Enterotoxigenic
(ETEC) contributes significantly to the substantial burden of infectious diarrhea among children living in low- and middle-income countries. In the absence of a vaccine for ETEC, ...children succumb to acute dehydration as well as nondiarrheal sequelae related to these infections, including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches defined by a subset of ETEC pathovar-specific antigens known as colonization factors (CFs). To identify additional conserved immunogens unique to this pathovar, we employed an "open-aperture" approach to capture all potential conserved ETEC surface antigens, in which we mined the genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (
= 118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (
= 52) and toxin subunits. These arrays were then used to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this approach, we found that immune responses were largely constrained to a small number of antigens, including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children <2 years of age, both EtpA and a second antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing either
or
genes were significantly more likely to develop symptomatic disease. These studies support a role for antigens not presently targeted by vaccines (noncanonical) in virulence and the development of adaptive immune responses during ETEC infections. These findings may inform vaccine design efforts to complement existing approaches.
BACKGROUND Mammals have two types of full-grown oocytes: those with germinal vesicles (GVs) in which the chromatin is condensed and surrounds the nucleolus (surrounded-nucleolus (SN)-type) and those ...in which the chromatin is less condensed and does not surround the nucleolus (non-surrounded-nucleolus (NSN)-type). Although SN oocytes possess higher meiotic and developmental competence than NSN oocytes, the factors underlying this difference are unknown. METHODS AND RESULTS The GVs of murine SN and NSN oocytes were exchanged by nuclear transfer and the nucleus/cytoplasm of each reconstructed oocyte was classified as follows: SN/SN, NSN/SN, SN/NSN or NSN/NSN. After reconstruction, the meiotic maturation and preimplantation development of the oocytes were analysed. Few mature SN/NSN and NSN/NSN oocytes were observed (20–26%). In contrast, 88% of the NSN/SN oocytes matured; however, they rarely developed to the blastocyst stage after fertilization (4%), whereas most of the SN/SN oocytes matured (84%) and reached the blastocyst stage (83%). When the metaphase II (MII) plates of in vitro-matured NSN/SN oocytes were transferred into enucleated MII oocytes in which the contents of the SN-type GVs were spread into the cytoplasm, they completed full-term development. CONCLUSIONS The differences in meiotic and developmental competence between SN and NSN oocytes are determined by factors in the cytoplasm and nucleus, respectively. In addition, material(s) within SN-type GVs, and not the chromatin configuration itself, is essential for full-term development.
Bone marrow–derived mesenchymal stem/progenitor cells (BMSCs) are commonly used in regeneration therapy. The current primary source of BMSCs is the iliac crest; however, the procedure is associated ...with various burdens on the patient, including the risk of pain and infection. Hence, the possibility to collect BMSCs from other, more accessible, sources would be an attractive approach. It is well known that stem cells migrate from surrounding tissues and play important roles in wound healing. We thus hypothesized that stem/progenitor cells could be isolated from granulation tissue in the dental socket, and we subsequently collected granulation tissue from dog dental socket 3 d after tooth extraction. After enzyme digestion of the collected tissue, the cells forming colonies constituted the dental socket–derived stem/progenitor cells (dDSCs). Next, dDSCs were compared with dog BMSCs (dBMSCs) for phenotype characterization. A flow cytometric analysis showed that dDSCs were positive for CD44, CD90, and CD271 but negative for CD34 and CD45, similar to dBMSCs. dDSCs also exhibited osteogenic, adipogenic, and chondrogenic differentiation ability, similar to dBMSCs, with a higher capacity for colony formation, proliferation, and motility than dBMSCs. In addition, an in vivo ectopic bone formation assay showed that dDSCs and dBMSCs both induced hard tissue formation, although only dDSCs formed a fibrous tissue-like structure connected to the newly formed bone. Finally, we tested the ability of dDSCs to regenerate periodontal tissue in a one-wall defect model. The defects in the dDSC-transplanted group (β-TCP/PGA/dDSCs) were regenerated with cementum-like and periodontal ligament-like tissues and alveolar bone, whereas only bony tissue was observed in the control group (β-TCP/PGA). In conclusion, we identified and characterized a population of stem/progenitor cells in granulation tissue obtained from the dental socket that exhibited several characteristics similar to those of BMSCs. Dental sockets could therefore be a novel source for isolating stem/progenitor cells from bone.
