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De Novo Identification of Regulatory Regions in Intergenic Spaces of Prokaryotic Genomes
This project was begun to implement, test, and experimentally validate the results of a novel algorithm for genome-wide identification of candidate transcription-factor binding sites in prokaryotes. Most techniques used to identify regulatory regions rely on conservation between different genomes or have a predetermined sequence motif(s) to perform a genome-wide search. Therefore, such techniques cannot be used with new genome sequences, where information regarding such motifs has not yet been discovered. This project aimed to apply a de novo search algorithm to identify candidate binding-site motifs in intergenic regions of prokaryotic organisms, initially testing the available genomes of the Yersinia genus. We retrofitted existing nucleotide pattern-matching algorithms, analyzed the candidate sites identified by these algorithms as well as their target genes to screen for meaningful patterns. Using properly annotated prokaryotic genomes, this project aimed to develop a set of procedures to identify candidate intergenic sites important for gene regulation. We planned to demonstrate this in Yersinia pestis, a model biodefense, Category A Select Agent pathogen, and then follow up with experimental evidence that these regions are indeed involved in regulation. The ability to quickly characterize transcription-factor binding sites will help lead to a better understanding of how known virulence pathways are modulated in biodefense-related organisms, and will help our understanding and exploration of regulons--gene regulatory networks--and novel pathways for metabolic processes in environmental microbes
T cell receptor sequence clustering and antigen specificity
There has been increasing interest in the role of T cells and their involvement in cancer, autoimmune and infectious diseases. However, the nature of T cell receptor (TCR) epitope recognition at a repertoire level is not yet fully understood. Due to technological advances a plethora of TCR sequences from a variety of disease and treatment settings has become readily available. Current efforts in TCR specificity analysis focus on identifying characteristics in immune repertoires which can explain or predict disease outcome or progression, or can be used to monitor the efficacy of disease therapy. In this context, clustering of TCRs by sequence to reflect biological similarity, and especially to reflect antigen specificity have become of paramount importance. We review the main TCR sequence clustering methods and the different similarity measures they use, and discuss their performance and possible improvement. We aim to provide guidance for non-specialists who wish to use TCR repertoire sequencing for disease tracking, patient stratification or therapy prediction, and to provide a starting point for those aiming to develop novel techniques for TCR annotation through clustering
Complete genome sequence of the Medicago microsymbiont Ensifer (Sinorhizobium) medicae strain WSM419
Ensifer (Sinorhizobium) medicae is an effective nitrogen fixing microsymbiont of a diverse range of annual Medicago (medic) species. Strain WSM419 is an aerobic, motile, non-spore forming, Gram-negative rod isolated from a M. murex root nodule collected in Sardinia, Italy in 1981. WSM419 was manufactured commercially in Australia as an inoculant for annual medics during 1985 to 1993 due to its nitrogen fixation, saprophytic competence and acid tolerance properties. Here we describe the basic features of this organism, together with the complete genome sequence, and annotation. This is the first report of a complete genome se-quence for a microsymbiont of the group of annual medic species adapted to acid soils. We reveal that its genome size is 6,817,576 bp encoding 6,518 protein-coding genes and 81 RNA only encoding genes. The genome contains a chromosome of size 3,781,904 bp and 3 plasmids of size 1,570,951 bp, 1,245,408 bp and 219,313 bp. The smallest plasmid is a fea-ture unique to this medic microsymbiont
Genomics of Divergence along a Continuum of Parapatric Population Differentiation
MM received funding from the Max Planck innovation funds for this project. PGDF was supported by a Marie Curie European Reintegration Grant (proposal nr 270891). CE was supported by German Science Foundation grants (DFG, EI 841/4-1 and EI 841/6-1)
Naive B cell output in HIV-infected and HIV-uninfected children.
In this study, we aimed to quantify KREC (kappa-deleting recombination excision circle) levels and naive B cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (antiretroviral therapy). Samples were acquired from a Child Wellness Clinic (n = 288 HIV-uninfected South African children, 2 weeks-12 years) and the Children with HIV Early Antiretroviral Therapy (CHER) trial (n = 153 HIV-infected South African children, 7 weeks-8 years). Naive B cell output was estimated using a mathematical model combining KREC levels to reflect B cell emigration into the circulation, flow cytometry measures of naive unswitched B cells to quantify total body naive B cells, and their rates of proliferation using the intracellular marker Ki67. Naive B cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naive B cell outputs than their uninfected counterparts (p = .01 and p = .04). This is the first study to present reference ranges for measurements of KRECs and naive B cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggests that HIV may increase naive B cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naive B cell output in children
Gut barrier-microbiota imbalances in early life lead to higher sensitivity to inflammation in a murine model of C-section delivery
Background Most interactions between the host and its microbiota occur at the gut barrier, and primary colonizers
are essential in the gut barrier maturation in the early life. The mother–ofspring transmission of microorganisms is
the most important factor infuencing microbial colonization in mammals, and C‑section delivery (CSD) is an impor‑
tant disruptive factor of this transfer. Recently, the deregulation of symbiotic host‑microbe interactions in early life
has been shown to alter the maturation of the immune system, predisposing the host to gut barrier dysfunction and
infammation. The main goal of this study is to decipher the role of the early‑life gut microbiota‑barrier alterations and
its links with later‑life risks of intestinal infammation in a murine model of CSD.
Results The higher sensitivity to chemically induced infammation in CSD mice is related to excessive exposure to a
too diverse microbiota too early in life. This early microbial stimulus has short‑term consequences on the host homeo‑
stasis. It switches the pup’s immune response to an infammatory context and alters the epithelium structure and
the mucus‑producing cells, disrupting gut homeostasis. This presence of a too diverse microbiota in the very early
life involves a disproportionate short‑chain fatty acids ratio and an excessive antigen exposure across the vulnerable
gut barrier in the frst days of life, before the gut closure. Besides, as shown by microbiota transfer experiments, the
microbiota is causal in the high sensitivity of CSD mice to chemical‑induced colitis and in most of the phenotypical
parameters found altered in early life. Finally, supplementation with lactobacilli, the main bacterial group impacted by
CSD in mice, reverts the higher sensitivity to infammation in ex‑germ‑free mice colonized by CSD pups’ microbiota.
Conclusions Early‑life gut microbiota‑host crosstalk alterations related to CSD could be the linchpin behind the phe‑
notypic efects that lead to increased susceptibility to an induced infammation later in life in mice.
Keywords C‑section delivery, Microbiota, Primary colonization, Early life, Infammation, Gut barrier, Murine modelinfo:eu-repo/semantics/publishedVersio
Gut barrier-microbiota imbalances in early life lead to higher sensitivity to inflammation in a murine model of C-section delivery
Most interactions between the host and its microbiota occur at the gut barrier, and primary colonizers are essential in the gut barrier maturation in the early life. The mother-offspring transmission of microorganisms is the most important factor influencing microbial colonization in mammals, and C-section delivery (CSD) is an important disruptive factor of this transfer. Recently, the deregulation of symbiotic host-microbe interactions in early life has been shown to alter the maturation of the immune system, predisposing the host to gut barrier dysfunction and inflammation. The main goal of this study is to decipher the role of the early-life gut microbiota-barrier alterations and its links with later-life risks of intestinal inflammation in a murine model of CSD.
The higher sensitivity to chemically induced inflammation in CSD mice is related to excessive exposure to a too diverse microbiota too early in life. This early microbial stimulus has short-term consequences on the host homeostasis. It switches the pup's immune response to an inflammatory context and alters the epithelium structure and the mucus-producing cells, disrupting gut homeostasis. This presence of a too diverse microbiota in the very early life involves a disproportionate short-chain fatty acids ratio and an excessive antigen exposure across the vulnerable gut barrier in the first days of life, before the gut closure. Besides, as shown by microbiota transfer experiments, the microbiota is causal in the high sensitivity of CSD mice to chemical-induced colitis and in most of the phenotypical parameters found altered in early life. Finally, supplementation with lactobacilli, the main bacterial group impacted by CSD in mice, reverts the higher sensitivity to inflammation in ex-germ-free mice colonized by CSD pups' microbiota.
Early-life gut microbiota-host crosstalk alterations related to CSD could be the linchpin behind the phenotypic effects that lead to increased susceptibility to an induced inflammation later in life in mice
Valence band excitations in V_2O_5
We present a joint theoretical and experimental investigation of the
electronic and optical properties of vanadium pentoxide. Electron energy-loss
spectroscopy in transmission was employed to measure the momentum-dependent
loss function. This in turn was used to derive the optical conductivity, which
is compared to the results of band structure calculations. A good qualitative
and quantitative agreement between the theoretical and the experimental optical
conductivity was observed. The experimentally observed anisotropy of the
optical properties of V_2O_5 could be understood in the light of an analysis of
the theoretical data involving the decomposition of the calculated optical
conductivity into contributions from transitions into selected energy regions
of the conduction band. In addition, based upon a tight binding fit to the band
structure, values are given for the effective V3d_xy-O2p hopping terms and are
compared to the corresponding values for alpha'-NaV_2O_5.Comment: 6 pages (revtex),6 figures (jpg
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