus hyphal Ag, and serve as immune enhancers or modulators in the overarching fungal immune response.

Compendium of naringenin: potential sources, analytical aspects, chemistry, nutraceutical potentials and pharmacological profile.

Naringenin is flavorless, water insoluble active principle belonging to flavanone subclass. It exhibits a diverse pharmacological profile as well as divine nutraceutical values. Although several researchers have explored this phytoconstituent to evaluate its promising properties, still it has not gained recognition at therapeutic levels and more clinical investigations are still required. Also the neutraceutical potential has limited marketed formulations. This compilation includes the description of reported therapeutic potentials of naringenin in variety of pathological conditions alongwith the underlying mechanisms. Details of various analytical investigations carried on this molecule have been provided along with brief description of chemistry and structural activity relationship. In the end, various patents filed and clinical trial data has been provided. Naringenin has revealed promising pharmacological activities including cardiovascular diseases, neuroprotection, anti-diabetic, anticancer, antimicrobial, antiviral, antioxidant, anti-inflammatory and anti-platelet activity. It has been marketed in the form of nanoformulations, co-crystals, solid dispersions, tablets, capsules and inclusion complexes. It is also available in various herbal formulations as nutraceutical supplement. There are some pharmacokinetic issue with naringenin like poor absorption and low dissolution rate. Although these issues have been sorted out upto certain extent still further research to investigate the bioavailability of naringenin from herbal supplements and its clinical efficacy is essential.

A comprehensive compiled review is presented on source, health benefits, chemistry and analysis, and marketed products of naringenin.Naringenin is a promising phytoconstituent as nutraceutical.Valorization of fruit peels of citrus fruits is a critical step for food and nutraceutical industry.Structure-activity relationship of naringenin derivatives.Nano-formulations incorporating naringenin in themselves can be used for targeted delivery for critical disorders.Naringenin obtained from the peels can be efficiently used in breads, cookies, cakes and other food products.

Investigation of Fascin1, a Marker of Mature Dendritic Cells, Reveals a New Role for IL-6 Signaling in CCR7-Mediated Chemotaxis.

Migration of mature dendritic cells (DCs) to lymph nodes is critical for the initiation of adaptive immunity. CCR7, a G-protein-coupled receptor for CCL19/21 chemokines, is known to be essential for chemotaxis of mature DCs, but the molecular mechanism linking inflammation to chemotaxis remains unclear. We previously demonstrated that fascin1, an actin-bundling protein, increases chemotaxis of mature mouse DCs. In this article, we demonstrated that fascin1 enhanced IL-6 secretion and signaling of mature mouse DCs. Furthermore, we demonstrated that IL-6 signaling is required for chemotaxis. Blockage of IL-6 signaling in wild-type DCs with an anti-IL-6 receptor α (IL-6Rα) Ab inhibited chemotaxis toward CCL19. Likewise, knockout of IL-6Rα inhibited chemotaxis of bone marrow-derived DCs. The addition of soluble IL-6Rα and IL-6 rescued chemotaxis of IL-6Rα knockout bone marrow-derived DCs, underscoring the role of IL-6 signaling in chemotaxis. We found that IL-6 signaling is required for internalization of CCR7, the initial step of CCR7 recycling. CCR7 recycling is essential for CCR7-mediated chemotaxis, explaining why IL-6 signaling is required for chemotaxis of mature DCs. Our results have identified IL-6 signaling as a new regulatory pathway for CCR7/CCL19-mediated chemotaxis and suggest that rapid migration of mature DCs to lymph nodes depends on inflammation-associated IL-6 signaling.

Phosphatidylserine-Targeting Monoclonal Antibodies Exhibit Distinct Biochemical and Cellular Effects on Anti-CD3/CD28-Stimulated T Cell IFN-γ and TNF-α Production.

