Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans

Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10⁻¹⁰ mutations/bp/generation for recently transmitted tuberculosis and 7.3X10⁻¹¹ mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10⁻¹¹ mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques

Pilus distribution among lineages of group b <i>streptococcus</i>: an evolutionary and clinical perspective

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Group B Streptococcus (GBS) is an opportunistic pathogen in both humans and bovines. Epidemiological and phylogenetic analyses have found strains belonging to certain phylogenetic lineages to be more frequently associated with invasive newborn disease, asymptomatic maternal colonization, and subclinical bovine mastitis. Pilus structures in GBS facilitate colonization and invasion of host tissues and play a role in biofilm formation, though few large-scale studies have estimated the frequency and diversity of the three pilus islands (PIs) across diverse genotypes. Here, we examined the distribution of pilus islands (PI) 1, 2a and 2b among 295 GBS strains representing 73 multilocus sequence types (STs) belonging to eight clonal complexes. PCR-based RFLP was also used to evaluate variation in the genes encoding pilus backbone proteins of PI-2a and PI-2b.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; All 295 strains harbored one of the PI-2 variants and most human-derived strains contained PI-1. Bovine-derived strains lacked PI-1 and possessed a unique PI-2b backbone protein allele. Neonatal strains more frequently had PI-1 and a PI-2 variant than maternal colonizing strains, and most CC-17 strains had PI-1 and PI-2b with a distinct backbone protein allele. Furthermore, we present evidence for the frequent gain and loss of genes encoding certain pilus types.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt;&lt;p&gt;&lt;/p&gt; These data suggest that pilus combinations impact host specificity and disease presentation and that diversification often involves the loss or acquisition of PIs. Such findings have implications for the development of GBS vaccines that target the three pilus islands

Hollow futures? Tree decline, lag effects and hollow-dependent species

Tree hollows are a critical breeding resource for many organisms globally. Where hollow-bearing trees are in decline, population limitation can be a serious conservation issue. A particular problem in addressing hollow limitation is the long time that ho

Therapeutic Trial of Metformin and Bortezomib in a Mouse Model of Tuberous Sclerosis Complex (TSC)

Tuberous sclerosis complex (TSC) is a human genetic disorder in which loss of either TSC1 or TSC2 leads to development of hamartoma lesions, which can progress and be life-threatening or fatal. The TSC1/TSC2 protein complex regulates the state of activation of mTORC1. Tsc2+/− mice develop renal cystadenoma lesions which grow progressively. Both bortezomib and metformin have been proposed as potential therapeutics in TSC. We examined the potential benefit of 1 month treatment with bortezomib, and 4 month treatment with metformin in Tsc2+/− mice. Results were compared to vehicle treatment and treatment with the mTORC1 inhibitor rapamycin for 1 month. We used a quantitative tumor volume measurement on stained paraffin sections to assess the effect of these drugs. The median tumor volume per kidney was decreased by 99% in mice treated with rapamycin (p = 0.0004). In contrast, the median tumor volume per kidney was not significantly reduced for either the bortezomib cohort or the metformin cohort. Biochemical studies confirmed that bortezomib and metformin had their expected pharmacodynamic effects. We conclude that neither bortezomib nor metformin has significant benefit in this native Tsc2+/− mouse model, which suggests limited benefit of these compounds in the treatment of TSC hamartomas and related lesions

A variant in LIN28B is associated with 2D:4D finger-length ratio, a putative retrospective biomarker of prenatal testosterone exposure

The ratio of the lengths of an individual's second to fourth digit (2D:4D) is commonly used as a noninvasive retrospective biomarker for prenatal androgen exposure. In order to identify the genetic determinants of 2D:4D, we applied a genome-wide association approach to 1507 11-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in whom 2D:4D ratio had been measured, as well as a sample of 1382 12- to 16-year-olds from the Brisbane Adolescent Twin Study. A meta-analysis of the two scans identified a single variant in the LIN28B gene that was strongly associated with 2D:4D (rs314277: p = 4.1 108) and was subsequently independently replicated in an additional 3659 children from the ALSPAC cohort (p = 1.53 106). The minor allele of the rs314277 variant has previously been linked to increased height and delayed age at menarche, but in our study it was associated with increased 2D:4D in the direction opposite to that of previous reports on the correlation between 2D:4D and age at menarche. Our findings call into question the validity of 2D:4D as a simplistic retrospective biomarker for prenatal testosterone exposure

