The SseC translocon component in Salmonella enterica serovar Typhimurium is chaperoned by SscA

Background: Salmonella enterica is a causative agent of foodborne gastroenteritis and the systemic disease known as typhoid fever. This bacterium uses two type three secretion systems (T3SSs) to translocate protein effectors into host cells to manipulate cellular function. Salmonella pathogenicity island (SPI)-2 encodes a T3SS required for intracellular survival of the pathogen. Genes in SPI-2 include apparatus components, secreted effectors and chaperones that bind to secreted cargo to coordinate their release from the bacterial cell. Although the effector repertoire secreted by the SPI-2 T3SS is large, only three virulence-associated chaperones have been characterized. Results: Here we report that SscA is the chaperone for the SseC translocon component. We show that SscA and SseC interact in bacterial cells and that deletion of sscA results in a loss of SseC secretion, which compromises intracellular replication and leads to a loss of competitive fitness in mice. Conclusions: This work completes the characterization of the chaperone complement within SPI-2 and identifies SscA as the chaperone for the SseC translocon

Immunobiological barriers to xenotransplantation

Binding of natural anti-pig antibodies in humans and nonhuman primates to carbohydrate antigens expressed on the transplanted pig organ, the most important of which is galactose-α1,3-galactose (Gal), activate the complement cascade, which results in destruction of the graft within minutes or hours, known as hyperacute rejection. Even if antibody is removed from the recipient's blood by plasmapheresis, recovery of antibody is associated with acute humoral xenograft rejection. If immunosuppressive therapy is inadequate, the development of high levels of T cell-dependent elicited anti-pig IgG similarly results in graft destruction, though classical acute cellular rejection is rarely seen. Vascular endothelial activation by low levels of anti-nonGal antibody, coupled with dysregulation of the coagulation-anticoagulation systems between pigs and primates, leads to a thrombotic microangiopathy in the graft that may be associated with a consumptive coagulopathy in the recipient. The most successful approach to overcoming these barriers is by genetically-engineering the pig to provide it with resistance to the human humoral and cellular immune responses and to correct the coagulation discrepancies between the two species. Organs and cells from pigs that (i) do not express the important Gal antigen, (ii) express a human complement-regulatory protein, and (iii) express a human coagulation-regulatory protein, when combined with an effective immunosuppressive regimen, have been associated with prolonged pig graft survival in nonhuman primates

The need for xenotransplantation as a source of organs and cells for clinical transplantation

The limited availability of deceased human organs and cells for the purposes of clinical transplantation remains critical worldwide. Despite the increasing utilization of 'high-risk', 'marginal', or 'extended criteria' deceased donors, in the U.S. each day 30 patients either die or are removed from the waiting list because they become too sick to undergo organ transplantation. In certain other countries, where there is cultural resistance to deceased donation, e.g., Japan, the increased utilization of living donors, e.g., of a single kidney or partial liver, only very partially addresses the organ shortage. For transplants of tissues and cells, e.g., pancreatic islet transplantation for patients with diabetes, and corneal transplantation for patients with corneal blindness (whose numbers worldwide are potentially in the millions), allotransplantation will never prove a sufficient source. There is an urgent need for an alternative source of organs and cells. The pig could prove to be a satisfactory source, and clinical xenotransplantation using pig organs or cells, particularly with the advantages provided by genetic engineering to provide resistance to the human immune response, may resolve the organ shortage. The physiologic compatibilities and incompatibilities of the pig and the human are briefly reviewed

A brief history of clinical xenotransplantation

Between the 17th and 20th centuries, blood was transfused from various animal species into patients with a variety of pathological conditions. Skin grafts were carried out in the 19th century, with grafts from a variety of animals, with frogs being the most popular. In the 1920s, Voronoff advocated the transplantation of slices of chimpanzee testis into elderly men, believing that the hormones produced by the testis would rejuvenate his patients. In 1963-4, when human organs were not available and dialysis was not yet in use, Reemtsma transplanted chimpanzee kidneys into 13 patients, one of whom returned to work for almost 9 months before suddenly dying from what was believed to be an electrolyte disturbance. The first heart transplant in a human ever performed was by Hardy in 1964, using a chimpanzee heart, but the patient died within 2 h. Starzl carried out the first chimpanzee-to-human liver transplantation in 1966; in 1992 he obtained patient survival for 70 days following a baboon liver transplant. The first clinical pig islet transplant was carried out by Groth in 1993. Today, genetically-modified pigs offer hope of a limitless supply of organs and cells for those in need of a transplant