Phosphatidylserine (PS)-targeting monoclonal Abs (mAbs) that directly target PS and target PS via ß2-gp1 (ß2GP1) have been in preclinical and clinical development for over 10 y for the treatment of infectious diseases and cancer. Although the intended targets of PS-binding mAbs have traditionally included pathogens as well as stressed tumor cells and its associated vasculature in oncology, the effects of PS-targeting mAbs on activated immune cells, notably T cells, which externalize PS upon Ag stimulation, is not well understood. Using human T cells from healthy donor PBMCs activated with an anti-CD3 + anti-CD28 Ab mixture (anti-CD3/CD28) as a model for TCR-mediated PS externalization and T cell stimulation, we investigated effects of two different PS-targeting mAbs, 11.31 and bavituximab (Bavi), on TCR activation and TCR-mediated cytokine production in an ex vivo paradigm. Although 11.31 and Bavi bind selectivity to anti-CD3/28 activated T cells in a PS-dependent manner, surprisingly, they display distinct functional activities in their effect on IFN-γ and TNF-ɑ production, whereby 11.31, but not Bavi, suppressed cytokine production. This inhibitory effect on anti-CD3/28 activated T cells was observed on both CD4+ and CD8+ cells and independently of monocytes, suggesting the effects of 11.31 were directly mediated by binding to externalized PS on activated T cells. Imaging showed 11.31 and Bavi bind at distinct focal depots on the cell membrane. Collectively, our findings indicate that PS-targeting mAb 11.31 suppresses cytokine production by anti-CD3/28 activated T cells.

Genetic analysis of iron, zinc and grain yield in wheat-Aegilops derivatives using multi-locus GWAS.

BACKGROUND: Wheat is a major staple crop and helps to reduce worldwide micronutrient deficiency. Investigating the genetics that control the concentrations of iron (Fe) and zinc (Zn) in wheat is crucial. Hence, we undertook a comprehensive study aimed at elucidating the genomic regions linked to the contents of Fe and Zn in the grain. METHODS AND RESULTS: We performed the multi-locus genome-wide association (ML-GWAS) using a panel of 161 wheat-Aegilops substitution and addition lines to dissect the genomic regions controlling grain iron (GFeC), and grain zinc (GZnC) contents. The wheat panel was genotyped using 10,825 high-quality SNPs and phenotyped in three different environments (E1-E3) during 2017-2019. A total of 111 marker-trait associations (MTAs) (at p-value < 0.001) were detected that belong to all three sub-genomes of wheat. The highest number of MTAs were identified for GFeC (58), followed by GZnC (44) and yield (9). Further, six stable MTAs were identified for these three traits and also two pleiotropic MTAs were identified for GFeC and GZnC. A total of 1291 putative candidate genes (CGs) were also identified for all three traits. These CGs encode a diverse set of proteins, including heavy metal-associated (HMA), bZIP family protein, AP2/ERF, and protein previously associated with GFeC, GZnC, and grain yield. CONCLUSIONS: The significant MTAs and CGs pinpointed in this current study are poised to play a pivotal role in enhancing both the nutritional quality and yield of wheat, utilizing marker-assisted selection (MAS) techniques.

A Compiled Update on Nutrition, Phytochemicals, Processing Effects, Analytical Testing and Health Effects of Chenopodium album: A Non-Conventional Edible Plant (NCEP).

Bathua (Chenopodium album) is a rich source of extensive-ranging nutrients, including bio-active carbohydrates, flavonoids and phenolics, minerals, and vitamins that translate to countless health benefits such as anticancer, antidiabetic, anti-inflammatory, antimicrobial, and antioxidant activity. Ascaridole, an important phytoconstituent present in aerial parts of the plant, contributes to its anthelmintic property. Even with vast historical use and significant health benefits, its renown has not spread, and utilization has significantly decreased in recent decades. Gradually, the plant has become known under the name of Non-conventional edible plant (NCEP). This compilation is prepared to bring out the plant under the spotlight for further research by foregrounding previous studies on the plant. Scientific research databases, including PubMed, Google Scholar, Scopus, SpringerLink, ScienceDirect, and Wiley Online, were used to fetch data on C. album. This review offers over up-to-date knowledge on nutritious values, phytochemical composition, volatile compounds, as well as health benefits of C. album. The ethnobotanical and ethnomedicinal uses of the plant in India and other parts of the world are deliberately discussed. Scrutinizing the reported literature on C. album reveals its powerful nutrient composition advantageous in the development of food products. The impact of various cooking and processing methods on the nutritional profile and bioavailability are discussed. The future perspectives with regards to the potential for food and nutraceutical products are critically addressed. This review proves the necessity of breakthrough research to investigate the pharmacology and safety of phytochemicals and nutraceutical development studies on the C. album.