Avifauna and urban encroachment in time and space

AIM: Urban expansion significantly alters fringe environments often with unde-sirable impacts on biodiversity. Consequently, there is a need to define clearconservation objectives for areas subject to urban encroachment. Urban fringe development is a highly dynamic process, both spatially and temporally, but few studies are equipped to examine its temporal effects on biota. We aimed to explore the impacts of urban encroachment on avifauna through space and time.LOCATION: The Australian Capital Territory, Australia. METHODS: We used records from an extensive 14-year monitoring programme undertaken in temperate woodland. We fitted hierarchical generalized linear models to assess individual species responses to the distance from monitoring sites to the urban boundary, and the temporal rate of change in this distance through time. We used factorial analysis on mixed data to examine trait group responses to these predictors.RESULTS: Our results indicated that the occurrence of approximately half of the study region’s avifauna is strongly linked to the proximity of their habitat to the urban fringe, but that the impact of urban fringe development on the occurrence of some species changed through time. We identified several species of conservation concern that respond negatively to large annual increases in urban fringe development, irrespective of its proximity to suitable habitat. Species responses to urban proximity were linked to life history traits, with small,migratory, woodland-dependent species that rely on mid- and upper-canopy structures, clearly disadvantaged by urban environments.MAIN CONCLUSIONS: Our findings demonstrate the breadth of species responses to urban encroachment over much larger distances than is typically investigated in urban ecological studies. We identify guilds vulnerable to the impacts of urban fringe development and therefore in need of ecologically sensitive urban design. We argue that future urban expansion towards important fringe habitats will need to be planned strategically through space and time.This research received funding support from Conservation Planning and Research, Environment and Sustainable Devel-opment Directorate ACT Government and the Fenner Schoolof Environment and Society. DBL, PG and KI were sup-ported by the National Environmental Research Program. ADM was supported by an ARC Future Fellowship (FT100100358)

The impact of greyscale inversion for nodule detection in an anthropomorphic chest phantom: a free-response observer study

Objective: The aim of this work was to assess the impact of greyscale inversion on nodule detection on poster- oanterior chest X-ray images. Previous work has attemp- ted this, with no consensus opinion formed. We assessed the value of “fast-flicking” between standard and inverted display modes for nodule detection. Methods: Six consultant radiologists (with 5–32 years’ reporting experience) completed an observer task under the free-response paradigm. An anthropomorphic chest phantom was loaded with 50 different configurations of simulated nodules (1–4 nodules per case) measuring 5, 8, 10 and 12mm in spherical diameter; each configuration represented a single case. In addition, 25 cases contained no nodules. Images were displayed in three modes: (i) standard, (ii) inverted and (iii) fast-flicking between standard and inverted display modes. Each observer completed the study in a different order of display (i, ii, iii) using a calibrated 5-megapixel monitor. Nodules were localized with mouse clicks and ratings assigned using a 1–10 discrete slider-bar confidence scale. Rjafroc (Pitts- burgh, PA) was used for data analysis; differences in nodule detection performance were considered significant at 0.05. Results: The observer-averaged weighted jackknife alter- native free-response receiver-operating characteristic figures of merit were 0.715 (standard), 0.684 (inverted) and 0.717 (fast-flicking). Random-reader fixed-case anal- ysis revealed no statistically significant difference be- tween any treatment pair [F(2,8) 5 1.22; p 5 0.345]. Conclusion: No statistically significant difference in nodule detection was found for the three display conditions. Advances in knowledge: We have investigated the impact of fast-flicking between standard and inverted display modes for the detection of nodules. We found no benefit

New Dimensions for Wound Strings: The Modular Transformation of Geometry to Topology

We show, using a theorem of Milnor and Margulis, that string theory on compact negatively curved spaces grows new effective dimensions as the space shrinks, generalizing and contextualizing the results in hep-th/0510044. Milnor's theorem relates negative sectional curvature on a compact Riemannian manifold to exponential growth of its fundamental group, which translates in string theory to a higher effective central charge arising from winding strings. This exponential density of winding modes is related by modular invariance to the infrared small perturbation spectrum. Using self-consistent approximations valid at large radius, we analyze this correspondence explicitly in a broad set of time-dependent solutions, finding precise agreement between the effective central charge and the corresponding infrared small perturbation spectrum. This indicates a basic relation between geometry, topology, and dimensionality in string theory.Comment: 28 pages, harvmac big. v2: references and KITP preprint number added, minor change

Risk Factors for Postoperative Urinary Tract Infections in Patients Undergoing Total Joint Arthroplasty

Background. Urinary tract infections (UTIs) are the most common minor complication following total joint arthroplasty (TJA) with incidence as high as 3.26%. Bladder catheterization is routinely used during TJA and the Centers for Medicare and Medicaid Services (CMS) has recently identified hospital-acquired catheter associated UTI as a target for quality improvement. This investigation seeks to identify specific risk factors for UTI in TJA patients. Methods. We retrospectively studied patients undergoing TJA for osteoarthritis between 2006 and 2013 in the American College of Surgeon’s National Surgical Improvement Program Database (ACS-NSQIP). A univariate analysis screen followed by multivariate logistic regression identified specific patient demographics, comorbidities, preoperative laboratory values, and operative characteristics independently associated with postoperative UTI. Results. 1,239 (1.1%) of 115,630 TJA patients we identified experienced a postoperative UTI. The following characteristics are independently associated with postoperative UTI: female sex (OR 2.1, 95% CI 1.6–2.7), chronic steroid use (OR 2.0, 95% CI 1.2–3.2), ages 60–69 (OR 1.5, 95% CI 1.0–2.1), 70–79 (OR 2.0, 95% CI 1.4–2.9), and ≥80 (OR 2.3, 95% CI 1.5–3.6), ASA Classes 3–5 (OR 1.5, 95% CI 1.2–1.9), preoperative creatinine >1.35 (OR 1.8, 95% CI 1.3–2.6), and operation time greater than 130 minutes (OR 1.8, 95% CI 1.3–2.4). Conclusions. In this large database query, postoperative UTI occurs in 1.1% of patients following TJA and several variables including female sex, age greater than 60, and chronic steroid use are independent risk factors for occurrence. Practitioners should be aware of populations at greater risk to support efforts to comply with CMS initiated quality improvement