Cosmic shear, that is weak gravitational lensing by the large-scale matter structure of the Universe, is a primary cosmological probe for several present and upcoming surveys investigating dark ...matter and dark energy, such as Euclid or WFIRST. The probe requires an extremely accurate measurement of the shapes of millions of galaxies based on imaging data. Crucially, the shear measurement must address and compensate for a range of interwoven nuisance effects related to the instrument optics and detector, noise in the images, unknown galaxy morphologies, colors, blending of sources, and selection effects. This paper explores the use of supervised machine learning as a tool to solve this inverse problem. We present a simple architecture that learns to regress shear point estimates and weights via shallow artificial neural networks. The networks are trained on simulations of the forward observing process, and take combinations of moments of the galaxy images as inputs. A challenging peculiarity of the shear measurement task, in terms of machine learning applications, is the combination of the noisiness of the input features and the requirements on the statistical accuracy of the inverse regression. To address this issue, the proposed training algorithm minimizes bias over multiple realizations of individual source galaxies, reducing the sensitivity to properties of the overall sample of source galaxies. Importantly, an observational selection function of these source galaxies can be straightforwardly taken into account via the weights. We first introduce key aspects of our approach using toy-model simulations, and then demonstrate its potential on images mimicking Euclid data. Finally, we analyze images from the GREAT3 challenge, obtaining competitively low multiplicative and additive shear biases despite the use of a simple training set. We conclude that the further development of suited machine learning approaches is of high interest to meet the stringent requirements on the shear measurement in current and future surveys. We make a demonstration implementation of our technique publicly available.
Summary
Background
Interleukin (IL)‐25 is a member of the IL‐17 family, which can promote and augment T‐helper (Th) type 2 responses. The expression of IL‐25 and its cognate receptor, IL‐25 receptor ...(IL‐25R), is upregulated and correlated with disease activity in Th2‐associated diseases.
Objectives
To examine the expression and function of IL‐25 in cutaneous T‐cell lymphoma (CTCL).
Methods
Expression and location of IL‐25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL‐25 production from normal human epidermal keratinocytes was assessed by quantitative reverse‐transcription real‐time polymerase chain reaction. Serum IL‐25 levels were measured by enzyme‐linked immunosorbent assay. The direct effect of IL‐25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sézary syndrome.
Results
IL‐25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL‐4 and IL‐13, and periostin induced IL‐25 expression by normal human epidermal keratinocytes. Serum IL‐25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL‐25R and its expression was augmented by stimulation with IL‐25. IL‐25 enhanced IL‐13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL‐25R and showed increase of IL‐13 production by IL‐25.
Conclusions
Th2 cytokines highly expressed in CTCL lesional skin induce IL‐25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2‐dominant microenvironment through the direct induction of IL‐13 by tumour cells.
What's already known about this topic?
Cutaneous T‐cell lymphomas (CTCLs), such as mycosis fungoides and Sézary syndrome, are regarded as T helper 2 (Th2)‐type diseases, and a Th2‐dominant microenvironment is beneficial for tumour cells.
Interleukin (IL)‐25 has the capacity to promote and augment Th2 responses and is associated with several Th2‐type diseases, including atopic dermatitis.
What does this study add?
Th2 cytokines highly expressed in lesional skin of CTCL induce IL‐25 production by epidermal keratinocytes.
IL‐25 directly induces IL‐13 production from CTCL tumour cells through signal transducer and activator of transcription 6 (STAT6) signalling pathways, resulting in the formation of a Th2‐dominant microenvironment.
What is the translational message?
Our results support the notion that activation of STAT6 is a key signalling pathway for the creation of a Th2‐dominant microenvironment in CTCL.
As the destruction of a Th2‐dominant microenvironment is effective for CTCL, IL‐25 and STAT6 can be a therapeutic target for CTCL.
We report the first detection of asymmetry in a supernova (SN) photosphere based on SN light echo (LE) spectra of Cas A from the different perspectives of dust concentrations on its LE ellipsoid. New ...LEs are reported based on difference images, and optical spectra of these LEs are analyzed and compared. After properly accounting for the effects of finite dust-filament extent and inclination, we find one field where the He I Delta *l5876 and H Delta *a features are blueshifted by an additional ~4000 km s--1 relative to other spectra and to the spectra of the Type IIb SN 1993J. That same direction does not show any shift relative to other Cas A LE spectra in the Ca II near-infrared triplet feature. We compare the perspectives of the Cas A LE dust concentrations with recent three-dimensional modeling of the SN remnant (SNR) and note that the location having the blueshifted He I and H Delta *a features is roughly in the direction of an Fe-rich outflow and in the opposite direction of the motion of the compact object at the center of the SNR. We conclude that Cas A was an intrinsically asymmetric SN. Future LE spectroscopy of this object, and of other historical SNe, will provide additional insight into the connection of the explosion mechanism to SN then to SNR, as well as give crucial observational evidence regarding how stars explode.