Risk Management Strategies by Australian Farmers

Australian farmers operate in one of the most risky environment in the world. They have to cope with various sources of risk in their businesses. This paper reports results of two case studies undertaken to examine the issues of farming risks and risk management strategies in Australia. The first case study found that climate variability, financial risk, marketing risk, and personal risk were regarded as the major sources of farming risk in the Upper Eyre Peninsula of South Australia. The main management strategies used by farmers included diversifying varieties, minimising tillage, minimising area of risky crops and maximising area of the least-risky crop, having high equity, having farm management deposits and other off-farm investments, and "leaving marketing to experts". The second case study revealed that climate variability was ranked as the most important source of farming risk in southwest Queensland. This was then followed by financial risks, government policy, and marketing risks. The main management strategies used were enterprise diversification (having predominantly cattle and farming cash crops), conserving moisture, using zero till planting, diversified sales (selling only part of the farm's production at any one time), and having off-farm investments. The paper then attempts to reconcile the two case studies by comparing the results with studies from the United States of America, Canada, Netherlands, and New Zealand.risk, risk management, strategies, farmers, Australia, Farm Management, Risk and Uncertainty,

The DEEP2 Redshift Survey: Lyman Alpha Emitters in the Spectroscopic Database

We present the first results of a search for Lyman-alpha emitters (LAEs) in the DEEP2 spectroscopic database that uses a search technique that is different from but complementary to traditional narrowband imaging surveys. We have visually inspected ~20% of the available DEEP2 spectroscopic data and have found nine high-quality LAEs with clearly asymmetric line profiles and an additional ten objects of lower quality, some of which may also be LAEs. Our survey is most sensitive to LAEs at z=4.4-4.9 and that is indeed where all but one of our high-quality objects are found. We find the number density of our spectroscopically-discovered LAEs to be consistent with those found in narrowband imaging searches. The combined, averaged spectrum of our nine high-quality objects is well fit by a two-component model, with a second, lower-amplitude component redshifted by ~420 km/s with respect to the primary Lyman-alpha line, consistent with large-scale outflows from these objects. We conclude by discussing the advantages and future prospects of blank-sky spectroscopic surveys for high-z LAEs.Comment: Accepted for publication in Ap

The potential role of 3D-bioprinting in xenotransplantation

Purpose of review To review the impact of a new technology, 3D-bioprinting, in xenotransplantation research. Recent findings Genetically engineered pigs, beginning with human (h) CD55-transgenic and Gal-knockout pigs, have improved the outcomes of xenotransplantation research. Today, there are more than 30 different genetically engineered pigs either expressing human gene(s) or lacking pig gene(s). CRIPSR/cas9 technology has facilitated the production of multigene pigs (up to nine genes in a single pig), which lack multiple pig xenoantigens, and express human transgenes, such as hCD46, hCD55, hThrombomodulin, hCD39, etc. Although recent studies in nonhuman primates (NHPs) have demonstrated prolonged survival after life-supporting pig kidney, heart, and islet xenotransplantation, researchers have difficulty determining the best genetic combination to test in NHPs because of a potential greater than 100 000 genetic combinations. 3D-bioprinting of genetically engineered pig cells: is superior to 2D in-vitro testing, enables organ-specific testing, helps to understand differences in immunogenicity between organs, and is faster and cheaper than testing in NHPs. Moreover, 3D-bioprinted cells can be continuously perfused in a bioreactor, controlling for all variables, except the studied variable. Summary 3D-bioprinting can help in the study of the impact of specific genes (human or pig) in xenotransplantation in a rapid, inexpensive, and reliable way

The DEEP2 Galaxy Redshift Survey: Color and Luminosity Dependence of Galaxy Clustering at z~1