Triggering of the cGAS-STING Pathway in Human Plasmacytoid Dendritic Cells Inhibits TLR9-Mediated IFN Production.

Plasmacytoid dendritic cells (pDCs) are potent producers of type I and type III IFNs and play a major role in antiviral immunity and autoimmune disorders. The innate sensing of nucleic acids remains the major initiating factor for IFN production by pDCs. TLR-mediated sensing of nucleic acids via endosomal pathways has been studied and documented in detail, whereas the sensing of DNA in cytosolic compartment in human pDCs remains relatively unexplored. We now demonstrate the existence and functionality of the components of cytosolic DNA-sensing pathway comprising cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of IFN gene (STING) in human pDCs. cGAS was initially located in the cytosolic compartment of pDCs and time-dependently colocalized with non-CpG double-stranded immunostimulatory DNA (ISD). Following the colocalization of ISD with cGAS, the downstream pathway was triggered as STING disassociated from its location at the endoplasmic reticulum. Upon direct stimulation of pDCs by STING agonist 2'3' cGAMP or dsDNA, pDC-s produced type I, and type III IFN. Moreover, we documented that cGAS-STING-mediated IFN production is mediated by nuclear translocation of IRF3 whereas TLR9-mediated activation occurs through IRF7. Our data also indicate that pDC prestimulation of cGAS-STING dampened the TLR9-mediated IFN production. Furthermore, triggering of cGAS-STING induced expression of SOCS1 and SOCS3 in pDCs, indicating a possible autoinhibitory loop that impedes IFN production by pDCs. Thus, our study indicates that the cGAS-STING pathway exists in parallel to the TLR9-mediated DNA recognition in human pDCs with cross-talk between these two pathways.

Elevated CO2 modulates the effect of heat stress responses in Triticum aestivum by differential expression of isoflavone reductase-like (IRL) gene.

Two wheat genotypes forming high and low biomass (HB and LB), exhibiting differential expression of an isoflavone reductase-like (IRL) gene, and resulting in contrasting grain yield under heat stress field conditions, were analyzed in detail for their responses under controlled heat and elevated CO2 conditions. Significant differences in IRL expression between the two lines were hypothesized to be the basis of their differential performance under the tested conditions and their stress tolerance potential. By a holistic approach integrating advanced cell physiological phenotyping of the antioxidative and phytohormone system in spikes and leaves with measurements of ecophysiological and agronomic traits, the genetic differences of the genotypes in IRL expression were assessed. In response to heat and elevated CO2, the two genotypes showed opposite regulation of IRL expression, which was associated with cytokinin concentration, total flavonoid contents, activity of superoxide dismutase, antioxidant capacity and photosynthetic rate in leaves and cytokinin concentration and ascorbate peroxidase activity in spikes. Our study showed that IRL expression is associated with wheat yield performance under heat stress at anthesis, mediated by diverse physiological mechanisms. Hence, based on our results, the IRL gene is a promising candidate for developing genetic markers for breeding heat-tolerant wheat.

Population-dependent reproducible deviation from natural bread wheat genome in synthetic hexaploid wheat.

Sequence elimination is one of the main mechanisms that increases the divergence among homoeologous chromosomes after allopolyploidization to enhance the stability of recently established lineages, but it can cause a loss of some economically important genes. Synthetic hexaploid wheat (SHW) is an important source of genetic variation to the natural hexaploid wheat (NHW) genepool that has low genetic diversity. Here, we investigated the change between SHW and NHW genomes by utilizing a large germplasm set of primary synthetics and synthetic derivatives. Reproducible segment elimination (RSE) was declared if a large chromosomal chunk (>5 cM) produced no aligned reads in more than five SHWs. RSE in five genomic regions was the major source of variation between SHW and NHW. One RSE eliminated almost the complete short arm of chromosome 1B, which contains major genes for flour quality, disease resistance and different enzymes. The occurrence of RSE was highly dependent on the choice of diploid and tetraploid parental lines, their ancestral subpopulation and admixture, e.g. SHWs derived from Triticum dicoccon or from one of two Aegilops tauschii subpopulations were almost free of RSE, while highly admixed parents had higher RSE rates. The rate of RSE in synthetic derivatives was almost double that in primary synthetics. Genome-wide association analysis detected four loci with minor effects on the occurrence of RSE, indicating that both parental lines and genetic factors were affecting the occurrence of RSE. Therefore, pre-pre-breeding strategies should be applied before introducing SHW into pre-breeding programs to ensure genomic stability and avoid undesirable gene loss.

