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In this paper the space-fractional Schrodinger equations with singular potentials are studied. Delta like or even higher-order singularities are allowed. By using the regularising techniques, we introduce a family of ‘weakened’ solutions, calling them very weak solutions. The existence, uniqueness and consistency results are proved in an appropriate sense. Numerical simulations are done, and a particles accumulating effect is observed in the singular cases. From the mathematical point of view a “splitting of the strong singularity” phenomena is also observed.

This study was designed to investigate the relationship between Delta-like 1 homolog (DLK1) polymorphisms and the occurrence of antituberculosis drug-induced hepatotoxicity (ATDH) in the Western Ch...

In this paper, we give a correct definition of the Laplace operator with delta-like potentials. Correctly solvable pointwise perturbation is investigated and formulas of resolvent are described. We study some properties of the resolvent. In particular, we obtain Krein formula for these resolvents., Comment: 20

The migration and invasion of trophoblasts during early pregnancy in known to play an important role in placental development, which ensures the oxygen and nutrients to the fetus. Accumulating evidences suggest that Delta-Like 4(DLL4)-Notch signaling may be involved in the process of trophoblast regulation. However, the potential role of DLL4-Notch signaling as well as its molecular mechanism in trophoblast controlling has not been fully studied. This study is designed to investigate the effects of DLL4-Notch signaling on trophoblast functions in human extravillous trophoblast cell line, HTR-8/SVneo. The possible molecular mechanism of DLL4-Notch signaling in trophoblast was also explored. We observed that activation of DLL4-Notch signaling enhanced cell migration and invasion ability while blockage of DLL4-Notch signaling impaired. Control of DLL4-Notch signaling did not affect cell viability. The expression of EphrinB2 was regulated by DLL4-Notch signaling. In addition, up-regulation of EphrinB2 resulted in the similar effects on trophoblast cell functions as DLL4-Notch signaling activation. Moreover, activation of DLL4-Notch signaling reversed the negative impact of EphrinB2 knock-down on trophoblasts migration and invasion. Our study suggested that DLL4-Notch signaling involved in the regulation of trophoblast migration and invasion, which may be induced by direct regulation of EphrinB2 expression.

Hepatitis D (delta, δ) virus (HDV) was discovered more than 40 years ago, but the understanding of its origin and evolution is poor. This is mainly due to the lack, until recently, of data on the existence of any viruses similar to HDV. The discovery in recent years of sequences of new delta-like agents in a wide range of vertebrate (Vertebrata) and invertebrate (Invertebrata) species has facilitated a revision of views on the origin of HDV and contributed to understanding the place of this unique virus among other animals’ viral agents. The purpose of this review is to analyze the latest published data on new delta-like agents and their biological characteristics.

Herein we report the construction of a nanoparticle-based drug delivery system which targets a key regulator in tumour angiogenesis. We exploit a Variable New Antigen Receptor (VNAR) domain, conjugated using site-specific chemistry, to direct poly lactic acid-co-glycolic acid-polyethylene glycol (PLGA-PEG) nanoparticles to delta like canonical Notch ligand 4 (DLL4). The importance of site-specific chemistry is demonstrated.

Vitamin D effects on bone and mineral metabolism are well recognized, and its anti-inflammatory actions are gaining particular interest. Delta-like 1 (DLK1) is a protein, expressed by progenitor cells of different tissues, and increases the size of progenitor cell population during the inflammatory phase of tissue regeneration. DLK1 also plays a role in energy metabolism as it antagonizes insulin signaling in bone. In this one-year randomized clinical trial of overweight elderly individuals that received either 600 or 3750 IU daily cholecalciferol we assessed the effect of vitamin D supplementation on pre-specified secondary outcomes: DLK1, leptin, adiponectin, C-Reactive Protein (CRP) and Vascular Cell Adhesion Molecule (VCAM). We also examined correlations between DLK1 and bone (BMD, bone markers), fat (adipokines, body composition), insulin sensitivity and inflammatory markers. Multivariate analyses were conducted to further explore these associations. Overall, there was a significant increase in serum DLK1 and leptin and a decrease in VCAM, but no change in CRP, after 12 months of vitamin D supplementation. DLK1 was negatively correlated with BMD and positively correlated with bone markers, associations that persisted after adjusting for age, gender and BMI. DLK1 was also positively associated with indices of insulin resistance and negatively with indices of insulin sensitivity. Correlations between DLK1 and fat parameters, such as adipokines, and DXA derived fat mass were less consistent. There were no correlations between DLK1 and inflammatory markers. In conclusion, twelve months supplementation of vitamin D3 increased serum DLK1. DLK1 was negatively associated with indices of bone health and fuel metabolism, and with 1,25(OH)2D levels. Similar to the role of DLK1 in animal models, our findings support the hypothesis that DLK1 can be targeted to regulate bone and energy metabolism and develop drugs to improve BMD and insulin sensitivity. However, further studies are needed to explore the role of DLK1 and its relationship to vitamin D metabolites in vivo.

