Quorum Sensing Controls Adaptive Immunity through the Regulation of Multiple CRISPR-Cas Systems

Bacteria commonly exist in high cell density populations, making them prone to viral predation and horizontal gene transfer (HGT) through transformation and conjugation. To combat these invaders, bacteria possess an arsenal of defenses, such as CRISPR-Cas adaptive immunity. Many bacterial populations coordinate their behavior as cell density increases, using quorum sensing (QS) signaling. In this study, we demonstrate that QS regulation results in increased expression of the type I-E, I-F, and III-A CRISPR-Cas systems in $\textit{Serratia}$ cells in high-density populations. Strains unable to communicate via QS were less effective at defending against invaders targeted by any of the three CRISPR-Cas systems. Additionally, the acquisition of immunity by the type I-E and I-F systems was impaired in the absence of QS signaling. We propose that bacteria can use chemical communication to modulate the balance between community-level defense requirements in high cell density populations and host fitness costs of basal CRISPR-Cas activity.This work was supported by a Rutherford Discovery Fellowship (P.C.F.) from the Royal Society of New Zealand (RSNZ) and the Marsden Fund, RSNZ. A.G.P. was supported by a University of Otago Doctoral Scholarship. G.P.C.S. is funded by the Biotechnology and Biological Sciences Research Council, UK

Antipsychotic dose escalation as a trigger for Neuroleptic Malignant Syndrome (NMS): literature review and case series report

Background: “Neuroleptic malignant syndrome” (NMS) is a potentially fatal idiosyncratic reaction to any medication which affects the central dopaminergic system. Between 0.5% and 1% of patients exposed to antipsychotics develop the condition. Mortality rates may be as high as 55% and many risk factors have been reported. Although rapid escalation of antipsychotic dose is thought to be an important risk factor, to date it has not been the focus of a published case series or scientifically defined. <p/>Aims: To identify cases of NMS and review risk factors for its development with a particular focus on rapid dose escalation in the 30 days prior to onset. <p/>Methodology: A review of the literature on rapid dose escalation was undertaken and a pragmatic definition of “rapid dose escalation” was made. NMS cases were defined using DSM-IV criteria and systematically identified within a secondary care mental health service. A ratio of titration rate was calculated for each NMS patient and “rapid escalators” and “non rapid escalators” were compared. <p/>Results: 13 cases of NMS were identified. A progressive mean dose increase 15 days prior to the confirmed episode of NMS was observed (241.7mg/day during days 1-15 to 346.9mg/day during days 16-30) and the mean ratio of dose escalation for NMS patients was 1.4. Rapid dose escalation was seen in 5/13 cases and non rapid escalators had markedly higher daily cumulative antipsychotic dose compared to rapid escalators. <p/>Conclusions: Rapid dose escalation occurred in less than half of this case series (n=5, 38.5%), although there is currently no consensus on the precise definition of rapid dose escalation. Cumulative antipsychotic dose – alongside other known risk factors - may also be important in the development of NMS

Kilohertz quasi-periodic oscillations in low-mass X-ray binaries

In early 1996 a series of discoveries begun with NASA's Rossi X-ray Timing Explorer of a new, up to then unknown astrophysical phenomenon. It turned out that accreting low magnetic-field neutron stars show quasi-periodic oscillations in their X-ray flux at rates of up to more than a kilohertz. These kHz QPO, now reported from eleven different systems, are among the fastest phenomena in the sky and can provide us with new information about the fundamental properties of neutron stars and help testing general relativity in the strong-field regime. If, for example, their frequencies can be identified with the Keplerian frequencies of matter in orbit around a 1.4 Solar-mass neutron star, then the radius of the star would have to be less than 15 km, which directly constrains the equation of state of bulk nuclear-density matter, and for an only slightly tighter orbit or slightly more massive neutron star the orbital radius would equal the Schwarzschild-geometry general-relativistic marginally stable orbit (12.5 km for a 1.4 Solar mass object). So far all models that have been put forward for explaining the new phenomenon have encountered problems. In this paper I review the relatively simple and highly suggestive phenomenology as it has emerged from the data up to now, and discuss some of the proposed models.Comment: To be published in the Proceedings of the Wise Observatory 25th Anniversary Symposium "Astronomical Time Series", Tel Aviv, January 199

Iron Age and Anglo-Saxon genomes from East England reveal British migration history