Storage lipid studies in tuberculosis reveal that foam cell biogenesis is disease-specific.

Foam cells are lipid-laden macrophages that contribute to the inflammation and tissue damage associated with many chronic inflammatory disorders. Although foam cell biogenesis has been extensively studied in atherosclerosis, how these cells form during a chronic infectious disease such as tuberculosis is unknown. Here we report that, unlike the cholesterol-laden cells of atherosclerosis, foam cells in tuberculous lung lesions accumulate triglycerides. Consequently, the biogenesis of foam cells varies with the underlying disease. In vitro mechanistic studies showed that triglyceride accumulation in human macrophages infected with Mycobacterium tuberculosis is mediated by TNF receptor signaling through downstream activation of the caspase cascade and the mammalian target of rapamycin complex 1 (mTORC1). These features are distinct from the known biogenesis of atherogenic foam cells and establish a new paradigm for non-atherogenic foam cell formation. Moreover, they reveal novel targets for disease-specific pharmacological interventions against maladaptive macrophage responses.

Toxoplasma gondii Inactivates Human Plasmacytoid Dendritic Cells by Functional Mimicry of IL-10.

Plasmacytoid dendritic cells (pDCs) are the major producers of IFN-α, an antiviral cytokine involved in immunomodulation and control of HIV type 1 replication, whereas Toxoplasma gondii is a life-threatening opportunistic infection in AIDS patients. During infection with HIV type 1, human pDCs decrease in circulation and remaining pDC produce lower amounts of IFN-α in response to viral stimulation. In this study, we investigated the impact of coinfection with T. gondii on the innate virus-directed responses of human pDCs. Using intracellular flow cytometry and fluorescence microscopy, we determined that T. gondii invaded but did not induce IFN-α or TNF-α in human pDC. However, T. gondii inhibited IFN-α and TNF-α produced in response to HSV and HIV, thus functionally inactivating pDC. IFN-α production was inhibited only in cells infected by T. gondii, which inhibited neither uptake of GFP-HSV nor localization of TLR9 in CD71+ endosomes, directing us to investigate downstream events. Using imaging flow cytometry, we found that both T. gondii and IL-10 inhibited virus-induced nuclear translocation, but not phosphorylation, of IFN response factor 7. Blockade of IFN response factor 7 nuclear translocation and inhibition of the IFN-α response was partially reversed by a deficiency in the T. gondii-derived ROP16 kinase, known to directly phosphorylate STAT3, a critical mediator of IL-10's anti-inflammatory effects. Taken together, our results indicate that T. gondii suppresses pDC activation by mimicking IL-10's regulatory effects through an ROP16 kinase-dependent mechanism. Our findings further imply a convergent mechanism of inhibition of TLR signaling by T. gondii and IL-10 and suggest potential negative consequences of HIV/T. gondii coinfection.

Molecular Markers Associated with Agro-Physiological Traits under Terminal Drought Conditions in Bread Wheat.

Terminal drought stress poses a big challenge to sustain wheat grain production in rain-fed environments. This study aimed to utilize the genetically diverse pre-breeding lines for identification of genomic regions associated with agro-physiological traits at terminal stage drought stress in wheat. A total of 339 pre-breeding lines panel derived from three-way crosses of 'exotics × elite × elite' lines were evaluated in field conditions at Obregon, Mexico for two years under well irrigated as well as drought stress environments. Drought stress was imposed at flowering by skipping the irrigations at pre and post anthesis stage. Results revealed that drought significantly reduced grain yield (Y), spike length (SL), number of grains spikes-1 (NGS) and thousand kernel weight (TKW), while kernel abortion (KA) was increased. Population structure analysis in this panel uncovered three sub-populations. Genome wide linkage disequilibrium (LD) decay was observed at 2.5 centimorgan (cM). The haplotypes-based genome wide association study (GWAS) identified significant associations of Y, SL, and TKW on three chromosomes; 4A (HB10.7), 2D (HB6.10) and 3B (HB8.12), respectively. Likewise, associations on chromosomes 6B (HB17.1) and 3A (HB7.11) were found for NGS while on chromosome 3A (HB7.12) for KA. The genomic analysis information generated in the study can be efficiently utilized to improve Y and/or related parameters under terminal stage drought stress through marker-assisted breeding.

