Summary
Throughout evolution, organisms have developed means to contain wounds by simultaneously limiting bleeding and eliminating pathogens and damaged host cells via the recruitment of innate ...defense mechanisms. Disease emerges when there is unchecked activation of innate immune and/or coagulation responses. A key component of innate immunity is the complement system. Concurrent excess activation of coagulation and complement – two major blood‐borne proteolytic pathways – is evident in numerous diseases, including atherosclerosis, diabetes, venous thromboembolic disease, thrombotic microangiopathies, arthritis, cancer, and infectious diseases. Delineating the cross‐talk between these two cascades will uncover novel therapeutic insights.
Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic ...progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small-molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1-110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.
Intestinal helminth infection can impair host resistance to co-infection with enteric bacterial pathogens. However, it is not known whether helminth drug-clearance can restore host resistance to ...bacterial infection. Using a mouse helminth-Salmonella co-infection system, we show that anthelmintic treatment prior to Salmonella challenge is sufficient to restore host resistance to Salmonella. The presence of the small intestine-dwelling helminth Heligmosomoides polygyrus at the point of Salmonella infection supports the initial establishment of Salmonella in the small intestinal lumen. Interestingly, if helminth drug-clearance is delayed until Salmonella has already established in the small intestinal lumen, anthelmintic treatment does not result in complete clearance of Salmonella. This suggests that while the presence of helminths supports initial Salmonella colonization, helminths are dispensable for Salmonella persistence in the host small intestine. These data contribute to the mechanistic understanding of how an ongoing or prior helminth infection can affect pathogenic bacterial colonization and persistence in the mammalian intestine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Until recently, Plasmodium knowlesi malaria in humans was misdiagnosed as Plasmodium malariae malaria. The objectives of the present study were to determine the geographic distribution of ...P. knowlesi malaria in the human population in Malaysia and to investigate 4 suspected fatal cases. Methods. Sensitive and specific nested polymerase chain reaction was used to identify all Plasmodium species present in (1) blood samples obtained from 960 patients with malaria who were hospitalized in Sarawak, Malaysian Borneo, during 2001–2006; (2) 54 P. malariae archival blood films from 15 districts in Sabah, Malaysian Borneo (during 2003–2005), and 4 districts in Pahang, Peninsular Malaysia (during 2004–2005); and (3) 4 patients whose suspected cause of death was P. knowlesi malaria. For the 4 latter cases, available clinical and laboratory data were reviewed. Results. P. knowlesi DNA was detected in 266 (27.7%) of 960 of the samples from Sarawak hospitals, 41 (83.7%) of 49 from Sabah, and all 5 from Pahang. Only P. knowlesi DNA was detected in archival blood films from the 4 patients who died. All were hyperparasitemic and developed marked hepatorenal dysfunction. Conclusions. Human infection with P. knowlesi, commonly misidentified as the more benign P. malariae, are widely distributed across Malaysian Borneo and extend to Peninsular Malaysia. Because P. knowlesi replicates every 24 h, rapid diagnosis and prompt effective treatment are essential. In the absence of a specific routine diagnostic test for P. knowlesi malaria, we recommend that patients who reside in or have traveled to Southeast Asia and who have received a “P. malariae” hyperparasitemia diagnosis by microscopy receive intensive management as appropriate for severe falciparum malaria.
Context. We describe the new Swedish-ESO PI Instrument for APEX (SEPIA) receiver, which was designed and built by the Group for Advanced Receiver Development (GARD), at Onsala Space Observatory (OSO) ...in collaboration with ESO. It was installed and commissioned at the APEX telescope during 2015 with an ALMA Band 5 receiver channel and updated with a new frequency channel (ALMA Band 9) in February 2016. Aim. This manuscript aims to provide, for observers who use the SEPIA receiver, a reference in terms of the hardware description, optics and performance as well as the commissioning results. Methods. Out of three available receiver cartridge positions in SEPIA, the two current frequency channels, corresponding to ALMA Band 5, the RF band 158–211 GHz, and Band 9, the RF band 600–722 GHz, provide state-of-the-art dual polarization receivers. The Band 5 frequency channel uses 2SB SIS mixers with an average SSB noise temperature around 45 K with IF (intermediate frequency) band 4–8 GHz for each sideband providing total 4 × 4 GHz IF band. The Band 9 frequency channel uses DSB SIS mixers with a noise temperature of 75–125 K with IF band 4–12 GHz for each polarization. Results. Both current SEPIA receiver channels are available to all APEX observers.
Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still ...die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.
Eosinophils are present in the thymus of mammals, yet their function at this site during homeostatic development is unknown. We used flow cytometry to determine the abundance and phenotype of ...eosinophils (here defined as SSchigh SiglecF+ CD11b+ CD45+ cells) in the thymus of mice during the neonatal period, the later postnatal period and into adulthood. We show that both the total number of thymic eosinophils and their frequency amongst leukocytes increase over the first two weeks of life, and that their accumulation in the thymus is dependent on the presence of an intact bacterial microbiota. We report that thymic eosinophils express the IL-5R (CD125), CD80 and indoleamine 2, 3-dioxygenase (IDO), and that subsets of thymic eosinophils express CD11c and MHCII. We found that the frequency of MHCII-expressing thymic eosinophils increases over the first two weeks of life, and that during this early life period the highest frequency of MHCII-expressing thymic eosinophils is located in the inner medullary region. These data suggest a temporal and microbiota-dependent regulation of eosinophil abundance and functional capabilities in the thymus.
We present the results of a four-month campaign searching for low-frequency radio transients near the North Celestial Pole with the Low-Frequency Array (LOFAR), as part of the Multifrequency Snapshot ...Sky Survey (MSSS). The data were recorded between 2011 December and 2012 April and comprised 2149 11-min snapshots, each covering 175 deg2. We have found one convincing candidate astrophysical transient, with a duration of a few minutes and a flux density at 60 MHz of 15–25 Jy. The transient does not repeat and has no obvious optical or high-energy counterpart, as a result of which its nature is unclear. The detection of this event implies a transient rate at 60 MHz of
$3.9^{+14.7}_{-3.7}\times 10^{-4}$
d−1 deg−2, and a transient surface density of 1.5 × 10−5 deg−2, at a 7.9-Jy limiting flux density and ∼10-min time-scale. The campaign data were also searched for transients at a range of other time-scales, from 0.5 to 297 min, which allowed us to place a range of limits on transient rates at 60 MHz as a function of observation duration.
The basic molecular mechanisms governing how endothelial cells, periendothelial cells and matrix molecules interact with each other and with numerous growth factors and receptors, to form blood ...vessels have been presented. The many insights gained from this basic knowledge are being extended to further understand pathological angiogenesis associated with disorders such as arterial stenosis, myocardial ischemia, atherosclerosis, allograft transplant stenosis. wound healing and tissue repair. As a result, novel angiogenic and anti-angiogenic molecules are rapid-ly entering the clinic, with the promise of relief from a host of medical disorders.
Introduction
Syphilis is a chronic, multi-stage infection caused by the extracellular bacterium
Treponema pallidum
ssp.
pallidum
.
Treponema pallidum
widely disseminates through the vasculature, ...crosses endothelial, blood–brain and placental barriers, and establishes systemic infection. Although the capacity of
T. pallidum
to traverse the endothelium is well-described, the response of endothelial cells to
T. pallidum
exposure, and the contribution of this response to treponemal traversal, is poorly understood.
Methods
To address this knowledge gap, we used quantitative proteomics and cytokine profiling to characterize endothelial responses to
T. pallidum
.
Results
Proteomic analyses detected altered host pathways controlling extracellular matrix organization, necroptosis and cell death, and innate immune signaling. Cytokine analyses of endothelial cells exposed to
T. pallidum
revealed increased secretion of interleukin (IL)-6, IL-8, and vascular endothelial growth factor (VEGF), and decreased secretion of monocyte chemoattractant protein-1 (MCP-1).
Discussion
This study provides insight into the molecular basis of syphilis disease symptoms and the enhanced susceptibility of individuals infected with syphilis to HIV co-infection. These investigations also enhance understanding of the host response to
T. pallidum
exposure and the pathogenic strategies used by
T. pallidum
to disseminate and persist within the host. Furthermore, our findings highlight the critical need for inclusion of appropriate controls when conducting
T. pallidum
-host cell interactions using
in vitro-
and
in vivo-
grown
T. pallidum
.
PDF
