Antibiotic resistant bacteria in terrestrial and aquatic environments: A review

Antibiotic resistant bacteria have become increasingly widespread in environment and their prevalence is a serious problem for health. The rise and spread of this resistance is primarily due to overuse of antibiotics in clinical therapeutics and as growth promoters for livestock. Overuse undermines the usefulness of antibiotics by giving a selective advantage to microbes that are resistant. The problem has been exacerbated by the emergence of bacteria that are resistant to multiple antibiotics, and by the ability of these resistance determinants to spread horizontally between different bacteria via horizontal gene transfer. Such transfer can, for example, take place in the guts of farm animals, which can become reservoirs of multiple antibiotic resistant bacteria (MARB). Antibiotics and MARB enter the environment via wastewater, especially from hospitals and pharmaceutical plants, and through agricultural runoff, leading to contamination of surface and ground water. This is a serious problem in arid regions such as Oman where wastewater is recycled for irrigation and recharging aquifers. Even treatment with chlorine does not completely remove bacteria from wastewater or prevent their re-growth in downstream distribution systems. MARB can reach humans via contaminated food and drinking water, or directly from the environment. Agricultural runoff and sewage, either treated or untreated, are also the main sources of antibiotic resistant bacteria in coastal sea water. It is necessary to use antibiotics more prudently in medicine, treat wastewater more effectively, eliminate the discharge of untreated waste into the environment, and curtail the profligate use of antibiotics as growth promoters for livestock.Â

A Formalization of the Theorem of Existence of First-Order Most General Unifiers

This work presents a formalization of the theorem of existence of most general unifiers in first-order signatures in the higher-order proof assistant PVS. The distinguishing feature of this formalization is that it remains close to the textbook proofs that are based on proving the correctness of the well-known Robinson's first-order unification algorithm. The formalization was applied inside a PVS development for term rewriting systems that provides a complete formalization of the Knuth-Bendix Critical Pair theorem, among other relevant theorems of the theory of rewriting. In addition, the formalization methodology has been proved of practical use in order to verify the correctness of unification algorithms in the style of the original Robinson's unification algorithm.Comment: In Proceedings LSFA 2011, arXiv:1203.542

Isolation of chromosome clusters from metaphase-arrested HeLa cells

We have developed a simplified approach for the isolation of metaphase chromosomes from HeLa cells. In this method, all the chromosomes from a cell remain together in a bundle which we call a “metaphase chromosome cluster”. Cells are arrested to 90–95% in metaphase, collected by centrifugation, extracted with non-ionic detergent in a low ionic strength buffer at neutral pH, and homogenised to strip away the cytoskeleton. The chromosome clusters which are released can then be isolated in a crude state by pelleting or they can be purified away from nearly all the interphase nuclei and cytoplasmic debris by banding in a Percoll TM density gradient. — This procedure has the advantages that it is quick and easy, metaphase chromatin is recovered in high yield, and Ca ++ is not needed to stabilise the chromosomes. Although the method does not yield individual chromosomes, it is nevertheless very useful for both structural and biochemical studies of mitotic chromatin. The chromosome clusters also make possible biochemical and structural studies of what holds the different chromosomes together. Such information could be useful in improving chromosome isolation procedures and for understanding suprachromosomal organisation of the nucleus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47359/1/412_2004_Article_BF00327351.pd

Quantum phase transitions from topology in momentum space

Many quantum condensed matter systems are strongly correlated and strongly interacting fermionic systems, which cannot be treated perturbatively. However, physics which emerges in the low-energy corner does not depend on the complicated details of the system and is relatively simple. It is determined by the nodes in the fermionic spectrum, which are protected by topology in momentum space (in some cases, in combination with the vacuum symmetry). Close to the nodes the behavior of the system becomes universal; and the universality classes are determined by the toplogical invariants in momentum space. When one changes the parameters of the system, the transitions are expected to occur between the vacua with the same symmetry but which belong to different universality classes. Different types of quantum phase transitions governed by topology in momentum space are discussed in this Chapter. They involve Fermi surfaces, Fermi points, Fermi lines, and also the topological transitions between the fully gapped states. The consideration based on the momentum space topology of the Green's function is general and is applicable to the vacua of relativistic quantum fields. This is illustrated by the possible quantum phase transition governed by topology of nodes in the spectrum of elementary particles of Standard Model.Comment: 45 pages, 17 figures, 83 references, Chapter for the book "Quantum Simulations via Analogues: From Phase Transitions to Black Holes", to appear in Springer lecture notes in physics (LNP