Delta-like (Dll) 1 and Dll4 differently function as Notch ligands in a context-dependent manner. As these ligands share structural properties, the molecular basis for their functional difference is poorly understood. Here, we investigated the superiority of Dll4 over Dll1 with respect to induction of T cell development using a domain-swapping approach in mice. The DOS motif, shared by Notch ligands—except Dll4—contributes to enhancing the activity of Dll for signal transduction. The module at the N-terminus of Notch ligand (MNNL) of Dll4 is inherently advantageous over Dll1. Molecular dynamic simulation revealed that the loop structure in MNNL domain of Dll1 contains unique proline residues with limited range of motion. The Dll4 mutant with Dll1-derived proline residues showed reduced activity. These results suggest that the loop structure—present within the MNNL domain—with a wide range of motion ensures the superiority of Dll4 and uniquely contributes to the triggering of Notch signaling.

Natural killer (NK) cells are an essential component of human innate immune, with a remarkable ability to provide protection against cancer and viral infections. NK-based immune therapy has several advantages over T cell immunotherapy: NK cells do not cause graft-versus-host disease and do not induce T-cell driven inflammatory cytokine storm. Moreover, unlike T cell, NK cells do not need prior sensitization, specific antigen recognition and clonal expansion for their cytotoxic effector functions and they can rapidly trigger cytotoxicity against their targets. NK cells can be expanded from multiple sources including peripheral blood mononuclear cells (PBMCs), umbilical cord blood (UCB), or mobilized peripheral blood (mPB) CD34 + cells. Yet the lack of efficient methods for in-vitro NK cell expansion, purification and genetic modification limits the clinical use of NK cell therapy. We aimed at developing a simple, scalable and clinically feasible technique for therapeutic NK cell production based on our recently published culture system that can produce large numbers of unmodified or genetically modified CD7 + T lymphoid progenitors from UCB and mPB CD34 + cells in 7 days on immobilized Notch-ligand delta-like 4 recombinant protein DLL4. Since T cells and NK cells share a common T/NK cell progenitor, we are interested to investigate the NK cell potential of DLL4 culture-generated T lymphoid progenitors. Firstly, we tested the NK cell potential of the transduced or non- transduced UCB or mPB CD34 +-derived progenitors from DLL4 culture by subjecting them to a feeder free NK cell differentiation for 3 weeks. HSPC-derived progenitors can be efficiently transduced with lentiviral vectors (average transduction efficacy: 50%). The transduced/ non-transduced progenitors were able to efficiently differentiate into NK (CD3 -CD56 +) cells beginning from one week of differentiation, reaching a frequencies of NK cells of >90% without any detectable T cell contamination at week 2. The phenotypic characterization of the NK cells demonstrates the presence of activation receptors such as NKG2D, DNAM-1, NKp30, NKp44 and NKp46 while lacking the inhibitory receptors like KLRG1, KIR2DL2/DL3 and KIR3DL1/DL2. Interestingly, these cells express the transcription factors known to be essential for NK cell differentiation and functions such as Eomes, T-bet and ID2. Additionally, the CB or mPB HSPC-derived NK cells (both transduced/ non-transduced) express perforin and granzyme B reflecting their ability to show cytotoxic potential. Further, the stimulation of UCB or mPB derived NK cells with myelogenous leukemia cell line K562 cells showed high level of degranulation, which is the key step for Interferon gamma (IFNg) induction. An analysis cytotoxic activity of the CB or mPB derived NK cells against K562 cells and monocytic leukemia cell line THP1 cells showed their ability to efficiently kill K562 cells compared to THP1 cells, however the UCB derived NK cells were highly cytotoxic compared to mPB derived NK cells. These data suggests that our DLL4 culture system, along with feeder-free NK cell differentiation is a unique combination that is able to give rise to high number of pure NK cell population with high cytotoxic potential. These results lay a foundation towards an easier approach to NK cell therapy for effective treatment of cancers and viral infections, which will be developed in collaboration with Smart Immune Inc. Disclosures Cavazzana: Smart Immune: Other: co-founder.

The formation processes of a new delta-like object with a hydromorphic landscape in the upper part of the Kapchagai Reservoir on the Ili R.—an internal delta—are considered. The quantitative characteristics of the development of this delta are evaluated using data of Landsat-2, 5, and 7 space images over period 1975–2012. These processes were found to accelerate considerably in the wet year of 2012, and intense under-flooding and salinization of nearby lands were revealed in the Chilikskii alluvial fan on the southern wing of the Kapchagai delta. A consequence of this accumulative process was found to be the development of planar channel deformations of the Ili R. 30 km upstream the Kapchagai delta.

During somite segmentation, the expression of clock genes such as Hes7 oscillates synchronously in the presomitic mesoderm (PSM). This synchronous oscillation slows down in the anterior PSM, leading to wave-like propagating patterns from the posterior to anterior PSM. Such dynamic expression depends on Notch signaling and is critical for somite formation. However, it remains to be determined how slowing oscillations in the anterior PSM are controlled, and whether the expression of the Notch ligand Delta-like1 (Dll1) oscillates on the surface of individual PSM cells, as postulated to be responsible for synchronous oscillation. Here, by using Dll1 fluorescent reporter mice, we performed live-imaging of Dll1 expression in PSM cells and found the oscillatory expression of Dll1 protein on the cell surface regions. Furthermore, a comparison of live-imaging of Dll1 and Hes7 oscillations revealed that the delay from Dll1 peaks to Hes7 peaks increased in the anterior PSM, suggesting that the Hes7 response to Dll1 becomes slower in the anterior PSM. These results raise the possibility that Dll1 protein oscillations on the cell surface regulate synchronous Hes7 oscillations, and that the slower response of Hes7 to Dll1 leads to slower oscillations in the anterior PSM.

In the original publication of the article, there is an error in one of the citations in the Discussion section.

ObjectiveAngiogenesis depends on interaction between a variety of promoting and inhibiting factors, and is known to involve vascular endothelial growth factor (VEGF) A and the Notch signaling pathway. The present study investigated the expression of Notch ligand delta-like ( DLL) 4 (Drosophila), and VEGFA in colon cancer and colorectal adenoma tissue, and the association with tumour angiogenesis.MethodsProtein level DLL4, VEGFA and CD34 molecule ( CD34) expression was detected immunohistochemically in tissue sections from patients with colon cancer and colorectal adenoma.ResultsOut of 80 cases (35 with colon cancer, 45 with colorectal adenoma) DLL4 and VEGFA expression was closely related to tumour diameter, clinical stage, histological grade and lymph node metastasis. DLL4 expression was significantly higher in colon cancer tissue than colorectal adenoma tissue.ConclusionHigh levels of DLL4 expression were closely related to metastasis and prognosis in patients with colon cancer. The results of the present study support the conclusion that prognosis of colon cancer is significantly correlated with angiogenesis.

