Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.

Are clinicians being prepared to care for abused women? A survey of health professional education in Ontario, Canada

Background: The current project undertook a province-wide survey and environmental scan of educational opportunities available to future health care providers on the topic of intimate partner violence (IPV) against women. Methods: A team of experts identified university and college programs in Ontario, Canada as potential providers of IPV education to students in health care professions at the undergraduate and post-graduate levels. A telephone survey with contacts representing these programs was conducted between October 2005 and March 2006. The survey asked whether IPV-specific education was provided to learners, and if so, how and by whom. Results: In total, 222 eligible programs in dentistry, medicine, nursing and other allied health professions were surveyed, and 95% (212/222) of programs responded. Of these, 57% reported offering some form of IPV-specific education, with undergraduate nursing (83%) and allied health (82%) programs having the highest rates. Fewer than half of undergraduate medical (43%) and dentistry (46%) programs offered IPV content. Postgraduate programs ranged from no IPV content provision (dentistry) to 41% offering content (nursing). Conclusion: Significant variability exists across program areas regarding the methods for IPV education, its delivery and evaluation. The results of this project highlight that expectations for an active and consistent response by health care professionals to women experiencing the effects of violence may not match the realities of professional preparation

Assessing the impact of prescribed medicines on health outcomes

This paper reviews methods that can be used to assess the impact of medicine use on population health outcomes. In the absence of a gold standard, we argue that a convergence of evidence from different types of studies using multiple methods of independent imperfection provides the best bases for attributing improvements in health outcomes to the use of medicines. The major requirements are: good evidence that a safe and effective medicine is being appropriately prescribed; covariation between medicine use and improved health outcomes; and being able to discount alternative explanations of the covariation (via covariate adjustment, propensity analyses and sensitivity analyses), so that medicine use is the most plausible explanation of the improved health outcomes. The strongest possible evidence would be provided by the coherence of the following types of evidence: (1) individual linked data showing that patients are prescribed the medicine, there are reasonable levels of patient compliance, and there is a relationship between medicine use and health improvements that is not explained by other factors; (2) ecological evidence of improvements in these health outcomes in the population in which the medicine is used. Confidence in these inferences would be increased by: the replication of these results in comparable countries and consistent trends in population vital statistics in countries that have introduced the medicine; and epidemiological modelling indicating that changes observed in population health outcomes are plausible given the epidemiology of the condition being treated

Inferring causal molecular networks: empirical assessment through a community-based effort.

It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense

The self-organizing fractal theory as a universal discovery method: the phenomenon of life

A universal discovery method potentially applicable to all disciplines studying organizational phenomena has been developed. This method takes advantage of a new form of global symmetry, namely, scale-invariance of self-organizational dynamics of energy/matter at all levels of organizational hierarchy, from elementary particles through cells and organisms to the Universe as a whole. The method is based on an alternative conceptualization of physical reality postulating that the energy/matter comprising the Universe is far from equilibrium, that it exists as a flow, and that it develops via self-organization in accordance with the empirical laws of nonequilibrium thermodynamics. It is postulated that the energy/matter flowing through and comprising the Universe evolves as a multiscale, self-similar structure-process, i.e., as a self-organizing fractal. This means that certain organizational structures and processes are scale-invariant and are reproduced at all levels of the organizational hierarchy. Being a form of symmetry, scale-invariance naturally lends itself to a new discovery method that allows for the deduction of missing information by comparing scale-invariant organizational patterns across different levels of the organizational hierarchy

Structure-Based Predictive Models for Allosteric Hot Spots

In allostery, a binding event at one site in a protein modulates the behavior of a distant site. Identifying residues that relay the signal between sites remains a challenge. We have developed predictive models using support-vector machines, a widely used machine-learning method. The training data set consisted of residues classified as either hotspots or non-hotspots based on experimental characterization of point mutations from a diverse set of allosteric proteins. Each residue had an associated set of calculated features. Two sets of features were used, one consisting of dynamical, structural, network, and informatic measures, and another of structural measures defined by Daily and Gray [1]. The resulting models performed well on an independent data set consisting of hotspots and non-hotspots from five allosteric proteins. For the independent data set, our top 10 models using Feature Set 1 recalled 68–81% of known hotspots, and among total hotspot predictions, 58–67% were actual hotspots. Hence, these models have precision P = 58–67% and recall R = 68–81%. The corresponding models for Feature Set 2 had P = 55–59% and R = 81–92%. We combined the features from each set that produced models with optimal predictive performance. The top 10 models using this hybrid feature set had R = 73–81% and P = 64–71%, the best overall performance of any of the sets of models. Our methods identified hotspots in structural regions of known allosteric significance. Moreover, our predicted hotspots form a network of contiguous residues in the interior of the structures, in agreement with previous work. In conclusion, we have developed models that discriminate between known allosteric hotspots and non-hotspots with high accuracy and sensitivity. Moreover, the pattern of predicted hotspots corresponds to known functional motifs implicated in allostery, and is consistent with previous work describing sparse networks of allosterically important residues

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version

Laparoscopic management of appendicitis and symptomatic cholelithiasis during pregnancy

BACKGROUND: Laparoscopic surgery during pregnancy is a challenging procedure that most surgeons are reluctant to perform. The objective of this study was to evaluate whether laparoscopic appendectomy and cholecystectomy is safe in pregnant women. The management of these situations remains controversial. We report a single center study describing the successful management of 16 patients during pregnancy. METHODS: More than 3,356 laparoscopic procedures were performed in our institutions between May 1990 and June 2005. Sixteen of these patients were operated on in the second and third trimester between 22 and 32 weeks of estimated gestational age. We performed 11 laparoscopic appendectomies and 5 laparoscopic cholecystectomies. We also reviewed the management and operative technique used in these patients. RESULTS: In this study, the laparoscopic appendectomy or cholecystectomy was performed successfully in all patients. Three patients were in their second trimester, weeks 22, 23, and 25, and 13 were in the third trimester, weeks 27 (three patients), 28 (five patients), 31 (three patients), and 32 (two patients). No maternal or fetal morbidity occurred. Open laparoscopy was performed safely in all patients and all patients delivered healthy babies. CONCLUSION: From our experience laparoscopic management of appendicitis and biliary colic during pregnancy is safe, however the second trimester is preferable for laparoscopic cholecystectomy. Pregnancy is not a contraindication to the laparoscopic approach to appendicitis or symptomatic cholelithiasis. We believe that laparoscopic operations, when performed by experienced surgeons, are safe and even preferable for the mother and the fetu

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

ICAR: endoscopic skull‐base surgery

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