Characterization of QTLs for Seedling Resistance to Tan Spot and Septoria Nodorum Blotch in the PBW343/Kenya Nyangumi Wheat Recombinant Inbred Lines Population.

Tan spot (TS) and Septoria nodorum blotch (SNB) induced by Pyrenophora tritici-repentis and Parastagonospora nodorum, respectively, cause significant yield losses and adversely affect grain quality. The objectives of this study were to decipher the genetics and map the resistance to TS and SNB in the PBW343/Kenya Nyangumi (KN) population comprising 204 F6 recombinant inbred lines (RILs). Disease screening was performed at the seedling stage under greenhouse conditions. TS was induced by P. tritici-repentis isolate MexPtr1 while SNB by P. nodorum isolate MexSN1. Segregation pattern of the RILs indicated that resistance to TS and SNB in this population was quantitative. Diversity Array Technology (DArTs) and simple sequence repeats (SSRs) markers were used to identify the quantitative trait loci (QTL) for the diseases using inclusive composite interval mapping (ICIM). Seven significant additive QTLs for TS resistance explaining 2.98 to 23.32% of the phenotypic variation were identified on chromosomes 1A, 1B, 5B, 7B and 7D. For SNB, five QTLs were found on chromosomes 1A, 5A, and 5B, explaining 5.24 to 20.87% of the phenotypic variation. The TS QTL on 1B chromosome coincided with the pleiotropic adult plant resistance (APR) gene Lr46/Yr29/Pm39. This is the first report of the APR gene Lr46/Yr29/Pm39 contributing to TS resistance.

Bacteremia by Chryseobacterium indologenes in a Patient with Lung Cancer: A Clinical and Microbiological Investigation.

We present a case of bacteremia by an unsual, instrinsically multidrug resistant organism, Chryseobacterium indologenes in a 59 year old gentleman with squamous cell carcinoma of lung with multiple metastasis. Despite of treating as per sensitivity report after isolatingChryseobacterium indologenes, patient could not be survived. The pathogenicity and predictability of the organism towards antibiotics, bothin vivo and in vitro needs further research. HOW TO CITE THIS ARTICLE: Bhagawati G, Bhardwaj A et al. Bacteremia by Chryseobacterium Indologenes in a Patient with Lung Cancer: A Clinical and Microbiological Investigation. Indian J Crit Care Med 2019;23(3):157-159.

Cytokine profile in prediction of acute lung injury in patients with acute pancreatitis.

OBJECTIVES: To study the role of cytokines in prediction of acute lung injury (ALI) in acute pancreatitis. METHODS: Levels of TNFα, IL-6, IL-10, IL-8 and IL-1ß were measured in 107 patients at presentation and at 72 h in patients who developed acute lung injury. A model was devised to predict development of ALI using cytokine levels and SIRS score. RESULTS: The levels of TNF α (p < 0.0001), IL-6 (p < 0.0001), IL-8 (p < 0.0001) and IL-1ß (p < 0.0001) were significantly higher in the ALI group. IL-10 levels were significantly lower in persistent ALI (p-ALI) than in transient ALI (t-ALI) patients (p < 0.038). p-ALI group had significant rise of TNFα (p = 0.019) and IL-1ß (p = 0.001) while t-ALI group had significant rise of only IL-1ß (p = 0.044) on day 3 vs day 1. Combined values of IL-6 and IL-8 above 251 pg/ml had sensitivity of 90.9% and a specificity of 100% to predict future development of ALI. Composite marker-I (IL6 ≥ 80 pg/ml + SIRS) yielded sensitivity and specificity of 73% and 98% whereas composite marker-II (IL8 ≥ 100 pg/ml + SIRS) yielded sensitivity and specificity of 73% and 95% to predict future ALI. CONCLUSIONS: IL-6 and IL-8 can predict future development of ALI. When they are combined with SIRS, they can be used as comprehensive composite markers.

