The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

Uptake and 4-week outcomes of an ‘opt-out’ smoking cessation referral strategy in a London-based lung cancer screening setting

INTRODUCTION: Lung cancer screening (LCS) enables the delivery of smoking cessation interventions to a population experiencing long-term tobacco dependence, but the optimal delivery method remains unclear. Here, we report uptake and short-term outcomes of an ‘opt-out’ smoking cessation referral strategy in an LCS cohort. METHODS: Individuals currently smoking tobacco who attended a face-to-face lung health check in the SUMMIT study (NCT03934866) were offered very brief advice on smoking cessation and where possible, an ‘opt-out’ referral to their local stop smoking service (SSS). Aggregate data on referral outcomes were obtained from each SSS individually. RESULTS: 33.7% (n=2090/6203) of individuals currently smoking tobacco consented to a practitioner-made ‘opt-out’ smoking cessation referral. 42.7% (n=893/2090) of these individuals resided in boroughs where SSS were not present or required self-referral. Males (adjusted OR (aOR) 1.16), younger individuals (55–59: aOR 1.70, 60–64: aOR 1.71 and 65–69: aOR 1.78) and those of ethnic minority backgrounds (Asian: aOR 1.31, Black: aOR 1.71 and Mixed: aOR 1.72) were more likely to consent, while individuals from the most deprived socioeconomic quintile were less likely to do so (aOR 0.65). High level of motivation to quit within a defined time frame (aOR 1.92), previous quit attempts in the past 12 months (1–4: aOR 1.65 and ≥5: aOR 1.54) and time to first cigarette of ≤60 min (<5: aOR 2.07, 6–30: aOR 1.55 and 31–60: aOR 1.56) were measures of tobacco dependence associated with a higher likelihood of providing consent. Outcomes were available for 742 referrals. An appointment with the service was accepted by 47.3% (n=351/742) of individuals, following which 65.5% (n=230/351) set a quit date. The 4-week quit rate among those setting a quit date and all individuals referred was 57.4% (n=132/230) and 17.8% (n=132/742), respectively. CONCLUSION: A proactive, ‘opt-out’ smoking cessation referral strategy for individuals currently smoking tobacco who interact with an LCS programme may be beneficial

The GimA Locus of Extraintestinal Pathogenic E. coli: Does Reductive Evolution Correlate with Habitat and Pathotype?

IbeA (invasion of brain endothelium), which is located on a genomic island termed GimA, is involved in the pathogenesis of several extraintestinal pathogenic E. coli (ExPEC) pathotypes, including newborn meningitic E. coli (NMEC) and avian pathogenic E. coli (APEC). To unravel the phylogeny of GimA and to investigate its island character, the putative insertion locus of GimA was determined via Long Range PCR and DNA-DNA hybridization in 410 E. coli isolates, including APEC, NMEC, uropathogenic (UPEC), septicemia-associated E. coli (SEPEC), and human and animal fecal isolates as well as in 72 strains of the E. coli reference (ECOR) collection. In addition to a complete GimA (∼20.3 kb) and a locus lacking GimA we found a third pattern containing a 342 bp remnant of GimA in this strain collection. The presence of GimA was almost exclusively detected in strains belonging to phylogenetic group B2. In addition, the complete GimA was significantly more frequent in APEC and NMEC strains while the GimA remnant showed a higher association with UPEC strains. A detailed analysis of the ibeA sequences revealed the phylogeny of this gene to be consistent with that obtained by Multi Locus Sequence Typing of the strains. Although common criteria for genomic islands are partially fulfilled, GimA rather seems to be an ancestral part of phylogenetic group B2, and it would therefore be more appropriate to term this genomic region GimA locus instead of genomic island. The existence of two other patterns reflects a genomic rearrangement in a reductive evolution-like manner

Peripheral chondrosarcoma progression is associated with increased type X collagen and vascularisation

Endochondral bone formation requires a cartilage template, known as the growth plate, and vascular invasion, bringing osteoblasts and osteoclasts. Endochondral chondrocytes undergo sequences of cell division, matrix secretion, cell hypertrophy, apoptosis, and matrix calcification/mineralisation. In this study, two critical steps of endochondral bone formation, the deposition of collagen X-rich matrix and blood vessel attraction/invasion, were investigated by immunohistochemistry. Fourteen multiple osteochondromas and six secondary peripheral chondrosarcomas occurring in patients with multiple osteochondromas were studied and compared to epiphyseal growth plate samples. Mutation analysis showed all studied patients (expect one) to harbour a germ-line mutations in either EXT1 or EXT2. Here, we described that homozygous mutations in EXT1/EXT2, which are causative for osteochondroma formation, are likely to affect terminal chondrocyte differentiation and vascularisation in the osteocartilaginous interface. Contrastingly, terminal chondrocyte differentiation and vascularisation seem to be unaffected in secondary peripheral chondrosarcoma. In addition, osteochondromas with high vascular density displayed a higher proliferation rate. A similar apoptotic rate was observed in osteochondromas and secondary peripheral chondrosarcomas. Recently, it has been shown that cells with functional EXT1 and EXT2 are outnumbering EXT1/EXT2 mutated cells in secondary peripheral chondrosarcomas. This might explain the increased type X collagen production and blood vessel attraction in these malignant tumours