Delta-like 4 (Dll4)-mediated Notch signaling is critical for specifying T-cell fate, but how Dll4-mediated Notch signaling actually contributes to T-cell development in the thymus remains unclear. To explore this mechanism in the thymic three-dimensional structure, we performed fetal thymus organ culture using Dll4-deficient mice. DN1a/b+DN2mt cells, which had not yet committed to either the αβ T or γδ T/NK cell lineage, did not differentiate into the αβ T-cell lineage in Dll4-deficient thymus despite the lack of cell fate conversion into other lineages. However, DN3 cells efficiently differentiated into a later developmental stage of αβ T cells, the double-positive (DP) stage, although the proliferation was significantly impaired during the differentiation process. These findings suggest that the requirement for Notch signaling differs between the earliest and pre-TCR-bearing precursors and that continued Notch signaling is required for proper differentiation with active proliferation of αβ T lineage cells. Furthermore, we showed that Notch signaling increased the c-Myc expression in DN3 cells in the thymus and that its overexpression rescued the proliferation and differentiation of DN3 cells in the Dll4-null thymus. Therefore, c-Myc plays a central role in the transition from stage DN3 to DP as a downstream target of Notch signaling.

Objective To investigate the diagnostic value of Delta-like 1 ligand (DLL1) in cerebrospinal fluid (CSF) and serum, in tuberculous meningitis (TBM). Methods Patients with a definite diagnosis of central nervous system infection (TBM, viral meningitis/encephalitis or bacterial meningitis) were prospectively enrolled alongside patients with intracranial metastatic tumour and patients with no diagnosis (who served as controls). DLL1 content in CSF and serum was measured quantitatively by enzyme-linked immunosorbent assay; analyses were blinded. Results A total of 173 patients were enrolled: 62 with TBM; 38 with viral meningitis/encephalitis; 26 with bacterial meningitis; 17 with intracranial metastatic tumour; 30 with no diagnosis. CSF DLL1 content was highest for TBM; there were no differences in CSF DLL1 between the other groups. Serum DLL1 content was highest for the TBM and intracranial metastatic tumour groups, with significant differences between the TBM group and the viral meningitis/encephalitis, bacterial meningitis and nondiagnosed groups. There were no differences in serum DLL1 between the viral meningitis/encephalitis, bacterial meningitis and nondiagnosed groups, or between the TBM group and the tumour group. Conclusion As a new biomarker, DLL1 may be of great clinical importance in the diagnosis of TBM.

The thymus provides a unique and essential microenvironment for T-cell precursors to develop into mature functionally competent T lymphocytes. Ageing causes architectural changes in the thymus resulting in a loss of thymic epithelial space required for thymopoiesis - a process known as thymic involution. Additionally, cytoablative regimens used to treat malignancies also destroy thymic architecture. The net result of both processes is diminished thymic output and function that may lead to impaired immunity. Thus, immunocompromised individuals would benefit from strategies aimed at enhancing T-cell reconstitution.Here we discuss strategies such as the use of sex steroid ablation, keratinocyte growth factor, interleukin-7, and in-vitro-generated progenitor T cells as candidates for restoring T-cell immunity. Using various animal models of ageing or hematopoietic stem cell transplantation, these strategies have been shown to restore thymic architecture and cellularity, resulting in increased output and T-cell function in the periphery.These candidate approaches are currently being tested in clinical trials, with preliminary evidence showing encouraging effects on T-cell reconstitution. Nevertheless, although these strategies show clear promise in animal models, and in early human trials, further data are needed to determine their efficacy in patients.

Angiogenesis is regulated by the local balance between angiogenesis stimulators and inhibitors. A number of endogenous angiogenesis inhibitors have been found in the body. The origin of these inhibitors is mostly extrinsic to the vasculature. Recently however, endothelial cells themselves have been found to produce angiogenesis inhibitors including delta-like 4 and vasohibin 1. These intrinsic factors are thought to regulate angiogenesis by an autoregulatory or negative-feedback mechanism. This review focuses on such negative regulators of angiogenesis produced by endothelial cells.