Entanglement and Nonlocality in Infinite 1D Systems.

We consider the problem of detecting entanglement and nonlocality in one-dimensional (1D) infinite, translation-invariant (TI) systems when just near-neighbor information is available. This issue is deeper than one might think a priori, since, as we show, there exist instances of local separable states (classical boxes) which admit only entangled (nonclassical) TI extensions. We provide a simple characterization of the set of local states of multiseparable TI spin chains and construct a family of linear witnesses which can detect entanglement in infinite TI states from the nearest-neighbor reduced density matrix. Similarly, we prove that the set of classical TI boxes forms a polytope and devise a general procedure to generate all Bell inequalities which characterize it. Using an algorithm based on matrix product states, we show how some of them can be violated by distant parties conducting identical measurements on an infinite TI quantum state. All our results can be easily adapted to detect entanglement and nonlocality in large (finite, not TI) 1D condensed matter systems.

Characterization of Architectural Distortion in Mammograms Based on Texture Analysis Using Support Vector Machine Classifier with Clinical Evaluation.

Architecture distortion (AD) is an important and early sign of breast cancer, but due to its subtlety, it is often missed on the screening mammograms. The objective of this study is to create a quantitative approach for texture classification of AD based on various texture models, using support vector machine (SVM) classifier. The texture analysis has been done on the region of interest (ROI) selected from the original mammogram. A comprehensive analysis has been done on samples from three databases; out of which, two data sets are from the public domain, and the third data set is for clinical evaluation. The public domain databases are IRMA version of digital database for screening mammogram (DDSM) and Mammographic Image Analysis Society (MIAS). For clinical evaluation, the actual patient's database has been obtained from ACE Healthways, Diagnostic Centre Ludhiana, India. The significant finding of proposed study lies in appropriate selection of the size of ROIs. The experiments have been done on fixed size of ROIs as well as on the ground truth (variable size) ROIs. Best results pertain to an accuracy of 92.94 % obtained in case of DDSM database for fixed-size ROIs. In case of MIAS database, an accuracy of 95.34 % is achieved in AD versus non-AD (normal) cases for ground truth ROIs. Clinically, an accuracy of 88 % was achieved for ACE dataset. The results obtained in the present study are encouraging, as optimal result has been achieved for the proposed study in comparison with other related work in the same area.

Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity.

MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in age-dependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKT-mediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggesting MERTK may preferentially interface with phosphatidylserine. Consistent with this idea, knockdown of MERTK in breast cancer cells MDA-MB 231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by soluble TAM receptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTK-driven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.

A high density GBS map of bread wheat and its application for dissecting complex disease resistance traits.

BACKGROUND: Genotyping-by-sequencing (GBS) is a high-throughput genotyping approach that is starting to be used in several crop species, including bread wheat. Anchoring GBS tags on chromosomes is an important step towards utilizing them for wheat genetic improvement. Here we use genetic linkage mapping to construct a consensus map containing 28644 GBS markers. RESULTS: Three RIL populations, PBW343 × Kingbird, PBW343 × Kenya Swara and PBW343 × Muu, which share a common parent, were used to minimize the impact of potential structural genomic variation on consensus-map quality. The consensus map comprised 3757 unique positions, and the average marker distance was 0.88 cM, obtained by calculating the average distance between two adjacent unique positions. Significant variation of segregation distortion was observed across the three populations. The consensus map was validated by comparing positions of known rust resistance genes, and comparing them to wheat reference genome sequences recently published by the International Wheat Genome Sequencing Consortium, Rye and Ae. tauschii genomes. Three well-characterized rust resistance genes (Sr58/Lr46/Yr29, Sr2/Yr30/Lr27, and Sr57/Lr34/Yr18) and 15 published QTLs for wheat rusts were validated with high resolution. Fifty-two per cent of GBS tags on the consensus map were successfully aligned through BLAST to the right chromosomes on the wheat reference genome sequence. CONCLUSION: The consensus map should provide a useful basis for analyzing genome-wide variation of complex traits. The identified genes can then be explored as genetic markers to be used in genomic applications in wheat breeding.