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

Pathogenic Adaptation of Intracellular Bacteria by Rewiring a Cis-Regulatory Input Function

The acquisition of DNA by horizontal gene transfer enables bacteria to adapt to previously unexploited ecological niches. Although horizontal gene transfer and mutation of protein-coding sequences are well-recognized forms of pathogen evolution, the evolutionary significance of cis-regulatory mutations in creating phenotypic diversity through altered transcriptional outputs is not known. We show the significance of regulatory mutation for pathogen evolution by mapping and then rewiring a cis-regulatory module controlling a gene required for murine typhoid. Acquisition of a binding site for the Salmonella pathogenicity island-2 regulator, SsrB, enabled the srfN gene, ancestral to the Salmonella genus, to play a role in pathoadaptation of S. typhimurium to a host animal. We identified the evolved cis-regulatory module and quantified the fitness gain that this regulatory output accrues for the bacterium using competitive infections of host animals. Our findings highlight a mechanism of pathogen evolution involving regulatory mutation that is selected because of the fitness advantage the new regulatory output provides the incipient clones

Stellar Dynamics and Black Holes

Chandrasekhar's most important contribution to stellar dynamics was the concept of dynamical friction. I briefly review that work, then discuss some implications of Chandrasekhar's theory of gravitational encounters for motion in galactic nuclei.Comment: Talk presented at the "Chandrasekhar Centenary Conference" (2010

Ejection of Supermassive Black Holes from Galaxy Cores

[Abridged] Recent numerical relativity simulations have shown that the emission of gravitational waves during the merger of two supermassive black holes (SMBHs) delivers a kick to the final hole, with a magnitude as large as 4000 km/s. We study the motion of SMBHs ejected from galaxy cores by such kicks and the effects on the stellar distribution using high-accuracy direct N-body simulations. Following the kick, the motion of the SMBH exhibits three distinct phases. (1) The SMBH oscillates with decreasing amplitude, losing energy via dynamical friction each time it passes through the core. Chandrasekhar's theory accurately reproduces the motion of the SMBH in this regime if 2 < ln Lambda < 3 and if the changing core density is taken into account. (2) When the amplitude of the motion has fallen to roughly the core radius, the SMBH and core begin to exhibit oscillations about their common center of mass. These oscillations decay with a time constant that is at least 10 times longer than would be predicted by naive application of the dynamical friction formula. (3) Eventually, the SMBH reaches thermal equilibrium with the stars. We estimate the time for the SMBH's oscillations to damp to the Brownian level in real galaxies and infer times as long as 1 Gyr in the brightest galaxies. Ejection of SMBHs also results in a lowered density of stars near the galaxy center; mass deficits as large as five times the SMBH mass are produced for kick velocities near the escape velocity. We compare the N-body density profiles with luminosity profiles of early-type galaxies in Virgo and show that even the largest observed cores can be reproduced by the kicks, without the need to postulate hypermassive binary SMBHs. Implications for displaced AGNs and helical radio structures are discussed.Comment: 18 pages, The Astrophysical Journal, in press. Replaced with revised versio

Designing a course model for distance-based online bioinformatics training in Africa: the H3ABioNet experience

Africa is not unique in its need for basic bioinformatics training for individuals from a diverse range of academic backgrounds. However, particular logistical challenges in Africa, most notably access to bioinformatics expertise and internet stability, must be addressed in order to meet this need on the continent. H3ABioNet (www.h3abionet.org), the Pan African Bioinformatics Network for H3Africa, has therefore developed an innovative, free-of-charge "Introduction to Bioinformatics" course, taking these challenges into account as part of its educational efforts to provide on-site training and develop local expertise inside its network. A multiple-delivery±mode learning model was selected for this 3-month course in order to increase access to (mostly) African, expert bioinformatics trainers. The content of the course was developed to include a range of fundamental bioinformatics topics at the introductory level. For the first iteration of the course (2016), classrooms with a total of 364 enrolled participants were hosted at 20 institutions across 10 African countries. To ensure that classroom success did not depend on stable internet, trainers pre-recorded their lectures, and classrooms downloaded and watched these locally during biweekly contact sessions. The trainers were available via video conferencing to take questions during contact sessions, as well as via online "question and discussion" forums outside of contact session time. This learning model, developed for a resource-limited setting, could easily be adapted to other settings.IS

Modern relationships between microscopic charcoal in marine sediments and fire regimes on adjacent landmasses to refine the interpretation of marine paleofire records: An Iberian case study

Marine microcharcoal records provide invaluable information to understand changes in biomass burning and its drivers over multiple glacial and interglacial cycles and to evaluate fire models under warmer climates than today. However, quantitative reconstructions of burnt area, fire intensity and frequency from these records need calibration studies of the current fire-microcharcoal relationship. Here, we present the analysis of microcharcoal concentration and morphology in 102 core-top sediment samples collected in the Iberian margin and the Gulf of Cádiz. We show that microcharcoal concentrations are influenced by the water depth or the distance from the river mouth. At regional scale, the mean microcharcoal concentrations and microcharcoal elongation (length to width ratio) show a marked latitudinal variation in their distribution, primarily controlled by the type of burnt vegetation in the adjacent continent. High microcharcoal concentrations in marine sediments represent rare, large and intense fires in open Mediterranean woodlands. Based on these results, the increasing trend of microcharcoal concentrations recorded since 8 ka in the well-known marine sedimentary core MD95-2042 off the Iberian margin indicates the occurrence of large and infrequent fires of high intensity due to the progressive degradation of the Mediterranean forest and the expansion of shrublands

The Effect of Using Pazopanib With Food vs. Fasted on Pharmacokinetics, Patient Safety, and Preference (DIET Study)

Pazopanib is taken fasted in a fixed oral daily dose of 800 mg. We hypothesized that ingesting pazopanib with food may improve patients' comfort and reduce gastrointestinal (GI) adverse events. Therefore, we investigated the bioequivalent dose of pazopanib when taken with food compared with 800 mg pazopanib taken fasted. In addition, we investigated the differences in GI toxicity, patient satisfaction, and patient's preference for either intake. The intake of 600 mg pazopanib with food resulted in a bioequivalent exposure and was preferred over a standard pazopanib dose without food. No differences were seen in GI toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects and satisfaction with their therapy when pazopanib was taken with food. Forty-one of the patients (68%) preferred the intake with a continental breakfast