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950–2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2•72 (95% uncertainty interval [UI] 2•66–2•79) in 2000 to 2•31 (2•17–2•46) in 2019. Global annual livebirths increased from 134•5 million (131•5–137•8) in 2000 to a peak of 139•6 million (133•0–146•9) in 2016. Global livebirths then declined to 135•3 million (127•2–144•1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2•1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27•1% (95% UI 26•4–27•8) of global livebirths. Global life expectancy at birth increased from 67•2 years (95% UI 66•8–67•6) in 2000 to 73•5 years (72•8–74•3) in 2019. The total number of deaths increased from 50•7 million (49•5–51•9) in 2000 to 56•5 million (53•7–59•2) in 2019. Under-5 deaths declined from 9•6 million (9•1–10•3) in 2000 to 5•0 million (4•3–6•0) in 2019. Global population increased by 25•7%, from 6•2 billion (6•0–6•3) in 2000 to 7•7 billion (7•5–8•0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58•6 years (56•1–60•8) in 2000 to 63•5 years (60•8–66•1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation: Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global burden of 87 risk factors in 204 countries and territories, 1990�2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. Methods: GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk�outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk�outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk�outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. Findings: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95 uncertainty interval UI 9·51�12·1) deaths (19·2% 16·9�21·3 of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12�9·31) deaths (15·4% 14·6�16·2 of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253�350) DALYs (11·6% 10·3�13·1 of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0�9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10�24 years, alcohol use for those aged 25�49 years, and high systolic blood pressure for those aged 50�74 years and 75 years and older. Interpretation: Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Supporting reuse of Event-B developments through generic instantiation

It is believed that reusability in formal development should reduce the time and cost of formal modelling within a production environment. Along with the ability to reuse formal models, it is desirable to avoid unnecessary re-proof when reusing models. Event-B is a formal method that allows modelling and refinement of systems. Event-B supports generic developments through the context construct. Nevertheless Event-B lacks the ability to instantiate and reuse generic developments in other formal developments. We propose a way of instantiating generic models and extending the instantiation to a chain of refinements. We define sufficient proof obligations to ensure that the proofs associated to a generic development remain valid in an instantiated development thus avoiding re-proofs

Maturation of the head of bacteriophage T4. V. A possible DNA packaging mechanism: in vitro cleavage of the head proteins and the structure of the core of the polyhead

The most recent developments in studies on the maturation of the head of bacteriophage T4 are described and discussed. The major features of the maturation steps of the head are the following: (a) The viral DNA is pulled into an empty head in a series of events. (b) Cleavage of two core proteins, P22 (MW = 31,000), to small fragments and the internal protein IPIII (MW = 23,000) to IPIII* (MW = 21,000) appears to be intimately linked to the DNA packaging event, whereas the cleavage of the major head protein of the viral coat, P23 (MW = 55,000), to P23* (MW = 45,000) precedes the DNA packaging event. The P22 core proteins appear to be the precursors of the well-known, highly acidic internal peptides. We have tested the idea that these internal peptides collapse DNA by a repulsive interaction as various polymers like polyethylene oxide (PeO) and polyacrylate(PAA) do. We found that high concentrations of the internal peptides, polyaspartic acid, and polyglutamic acid, collapse DNA. This supports the idea that repulsive interactions with the internal peptides may collapse the DNA inside the head, and thus pull the DNA in. The structure of the DNA collapsed by PeO was studied with the electron microscope and contrasted with the structure of DNA collapsed by polylysine. We find PeO collapses T4 DNA into compact particles best described as a ball of string, of about the size of the T4 head. Two structures are seen in preparations of polylysine-collapsed DNA. One has the shape of a donut and the DNA strand appears to be radially distributed as a spiral; the other is a stemlike structure in which the DNA is folded back and forth in a pleated structure. The aberrant tubular polyhead contains the precursor protein P23, P22, and the internal proteins IPIII and IPII. Addition of chloroform to a polyhead preparation extracts the proteins P22, IPIII, and IPII. This removes the inside material (core) seen in polyheads prior to the chloroform extraction, as judged by electron microscopy. We conclude that P22, IPIII, and IPII (and supposedly IPI) are the major structural constituents of the core of polyheads, while P23 is the major constituent of the outer coat. Structural studies reveal that the core of the polyhead is highly organized into a helical structure consisting of 4–6 helical chains wound about a hollow center of approximately 150 a diameter. Cleavage of the various head proteins occurs when partially purified polyheads are incubated at 37°C. In a 100 minute incubation, about 60–70% of P23 (MW = 55,000) is converted to P23* (MW = 45,000) and a significant conversion of IPIII (MW = 23,000) to IPIII* (MW = 21,000) is seen. The protein P22 (MW = 31,000) disappears during this incubation and is supposedly cleaved to small fragments. The in vitro products, P23* and IPIII*, have the same molecular weight as the in vivo products, suggesting that the protease cleavage is specific. However, several other protein fragments are generated during the in vitro cleavage reaction which have not been observed in vivo. Appropriate mutant studies reveal that the products of genes 21 and 22 are required for these in vitro cleavage reactions.</p