Lymphatic mapping and sentinel node biopsy in gynecological cancers: a critical review of the literature

Although it does not have a long history of sentinel node evaluation (SLN) in female genital system cancers, there is a growing number of promising study results, despite the presence of some aspects that need to be considered and developed. It has been most commonly used in vulvar and uterine cervivcal cancer in gynecological oncology. According to these studies, almost all of which are prospective, particularly in cases where Technetium-labeled nanocolloid is used, sentinel node detection rate sensitivity and specificity has been reported to be 100%, except for a few cases. In the studies on cervical cancer, sentinel node detection rates have been reported around 80–86%, a little lower than those in vulva cancer, and negative predictive value has been reported about 99%. It is relatively new in endometrial cancer, where its detection rate varies between 50 and 80%. Studies about vulvar melanoma and vaginal cancers are generally case reports. Although it has not been supported with multicenter randomized and controlled studies including larger case series, study results reported by various centers around the world are harmonious and mutually supportive particularly in vulva cancer, and cervix cancer. Even though it does not seem possible to replace the traditional approaches in these two cancers, it is still a serious alternative for the future. We believe that it is important to increase and support the studies that will strengthen the weaknesses of the method, among which there are detection of micrometastases and increasing detection rates, and render it usable in routine clinical practice

Circulating levels of insulin-like growth factor-I (IGF-I) correlate with disease status in leprosy

<p>Abstract</p> <p>Background</p> <p>Caused by <it>Mycobacterium leprae </it>(ML), leprosy presents a strong immune-inflammatory component, whose status dictates both the clinical form of the disease and the occurrence of reactional episodes. Evidence has shown that, during the immune-inflammatory response to infection, the growth hormone/insulin-like growth factor-I (GH/IGF-I) plays a prominent regulatory role. However, in leprosy, little, if anything, is known about the interaction between the immune and neuroendocrine systems.</p> <p>Methods</p> <p>In the present retrospective study, we measured the serum levels of IGF-I and IGBP-3, its major binding protein. These measurements were taken at diagnosis in nonreactional borderline tuberculoid (NR BT), borderline lepromatous (NR BL), and lepromatous (NR LL) leprosy patients in addition to healthy controls (HC). LL and BL patients who developed reaction during the course of the disease were also included in the study. The serum levels of IGF-I, IGFBP-3 and tumor necrosis factor-alpha (TNF-α) were evaluated at diagnosis and during development of reversal (RR) or erythema nodosum leprosum (ENL) reaction by the solid phase, enzyme-labeled, chemiluminescent-immunometric method.</p> <p>Results</p> <p>The circulating IGF-I/IGFBP-3 levels showed significant differences according to disease status and occurrence of reactional episodes. At the time of leprosy diagnosis, significantly lower levels of circulating IGF-I/IGFBP-3 were found in NR BL and NR LL patients in contrast to NR BT patients and HCs. However, after treatment, serum IGF-I levels in BL/LL patients returned to normal. Notably, the levels of circulating IGF-I at diagnosis were low in 75% of patients who did not undergo ENL during treatment (NR LL patients) in opposition to the normal levels observed in those who suffered ENL during treatment (R LL patients). Nonetheless, during ENL episodes, the levels observed in RLL sera tended to decrease, attaining similar levels to those found in NR LL patients. Interestingly, IGF-I behaved contrary to what was observed during RR episodes in R BL patients.</p> <p>Conclusions</p> <p>Our data revealed important alterations in the IGF system in relation to the status of the host immune-inflammatory response to ML while at the same time pointing to the circulating IGF-I/IGFBP-3 levels as possible predictive biomarkers for ENL in LL patients at diagnosis.</p

Methamphetamine Increases LPS-Mediated Expression of IL-8, TNF-α and IL-1β in Human Macrophages through Common Signaling Pathways