Background: Our study characterizes Delta-like 1 (Dll1) in the adult mouse, particularly in normal versus injured vasculature, with the aid of the transgenic Dll1LacZ line. Methods: Normal mouse adult tissues or those from the Dll1LacZ reporter line were analyzed for Dll1 expression and promoter activity. Vascular tissue was analyzed before and after carotid artery ligation. Results: In wild-type mice, Dll1 transcript expression was widespread. Similarly, the Dll1LacZ reporter had β-galactosidase activity detectable in the cerebellum, cerebrum, spinal cord, liver, lung and cornea, although the normal adult vasculature had no reporter expression. Following arterial ligation, there was acute induction of Dll1LacZ reporter expression, both in the ligated left carotid artery, and the uninjured right contralateral artery. Expression returned to low/undetectable levels 4–10 days after arterial ligation. Conclusion: The expression of Dll1 in the adult mouse is more widespread than previously realized, although not in resting large arteries in the adult mouse. Following arterial injury, Dll1 promoter activity is induced selectively in the endothelial cells of both the injured artery and the contralateral uninjured artery. Our results show that while overall expression in the adult mouse is widespread, Dll1 may be selectively expressed in the endothelium of injured vasculature, similar to the endothelial-restricted expression of Dll4.

The DELTA robot and the manipulators derived from the DELTA robot are a relevant class of translational manipulators. In this paper, the mobility analysis of these parallel translational manipulators is developed in full. The manufacturing and mounting conditions that guarantee the pure translation of the platform are analytically derived. Moreover, it is demonstrated that these manipulators can assume singular configurations, called rotation singularities, in which they are no longer able to impose the platform translation. Finally, the geometric and analytic conditions that make it possible to find all the singular configurations of these manipulators are provided.

The Notch pathway plays a role in the processes of cell proliferation, differentiation, and apoptosis, which affect the development and function of various organs. Dendritic cells (DCs), as professional antigen-presenting cells (APCs), induce T cell activation and promote T cell differentiation by antigen stimulation. Research has shown that Notch ligand delta-like 4 (Dll4) in APCs is associated with stimulation of a Th1-type response. However, the regulatory roles of Dll4 in the activation and function of DCs have yet to be clearly elucidated. In this study, we demonstrated that activation of Dll4-pretreated bone marrow-derived DCs by performing ovalbumin (OVA) stimulation expressed a high level of interleukin (IL)-10 without diminishing IL-12 production. By contrast, the proinflammatory cytokines, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, decreased in Dll4-pretreated DCs by performing either lipopolysaccharide (LPS) or OVA stimulation. Compared to fully mature DCs, lower levels of MHC class II CD40 and higher levels of CD80 and CD86 molecules were expressed in these semi-mature like DCs. Dll4 Notch signaling also enhanced Notch ligand mRNA expression of Dll1, Dll4, and Jagged1 in DCs. Dll4-modified DCs exhibited a reduced capacity to stimulate the proliferation of OVA-specific CD4(+) T cells, but actively promoted large amounts of IL-10 production in these activated T cells. Furthermore, immunomodulatory effects of Dll4-modified DCs were examined in an established asthmatic animal model. After adoptive transfer of OVA-pulsed plus Dll4-pretreated DCs in OVA-immunized mice, OVA challenge induced lower OVA-specific immunoglobulin E (IgE) and higher IgG2a antibody production, lower eotaxin, keratinocyte-derived chemokine (KC), IL-5, and IL-13 release in bronchial alveolar lavage fluid, attenuated airway hyper-responsiveness, and promoted higher IL-10 and interferon (IFN)-γ production in the spleen. In summary, our findings elucidate the new role of Dll4 in the phenotype and function of DCs and provide a novel approach for manipulating T cell-driven deleterious immune diseases.

This paper treats the workspace analysis of a delta-like robot using a different placement of the actuators to improve the overall reachable workspace. Instead of having the actuators separated 120° between each other, it is proposed to provide different separations to create a greatly improved workspace suitable for custom applications. The general analysis of inverse and direct kinematics is explained and implemented in a software created to analyse this type of robot. Finally a comparison to prove the advantages of changing the angles between legs is shown.