We present measurements of the color and luminosity dependence of galaxy clustering at z~1 in the DEEP2 Galaxy Redshift Survey. Using volume-limited subsamples in bins of both color and luminosity, we find that: 1) The clustering dependence is much stronger with color than with luminosity and is as strong with color at z~1 as is found locally. We find no dependence of the clustering amplitude on color for galaxies on the red sequence, but a significant dependence on color for galaxies within the blue cloud. 2) For galaxies in the range L/L*~0.7-2, a stronger large-scale luminosity dependence is seen for all galaxies than for red and blue galaxies separately. The small-scale clustering amplitude depends significantly on luminosity for blue galaxies, with brighter samples having a stronger rise on scales r_p<0.5 Mpc/h. 3) Redder galaxies exhibit stronger small-scale redshift-space distortions ("fingers of god"), and both red and blue populations show large-scale distortions in xi(r_p,pi) due to coherent infall. 4) While the clustering length, r_0, increases smoothly with galaxy color (in narrow bins), its power-law exponent, gamma, exhibits a sharp jump from the blue cloud to the red sequence. The intermediate color `green' galaxy population likely includes transitional galaxies moving from the blue cloud to the red sequence; on large scales green galaxies are as clustered as red galaxies but show infall kinematics and a small-scale correlation slope akin to the blue galaxy population. 5) We compare our results to a semi-analytic galaxy formation model applied to the Millenium Run simulation. Differences between the data and the model suggest that in the model star formation is shut down too efficiently in satellite galaxies.Comment: 28 pages, 17 figures, emulateapj format, accepted to ApJ, updated to match published versio

Morphologies of Galaxies in and around a Protocluster at z=2.300

We present results from the first robust investigation of galaxy morphology as a function of environment at z>1.5. Our study is motivated by the fact that star-forming galaxies contained within a protocluster at z=2.3 in the HS1700+64 field have significantly older ages and larger stellar masses on average than those at similar redshifts but more typical environmental densities. In the analysis of HST/ACS images, we apply non-parametric statistics to characterize the rest-frame UV morphologies of a sample of 85 UV-selected star-forming galaxies at z=1.7-2.9, 22 of which are contained in the protocluster. The remaining 63 control-sample galaxies are not in the protocluster but have a similar mean redshift of ~2.3. We find no environmental dependence for the distributions of morphological properties. Combining the measured morphologies with the results of population synthesis modeling, we find only weak correlations, if any, between morphological and stellar population properties such as stellar mass, age, extinction and star-formation rate. Given the incomplete census of the protocluster galaxy population, and the lack of correlation between rest-frame UV morphology and star-formation history at z~2 within our sample, the absence of environmental trends in the distribution of morphological properties is not surprising. Additionally, using a larger sample of photometric candidates, we compare morphological distributions for 282 UV-selected and 43 near-IR-selected galaxies. While the difference in the degree of nebulosity between the two samples appears to be a byproduct of the fainter average rest-frame UV surface brightness of the near-IR-selected galaxies, we find that, among the lowest surface brightness galaxies, the near-IR-selected objects have significantly smaller angular sizes (abridged).Comment: 25 pages including 16 figures. Accepted for publication in ApJ. Version with full resolution figures available at http://www.astro.princeton.edu/~apeter/LBG/papers/peter2007_fullres.ps.g

Parallel Search with no Coordination

We consider a parallel version of a classical Bayesian search problem. $k$ agents are looking for a treasure that is placed in one of the boxes indexed by $\mathbb{N}^+$ according to a known distribution $p$. The aim is to minimize the expected time until the first agent finds it. Searchers run in parallel where at each time step each searcher can "peek" into a box. A basic family of algorithms which are inherently robust is \emph{non-coordinating} algorithms. Such algorithms act independently at each searcher, differing only by their probabilistic choices. We are interested in the price incurred by employing such algorithms when compared with the case of full coordination. We first show that there exists a non-coordination algorithm, that knowing only the relative likelihood of boxes according to $p$, has expected running time of at most $10+4(1+\frac{1}{k})^2 T$, where $T$ is the expected running time of the best fully coordinated algorithm. This result is obtained by applying a refined version of the main algorithm suggested by Fraigniaud, Korman and Rodeh in STOC'16, which was designed for the context of linear parallel search.We then describe an optimal non-coordinating algorithm for the case where the distribution $p$ is known. The running time of this algorithm is difficult to analyse in general, but we calculate it for several examples. In the case where $p$ is uniform over a finite set of boxes, then the algorithm just checks boxes uniformly at random among all non-checked boxes and is essentially $2$ times worse than the coordinating algorithm.We also show simple algorithms for Pareto distributions over $M$ boxes. That is, in the case where $p(x) \sim 1/x^b$ for $0< b < 1$, we suggest the following algorithm: at step $t$ choose uniformly from the boxes unchecked in ${1, . . . ,min(M, \lfloor t/\sigma\rfloor)}$, where $\sigma = b/(b + k - 1)$. It turns out this algorithm is asymptotically optimal, and runs about $2+b$ times worse than the case of full coordination