The use of methamphetamine (MA) has increased in recent years, and is a major health concern throughout the world. The use of MA has been associated with an increased risk of acquiring HIV-1, along with an increased probability of the acquisition of various sexually transmitted infections. In order to determine the potential effects of MA exposure in the context of an infectious agent, U937 macrophages were exposed to various combinations of MA and bacterial lipopolysaccharide (LPS). Treatment with MA alone caused significant increases in the levels of TNF-α, while treatment with both MA and LPS resulted in significant increases in TNF-α, IL-1β and the chemokine IL-8. The increases in cytokine or chemokine levels seen when cells were treated with both LPS and MA were generally greater than those increases observed when cells were treated with only LPS. Treatment with chemical inhibitors demonstrated that the signal transduction pathways including NF-kB, MAPK, and PI3-Akt were involved in mediating the increased inflammatory response. As discussed in the paper, these pathways appear to be utilized by both MA and LPS, in the induction of these inflammatory mediators. Since these pathways are involved in the induction of inflammation in response to other pathogens, this suggests that MA-exacerbated inflammation may be a common feature of infectious disease in MA abusers

Pliocene-Quaternary crustal melting in central and northern Tibet and insights into crustal flow

There is considerable controversy over the nature of geophysically recognized low-velocity-high-conductivity zones (LV-HCZs) within the Tibetan crust, and their role in models for the development of the Tibetan Plateau. Here we report petrological and geochemical data on magmas erupted 4.7-0.3 Myr ago in central and northern Tibet, demonstrating that they were generated by partial melting of crustal rocks at temperatures of 700-1,050°C and pressures of 0.5-1.5 GPa. Thus Pliocene-Quaternary melting of crustal rocks occurred at depths of 15-50 km in areas where the LV-HCZs have been recognized. This provides new petrological evidence that the LV-HCZs are sources of partial melt. It is inferred that crustal melting played a key role in triggering crustal weakening and outward crustal flow in the expansion of the Tibetan Plateau

Uptake and 4-week outcomes of an ‘opt-out’ smoking cessation referral strategy in a London-based lung cancer screening setting

IntroductionLung cancer screening (LCS) enables the delivery of smoking cessation interventions to a population experiencing long-term tobacco dependence, but the optimal delivery method remains unclear. Here, we report uptake and short-term outcomes of an ‘opt-out’ smoking cessation referral strategy in an LCS cohort.MethodsIndividuals currently smoking tobacco who attended a face-to-face lung health check in the SUMMIT study (NCT03934866) were offered very brief advice on smoking cessation and where possible, an ‘opt-out’ referral to their local stop smoking service (SSS). Aggregate data on referral outcomes were obtained from each SSS individually.Results33.7% (n=2090/6203) of individuals currently smoking tobacco consented to a practitioner-made ‘opt-out’ smoking cessation referral. 42.7% (n=893/2090) of these individuals resided in boroughs where SSS were not present or required self-referral. Males (adjusted OR (aOR) 1.16), younger individuals (55–59: aOR 1.70, 60–64: aOR 1.71 and 65–69: aOR 1.78) and those of ethnic minority backgrounds (Asian: aOR 1.31, Black: aOR 1.71 and Mixed: aOR 1.72) were more likely to consent, while individuals from the most deprived socioeconomic quintile were less likely to do so (aOR 0.65).High level of motivation to quit within a defined time frame (aOR 1.92), previous quit attempts in the past 12 months (1–4: aOR 1.65 and ≥5: aOR 1.54) and time to first cigarette of ≤60 min (&lt;5: aOR 2.07, 6–30: aOR 1.55 and 31–60: aOR 1.56) were measures of tobacco dependence associated with a higher likelihood of providing consent.Outcomes were available for 742 referrals. An appointment with the service was accepted by 47.3% (n=351/742) of individuals, following which 65.5% (n=230/351) set a quit date. The 4-week quit rate among those setting a quit date and all individuals referred was 57.4% (n=132/230) and 17.8% (n=132/742), respectively.ConclusionA proactive, ‘opt-out’ smoking cessation referral strategy for individuals currently smoking tobacco who interact with an LCS programme may be beneficial.</jats:sec

Obscured phylogeny and possible recombinational dormancy in Escherichia coli

<p>Abstract</p> <p>Background</p> <p><it>Escherichia coli </it>is one of the best studied organisms in all of biology, but its phylogenetic structure has been difficult to resolve with current data and analytical techniques. We analyzed single nucleotide polymorphisms in chromosomes of representative strains to reconstruct the topology of its emergence.</p> <p>Results</p> <p>The phylogeny of <it>E. coli </it>varies according to the segment of chromosome analyzed. Recombination between extant <it>E. coli </it>groups is largely limited to only three intergroup pairings.</p> <p>Conclusions</p> <p>Segment-dependent phylogenies most likely are legacies of a complex recombination history. However, <it>E. coli </it>are now in an epoch in which they no longer broadly share DNA. Using the definition of species as organisms that freely exchange genetic material, this recombinational dormancy could reflect either the end of <it>E. coli </it>as a species, or herald the coalescence of <it>E. coli </it>groups into new species.</p