British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain

The Dynamics of Nestedness Predicts the Evolution of Industrial Ecosystems

In economic systems, the mix of products that countries make or export has been shown to be a strong leading indicator of economic growth. Hence, methods to characterize and predict the structure of the network connecting countries to the products that they export are relevant for understanding the dynamics of economic development. Here we study the presence and absence of industries at the global and national levels and show that these networks are significantly nested. This means that the less filled rows and columns of these networks' adjacency matrices tend to be subsets of the fuller rows and columns. Moreover, we show that nestedness remains relatively stable as the matrices become more filled over time and that this occurs because of a bias for industries that deviate from the networks' nestedness to disappear, and a bias for the missing industries that reduce nestedness to appear. This makes the appearance and disappearance of individual industries in each location predictable. We interpret the high level of nestedness observed in these networks in the context of the neutral model of development introduced by Hidalgo and Hausmann (2009). We show that, for the observed fills, the model can reproduce the high level of nestedness observed in these networks only when we assume a high level of heterogeneity in the distribution of capabilities available in countries and required by products. In the context of the neutral model, this implies that the high level of nestedness observed in these economic networks emerges as a combination of both, the complementarity of inputs and heterogeneity in the number of capabilities available in countries and required by products. The stability of nestedness in industrial ecosystems, and the predictability implied by it, demonstrates the importance of the study of network properties in the evolution of economic networks.Comment: 26 page

Rapid intraoperative insulin assay: a novel method to differentiate insulinoma from nesidioblastosis in the pediatric patient

Introduction: Hyperinsulinism is the most common cause of recurrent and persistent hypoglycemia in infancy and childhood. Causes can include nesidioblastosis, pancreatic islet cell tumors such as insulinoma, and associations with multiple endocrine neoplasia syndromes. Although new, improved imaging techniques have allowed for more precise preoperative localization of insulinomas, the differentiation of nesidioblastosis and insulinoma, particularly in children, can be challenging. To improve intraoperative localization and confirmation of successful resection of insulinoma, a novel hormonal assay, the rapid intraoperative insulin assay, is reported for the first time in a pediatric patient. This intraoperative radioimmunoassay for insulin yields results within several minutes and confirms complete resection of insulinoma. Case description: We present a case of pancreatic insulinoma in a child with symptoms of severe hypoglycemia, causing seizures. The insulinoma was enucleated laparoscopically, and rapid intra-operative insulin assay used to determine the success of the procedure. Discussion and evaluation: This rapid intra-operative test provides a valuable adjunct for determining complete excision in complicated cases of recurrent or questionable insulinoma. Although not a common problem, for pediatric patients in whom the diagnosis is not clear, this test may provide a novel approach to confirming disease. Conclusion: We propose the use of this assay in facilitating intra-operative resection and confirmation of complete excision in pediatric patients. This population may especially benefit from this novel assay to confirm complete resection and to differentiate multiple etiologies of hyperinsulinism

Phylogeny and Taxonomy of the Round-Eared Sengis or Elephant-Shrews, Genus Macroscelides (Mammalia, Afrotheria, Macroscelidea)

The round-eared sengis or elephant-shrews (genus Macroscelides) exhibit striking pelage variation throughout their ranges. Over ten taxonomic names have been proposed to describe this variation, but currently only two taxa are recognized (M. proboscideus proboscideus and M. p. flavicaudatus). Here, we review the taxonomic history of Macroscelides, and we use data on the geographic distribution, morphology, and mitochondrial DNA sequence to evaluate the current taxonomy. Our data support only two taxa that correspond to the currently recognized subspecies M. p. proboscideus and M. p. flavicaudatus. Mitochondrial haplotypes of these two taxa are reciprocally monophyletic with over 13% uncorrected sequence divergence between them. PCA analysis of 14 morphological characters (mostly cranial) grouped the two taxa into non-overlapping clusters, and body mass alone is a relatively reliable distinguishing character throughout much of Macroscelides range. Although fieldworkers were unable to find sympatric populations, the two taxa were found within 50 km of each other, and genetic analysis showed no evidence of gene flow. Based upon corroborating genetic data, morphological data, near sympatry with no evidence of gene flow, and differences in habitat use, we elevate these two forms to full species

Mechanisms of improved survival from intensive followup in colorectal cancer: a hypothesis

A meta-analysis of six randomised trials demonstrated that intensive followup in colorectal cancer was associated with an absolute reduction in all-cause 5-year mortality of 10% (95% confidence interval (CI): 4–16) – however, only two percent (95% CI: 0–5) was attributable to cure from salvage re-operations. We postulate that other factors, such as increased psychological well-being and/or altered lifestyle, and/or improved treatment of coincidental disease may contribute to the remaining lives saved, and form important future research questions

The use of simulation to prepare and improve responses to infectious disease outbreaks like COVID-19: practical tips and resources from Norway, Denmark, and the UK.

In this paper, we describe the potential of simulation to improve hospital responses to the COVID-19 crisis. We provide tools which can be used to analyse the current needs of the situation, explain how simulation can help to improve responses to the crisis, what the key issues are with integrating simulation into organisations, and what to focus on when conducting simulations. We provide an overview of helpful resources and a collection of scenarios and support for centre-based and in situ simulations

Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6

Background: Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV. Methods: We investigated the effect of the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor R59949 and the phospholipase C inhibitor U73122 on the strength of HPV were investigated compared to those on non-hypoxia-induced vasoconstriction elicited by the thromboxane mimeticum U46619. Results: OAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, U73122, a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the inactive form of U73122, had no effect on HPV. Conclusion: These findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG