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"Matthews, Andrew"
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اتبع قلبك : تجد هدفك في الحياة والعمل
يتناول كتاب (اتبع قلبك : تجد هدفك في الحياة والعمل) والذي قام بتأليفه (أندرو ماثيوز) في حوالي (144) صفحة من القطع المتوسط موضوع (تحقيق الذات) مستعرضا المحتويات التالية : الفصل الأول : لماذا أحتاج إلى المصائب، الفصل الثاني : قانون البذرة، الفصل الثالث : المعتقدات، الفصل الرابع : التعلق، الفصل الخامس : لماذا التفكير الإيجابي، الفصل السادس : أعمل ما تحب، الفصل السابع : خذ الخطوة الأولى، الفصل الثامن : الحظ، الفصل التاسع : لم نحن هنا ؟، الفصل العاشر : حين تتغير.
Book
Increased copy number couples the evolution of plasmid horizontal transmission and plasmid-encoded antibiotic resistance
Conjugative plasmids are mobile elements that spread horizontally between bacterial hosts and often confer adaptive phenotypes, including antimicrobial resistance (AMR). Theory suggests that opportunities for horizontal transmission favor plasmids with higher transfer rates, whereas selection for plasmid carriage favors less-mobile plasmids. However, little is known about the mechanisms leading to variation in transmission rates in natural plasmids or the resultant effects on their bacterial host. We investigated the evolution of AMR plasmids confronted with different immigration rates of susceptible hosts. Plasmid RP4 did not evolve in response to the manipulations, but plasmid R1 rapidly evolved up to 1,000-fold increased transfer rates in the presence of susceptible hosts. Most evolved plasmids also conferred on their hosts the ability to grow at high concentrations of antibiotics. This was because plasmids evolved greater copy numbers as a function of mutations in the copA gene controlling plasmid replication, causing both higher transfer rates and AMR. Reciprocally, plasmids with increased conjugation rates also evolved when selecting for high levels of AMR, despite the absence of susceptible hosts. Such correlated selection between plasmid transfer and AMR could increase the spread of AMR within populations and communities.
Journal Article
كون أصدقاء : دليلك للتأقلم مع الآخرين
هذا الكتاب بسيط وعملي وممتع جدا ويتحدث عن الآخرين ومن نحب ومن يقومون بمساعدتنا ومن يعتمدون علينا ومن نرغب في رؤيتهم ومن نرغب في الابتعاد عنهم كما يتحدث هذا الكتاب أيضا عن كيفية الاستمتاع بالآخرين وكيفية التعامل مع المتشائمين وكيف يمكن أن تقول كلمة \"لا\" أحيانا وكيفية التغلب على الثرثرة والحماقة والغضب، كما يؤكد الكتاب هذا المفهوم \"لو أردت الصداقة فيجب أن تكون صديقا أولا\".
BOOK
Plasmid streamlining drives the extinction of antibiotic resistance plasmids under selection for horizontal transmission
Conjugative plasmids carrying antimicrobial resistance (AMR) genes are critical for the spread of AMR, due to their ability to transmit horizontally between bacterial hosts. We previously observed that during experimental evolution in the presence of abundant susceptible Escherichia coli hosts, the AMR plasmid R1 rapidly evolves variants with increased horizontal transmission due to mutations causing increased plasmid copy number. Yet AMR was progressively lost from the evolving populations. Here, we show that AMR loss was associated with evolution of streamlined plasmids in which the AMR region is spontaneously deleted, making plasmid carriage undetectable by plating on selective antibiotic-containing media. These plasmids transmit both vertically and horizontally more efficiently than the ancestral AMR plasmid, driving AMR extinction in bacterial populations and effectively acting as an intrinsic defence against AMR plasmids. A simple model of plasmid competition further shows that any horizontal or vertical transmission advantage conferred by plasmid streamlining would be enough to drive the displacement of competing AMR plasmids, with a given horizontal transmission advantage leading to faster replacement in conditions favoring horizontal transmission. Our results suggest that within-host plasmid evolution or engineered streamlined plasmids could be exploited to limit the spread of AMR in natural populations of bacteria.
Journal Article
Shifts along the parasite–mutualist continuum are opposed by fundamental trade-offs
Theory suggests that symbionts can readily evolve more parasitic or mutualistic strategies with respect to hosts. However, many symbionts have stable interactions with hosts that improve nutrient assimilation or confer protection from pathogens. We explored the potential for evolution of increased parasitism or decreased parasitism and mutualism in a natural gut symbiosis between larvae of Plutella xylostella and the microbe Enterobacter cloacae. We focused on interactions with the pathogen, Bacillus thuringiensis : selecting for parasitism in terms of facilitating pathogen infection, or increased mutualism in terms of host protection. Selection for parasitism led to symbionts increasing pathogen-induced mortality but reduced their competitive ability with pathogens and their in vitro growth rates. Symbionts did not evolve to confer protection from pathogens. However, several lineages evolved reduced parasitism, primarily in terms of moderating impacts on host growth, potentially because prudence pays dividends through increased host size. Overall, the evolution of increased parasitism was achievable but was opposed by trade-offs likely to reduce fitness. The evolution of protection may not have occurred because suppressing growth of B. thuringiensis in the gut might provide only weak protection or because evolution towards protective interactions was opposed by the loss of competitive fitness in symbionts.