The modified scalar boson propagator due to the presence of a hyperplane semi-transparent mirror is computed. From this, the classical interaction between static charges and the mirror is investigated employing delta-like potentials and sources. Although the calculations for hyperplane mirrors are performed in arbitrary dimensions, and in a completely general way, it is shown that the results give rise to the usual image method as a particular case. The interaction between a point-like mirror and a point-like source is also considered in $3+1$ dimensions, where a central $1/R^{2}$ attractive potential is also obtained as a special case., 8 pages, 1 figure

Propagation of light is studied in dielectric systems bearing a quasi-regular distribution of delta-like layers with different refraction indices. Special emphasis is made on the possibility to fabricate heterostructures based on porous silicon. The model calculation includes Fibonacci, Thue-Morse, and Period-Doubling porous-silicon-based systems. Experimental results are also presented for porous-silicon Thue-Morse dielectric layered systems.

Obesity occurs when an excessive dietary fat intake leads to expansion of adipose tissue, which mainly consists of adipocytes that arise from proliferating and differentiating adipose stem cells, the preadipocytes. Obesity is a consequence of both adipocyte hypertrophy and hyperplasia. Knowledge about preadipocyte differentiation is relatively well established, whereas the mechanism responsible for preadipocyte proliferation is incompletely understood and only in the early stage of comprehension. In this regard, we have recently identified that Delta-like 1 homolog (Dlk1) (also known as Preadipocyte factor 1 [Pref-1]) inhibits preadipocyte proliferation by regulating their entry into G1/S-phase. This novel disclosure, adding to the previous published data on Dlk1 repression of preadipocyte differentiation, has given us the chance to firmly place Dlk1 as a master regulator of preadipocyte homeostasis and adipose tissue expansion. Dlk1 manipulation may, therefore, open new perspectives in obesity treatments.

Angiogenesis is a complex multistep process by which new capillary structures arise from pre-existing vessels in response to angiogenic stimuli. This process plays a key role during tumorigenesis because the vascular network within the tumor enables malignant cells to establish distant metastases. Thus, it is not surprising that targeting tumors with angiogenesis-based therapy remains a significant area of preclinical and clinical studies. One of the most prominent factors considered as a promising target in such therapy is the Notch ligand Delta-like 4 (DLL4). Emerging evidence suggests that blockade of DLL4 in tumors results in excessive but non-productive angiogenesis which affects tumor growth, even in tumors which are insensitive to anti-VEGF therapy. Nevertheless, the careful evaluation of adverse effects on normal organs’ physiology in relation to therapeutic doses of DLL4 inhibitors will be critical for advancement of DLL4 blocking agents in clinical practice.

Delta–Notch signaling is a universal cell–cell communication pathway crucial for numerous developmental and physiological processes. Several proteins interact with and regulate the Notch pathway, including the E3 ubiquitin ligase Neuralized (Neur) that influences the stability and activity of Notch ligands. In mammals there are two homologs of Neur , Neur1 and Neur2, that both can interact with Notch ligands Delta-like1 and Jagged1. Here, we show that Neur2 , in contrast to Neur1 , is highly expressed during embryonic development of the brain and several non-neural tissues and its mRNA levels subside postnatally. In the hippocampal neurons of the adult brain Neur2 transcripts, in contrast to Neur1 , are excluded from the dendrites. Neur2 protein has a predominantly cytoplasmic localization. We also show that in addition to Delta-like1, Neur1 and Neur2 interact with another Notch ligand, Delta-like4.

SummaryNotch2 activation induced by Delta-like-1 (DL1) drives development of splenic marginal zone (MZ) B cells, an innate-like lineage that protects against sepsis. DL1 interacts with Notch2 weakly, but it is not known whether enhancement of DL1-induced Notch2 activation by Fringe glycosyltransferases is important for MZ B cell development. Furthermore, DL1-expressing cells that promote MZ B cell development have not been identified. We show that Lunatic Fringe (Lfng) and Manic Fringe (Mfng) cooperatively enhanced the DL1-Notch2 interaction to promote MZ B cell development. We also identified radio-resistant red pulp endothelial cells in the splenic MZ that express high amounts of DL1 and promoted MZ B generation. Finally, MZ B cell precursor competition for DL1 homeostatically regulated entry into the MZ B cell pool. Our study has revealed that the Fringe-Notch2 interaction has important functions in vivo and provides insights into mechanisms regulating MZ B cell development.