Abstract
Accurate photometric calibration of optical data is crucial for photometric redshift estimation. We present the Softassign Procrustes Matching (SPM) method to improve the colour calibration ...upon the commonly used Stellar Locus Regression (SLR) method for the COMBO-17 survey. Our colour calibration approach can be categorised as a point-set matching method, which is frequently used in medical imaging and pattern recognition. We attain a photometric redshift precision Δz/(1 + z
s) of better than 2 per cent. Our method is based on aligning the stellar locus of the uncalibrated stars to that of a spectroscopic sample of the Sloan Digital Sky Survey standard stars. We achieve our goal by finding a correspondence matrix between the two point-sets and applying the matrix to estimate the appropriate translations in multidimensional colour space. The SPM method is able to find the translation between two point-sets, despite the existence of noise and incompleteness of the common structures in the sets, as long as there is a distinct structure in at least one of the colour–colour pairs. We demonstrate the precision of our colour calibration method with a mock catalogue. The SPM colour calibration code is publicly available at https://neuronphysics@bitbucket.org/neuronphysics/spm.git.
Aims
Nakajo–Nishimura syndrome (NNS) is an autosomal recessive disease caused by biallelic mutations in the PSMB8 gene that encodes the immunoproteasome subunit β5i. There have been only a limited ...number of reports on the clinicopathological features of the disease in genetically confirmed cases.
Methods
We studied clinical and pathological features of three NNS patients who all carry the homozygous p.G201V mutations in PSMB8. Patients’ muscle specimens were analysed with histology and immunohistochemistry.
Results
All patients had episodes of typical periodic fever and skin rash, and later developed progressive muscle weakness and atrophy, similar to previous reports. Oral corticosteroid was used for treatment but showed no obvious efficacy. On muscle pathology, lymphocytes were present in the endomysium surrounding non‐necrotic fibres, as well as in the perimysium perivascular area. Nearly all fibres strongly expressed MHC‐I in the sarcolemma. In the eldest patient, there were abnormal protein aggregates in the sarcoplasm, immunoreactive to p62, TDP‐43 and ubiquitin antibodies.
Conclusions
These results suggest that inflammation, inclusion pathology and aggregation of abnormal proteins underlie the progressive clinical course of the NNS pathomechanism.
To better understand genomic and chromosomal organization and evolutionary patterns of the U1 snRNA gene in cichlid fish, the gene was cytogenetically mapped and comparatively analyzed in 19 species ...belonging to several clades of the group. Moreover, the distribution and organization of U1 snRNA gene was analyzed in the Oreochromis niloticus genome. The results indicated high conservation of one chromosomal cluster of U1 snRNA in the African, Asian, and South American species, with few variations in the chromosomal position of the clusters in the South American species. The genomic analysis of U1 revealed a distinct scenario from that observed under the cytogenetic mapping. An enrichment of the U1 gene on linkage group (LG) 14 was observed that did not correspond to the same chromosome that harbors the U1 cluster identified by cytogenetic mapping. Moreover, it was revealed that the presence of several distinct transposable elements in the U1 gene flanking regions could be involved in the spreading of this sequence, but the generation of new, large snRNA clusters (detectable by fluorescent in situ hybridization, FISH) is apparently hampered. These results contribute to the understanding of multigene families' evolution and reinforce the utility of integrative analysis and the use of cytogenetic and bioinformatic methods to address the genomic and chromosomal evolutionary patterns of repeated DNAs among vertebrates. Moreover, the U1 gene represents a useful new chromosomal marker for cytogenetic studies.
Structured
Authors – Nishijima Y, Yamaguchi M, Kojima T, Aihara N, Nakajima R, Kasai K
Objective – To determine the levels of the receptor activator of NFkB ligand (RANKL) and osteoprotegerin (OPG) ...in the gingival crevicular fluid (GCF) during orthodontic tooth movement. A second objective was to investigate the effect of compression force on RANKL and OPG production from human periodontal ligament (hPDL) cells.
Design – Ten adolescent patients were included. GCF was collected at the distal cervical margins of the experimental and control teeth 0, 1, 24, and 168 h after the retracting force was applied. Thisin vitro study was performed to examine the secretion of RANKL and OPG from hPDL cells following a compression force (0, 0.5, 1.0, 2.0, or 3.0 g/cm2 for 48 h). Enzyme‐linked immunosorbent assay (ELISA) kits were used to determine RANKL and OPG levels in the GCF and the conditioned medium.
Results – GCF levels of RANKL were significantly higher, and the levels of OPG significantly lower, in the experimental canines than in the control teeth at 24 h, but there were no such significant differences at 0, 1, or 168 h. In vitro study indicated that the compression force significantly increased the secretion of RANKL and decreased that of OPG in hPDL cells in a time‐ and force magnitude‐dependent manner. The compression‐stimulated secretion of RANKL increased approximately 16.7‐fold and that of OPG decreased 2.9‐fold, as compared with the control.
Conclusions – The results obtained suggest that the changes of amount of RANKL and OPG may be involved in bone resorption as a response to compression force.
PDF