Journal Article
Targeting Menin and CD47 to Address Unmet Needs in Acute Myeloid Leukemia
After forty years of essentially unchanged treatment in acute myeloid leukemia (AML), innovation over the past five years has been rapid, with nine drug approvals from 2016 to 2021. Increased understanding of the molecular changes and genetic ontology of disease have led to targeting mutations in isocitrate dehydrogenase, FMS-like tyrosine kinase 3 (FLT3), B-cell lymphoma 2 and hedgehog pathways. Yet outcomes remain variable; especially in defined molecular and genetic subgroups such as NPM1 (Nucleophosmin 1) mutations, 11q23/KMT2A rearranged and TP53 mutations. Emerging therapies seek to address these unmet needs, and all three of these subgroups have promising new therapeutic approaches. Here, we will discuss the normal biological roles of menin in acute leukemia, notably in KMT2A translocations and NPM1 mutation, as well as current drug development. We will also explore how CD47 inhibition may move immunotherapy into front-line settings and unlock new treatment strategies in TP53 mutated disease. We will then consider how these new therapeutic advances may change the management of AML overall.
Journal Article
Biofilms facilitate cheating and social exploitation of β-lactam resistance in Escherichia coli
Gram-negative bacteria such as Escherichia coli commonly resist β-lactam antibiotics using plasmid-encoded β-lactamase enzymes. Bacterial strains that express β-lactamases have been found to detoxify liquid cultures and thus to protect genetically susceptible strains, constituting a clear laboratory example of social protection. These results are not necessarily general; on solid media, for instance, the rapid bactericidal action of β-lactams largely prevents social protection. Here, we tested the hypothesis that the greater tolerance of biofilm bacteria for β-lactams would facilitate social interactions. We used a recently isolated E. coli strain, capable of strong biofilm formation, to compare how cooperation and exploitation in colony biofilms and broth culture drives the dynamics of a non-conjugative plasmid encoding a clinically important β-lactamase. Susceptible cells in biofilms were tolerant of ampicillin—high doses and several days of exposure were required to kill them. In support of our hypothesis, we found robust social protection of susceptible E. coli in biofilms, despite fine-scale physical separation of resistant and susceptible cells and lower rates of production of extracellular β-lactamase. In contrast, social interactions in broth were restricted to a relatively narrow range of ampicillin doses. Our results show that β-lactam selection pressure on Gram-negative biofilms leads to cooperative resistance characterized by a low equilibrium frequency of resistance plasmids, sufficient to protect all cells.
Journal Article
Cardiotoxicity of venetoclax in patients with acute myeloid leukemia: comparison with anthracyclines
Venetoclax is a promising drug for patients with acute myeloid leukemia (AML) ineligible for anthracycline-based treatments. In rats, venetoclax is reported to cause myocardial injury. Our objectives were to report the frequency of cardiovascular (CV) events in patients treated with venetoclax, and, subsequently, to compare CV outcomes in matched patients treated with venetoclax or anthracyclines. Patients diagnosed with AML and treated with venetoclax or anthracyclines from January 2017 to July 2021 were identified. Major adverse cardiac events (MACE, including new-onset heart failure (HF), acute myocardial infarction, new onset atrial fibrillation (AF)) were recorded. Propensity-score method was then used to compare patients treated with venetoclax or anthracyclines. Patients treated with venetoclax (
n
=103) were older, with more hyperlipidemia than patients treated with anthracyclines (
n=
217). However, only 63% of patients treated with venetoclax underwent echocardiographic screening (vs. 93% of patients treated with anthracyclines,
P
< 0.001). Eighteen patients with venetoclax (17%) and 27 patients with anthracyclines (12%) developed MACE, including 10 % of new HF in each group. The median time to MACE was 8 days (interquartile range 5-98 days). In the matched cohort (
n=
132 patients), the cumulative incidence of MACE at one year was not different (17.5 % venetoclax, 9.2% anthracyclines,
p =
0.27). Thus, MACE incidence is similar in matched patients receiving venetoclax or anthracyclines. Close CV monitoring during the early phase of treatment may be helpful in patients treated with venetoclax.
Journal Article
Bacterial Cooperation Causes Systematic Errors in Pathogen Risk Assessment due to the Failure of the Independent Action Hypothesis
The Independent Action Hypothesis (IAH) states that pathogenic individuals (cells, spores, virus particles etc.) behave independently of each other, so that each has an independent probability of causing systemic infection or death. The IAH is not just of basic scientific interest; it forms the basis of our current estimates of infectious disease risk in humans. Despite the important role of the IAH in managing disease interventions for food and water-borne pathogens, experimental support for the IAH in bacterial pathogens is indirect at best. Moreover since the IAH was first proposed, cooperative behaviors have been discovered in a wide range of microorganisms, including many pathogens. A fundamental principle of cooperation is that the fitness of individuals is affected by the presence and behaviors of others, which is contrary to the assumption of independent action. In this paper, we test the IAH in Bacillus thuringiensis (B.t), a widely occurring insect pathogen that releases toxins that benefit others in the inoculum, infecting the diamondback moth, Plutella xylostella. By experimentally separating B.t. spores from their toxins, we demonstrate that the IAH fails because there is an interaction between toxin and spore effects on mortality, where the toxin effect is synergistic and cannot be accommodated by independence assumptions. Finally, we show that applying recommended IAH dose-response models to high dose data leads to systematic overestimation of mortality risks at low doses, due to the presence of synergistic pathogen interactions. Our results show that cooperative secretions can easily invalidate the IAH, and that such mechanistic details should be incorporated into pathogen risk analysis.
Journal Article