The increasing rate of antibiotic resistance and slowing discovery of novel antibiotic treatments presents a growing threat to public health. Here, we consider a simple model of evolution in ...asexually reproducing populations which considers adaptation as a biased random walk on a fitness landscape. This model associates the global properties of the fitness landscape with the algebraic properties of a Markov chain transition matrix and allows us to derive general results on the non-commutativity and irreversibility of natural selection as well as antibiotic cycling strategies. Using this formalism, we analyze 15 empirical fitness landscapes of E. coli under selection by different β-lactam antibiotics and demonstrate that the emergence of resistance to a given antibiotic can be either hindered or promoted by different sequences of drug application. Specifically, we demonstrate that the majority, approximately 70%, of sequential drug treatments with 2-4 drugs promote resistance to the final antibiotic. Further, we derive optimal drug application sequences with which we can probabilistically 'steer' the population through genotype space to avoid the emergence of resistance. This suggests a new strategy in the war against antibiotic-resistant organisms: drug sequencing to shepherd evolution through genotype space to states from which resistance cannot emerge and by which to maximize the chance of successful therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by ...quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a “functional” stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC−/+). Furthermore, we show that, in adenomatous crypts (APC−/−), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30–40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.
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•Somatic mtDNA mutations for quantitative lineage tracing in human intestine•Human intestinal stem cells evolve according to a neutral drift process•Loss of APC causes an increase in the stem cell loss/replacement rate•Intestinal crypts divide once every 30–40 years in the normal human colon
Baker et al. examine the in vivo stem cell biology of human colonic crypts. They reveal that each crypt contains a small number of functional stem cells and that stem cell division is predominantly symmetric and also quantify perturbation of stem cell architecture within adenomas. Additionally, they measure the division rate of human colonic crypts as once every 30–40 years in the healthy colon and demonstrate that the crypt division rate is increased 10-fold within small adenomas.
Purpose:
To evaluate the image quality of virtual monochromatic images synthesized from dual-source dual-energy computed tomography (CT) in comparison with conventional polychromatic single-energy CT ...for the same radiation dose.
Methods:
In dual-energy CT, besides the material-specific information, one may also synthesize monochromatic images at different energies, which can be used for routine diagnosis similar to conventional polychromatic single-energy images. In this work, the authors assessed whether virtual monochromatic images generated from dual-source CT scanners had an image quality similar to that of polychromatic single-energy images for the same radiation dose. First, the authors provided a theoretical analysis of the optimal monochromatic energy for either the minimum noise level or the highest iodine contrast to noise ratio (CNR) for a given patient size and dose partitioning between the low- and high-energy scans. Second, the authors performed an experimental study on a dual-source CT scanner to evaluate the noise and iodine CNR in monochromatic images. A thoracic phantom with three sizes of attenuating rings was used to represent four adult sizes. For each phantom size, three dose partitionings between the low-energy (80 kV) and the high-energy (140 kV) scans were used in the dual-energy scan. Monochromatic images at eight energies (40 to 110 keV) were generated for each scan. Phantoms were also scanned at each of the four polychromatic single energy (80, 100, 120, and 140 kV) with the same radiation dose.
Results:
The optimal virtual monochromatic energy depends on several factors: phantom size, partitioning of the radiation dose between low- and high-energy scans, and the image quality metrics to be optimized. With the increase of phantom size, the optimal monochromatic energy increased. With the increased percentage of radiation dose on the low energy scan, the optimal monochromatic energy decreased. When maximizing the iodine CNR in monochromatic images, the optimal energy was lower than that when minimizing noise level. When the total radiation dose was equally distributed between low and high energy in dual-energy scans, for minimum noise, the optimal energies were 68, 71, 74, and 77 keV for small, medium, large, and extra-large (xlarge) phantoms, respectively; for maximum iodine CNR, the optimal energies were 66, 68, 70, 72 keV. With the optimal monochromatic energy, the noise level was similar to and the CNR was better than that in a single-energy scan at 120 kV for the same radiation dose. Compared to an 80 kV scan, however, the iodine CNR in monochromatic images was lower for the small, medium, and large phantoms.
Conclusions:
In dual-source dual-energy CT, optimal virtual monochromatic energy depends on patient size, dose partitioning, and the image quality metric optimized. With the optimal monochromatic energy, the noise level was similar to and the iodine CNR was better than that in 120 kV images for the same radiation dose. Compared to single-energy 80 kV images, the iodine CNR in virtual monochromatic images was lower for small to large phantom sizes.
Recent observational and modeling studies have demonstrated a link between eastern tropical Pacific Ocean (TPO) warming associated with the El Niño–Southern Oscillation (ENSO) and the negative phase ...of the wintertime northern annular mode (NAM). The TPO–NAM link involves a Rossby wave teleconnection from the tropics to the extratropics, and an increase in polar stratospheric wave driving that in turn induces a negative NAM anomaly in the stratosphere and troposphere. Previous work further suggests that tropical Indian Ocean (TIO) warming is associated with a positive NAM anomaly, which is of opposite sign to the TPO case. The TIO case is, however, difficult to interpret because the TPO and TIO warmings are not independent. To better understand the dynamics of tropical influences on the NAM, the current study investigates the NAM response to imposed TPO and TIO warmings in a general circulation model. The NAM responses to the two warmings have opposite sign and can be of surprisingly similar amplitude even though the TIO forcing is relatively weak. It is shown that the sign and strength of the NAM response is often simply related to the phasing, and hence the linear interference, between the Rossby wave response and the climatological stationary wave. The TPO (TIO) wave response reinforces (attenuates) the climatological wave and therefore weakens (strengthens) the stratospheric jet and leads to a negative (positive) NAM response. In additional simulations, it is shown that decreasing the strength of the climatological stationary wave reduces the importance of linear interference and increases the importance of nonlinearity. This work demonstrates that the simulated extratropical annular mode response to climate forcings can depend sensitively on the amplitude and phase of the climatological stationary wave and the wave response.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
When fast-growing cells are confronted with slow-growing cells in a mosaic tissue, the slow-growing cells are often progressively eliminated by apoptosis through a process known as cell competition. ...The underlying signalling pathways remain unknown, but recent findings have shown that cell crowding within an epithelium leads to the eviction of cells from the epithelial sheet. This suggests that mechanical forces could contribute to cell elimination during cell competition.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Bacteria inhibit and kill one another with a diverse array of compounds, including bacteriocins and antibiotics. These attacks are highly regulated, but we lack a clear understanding of the ...evolutionary logic underlying this regulation. Here, we combine a detailed dynamic model of bacterial competition with evolutionary game theory to study the rules of bacterial warfare. We model a large range of possible combat strategies based upon the molecular biology of bacterial regulatory networks. Our model predicts that regulated strategies, which use quorum sensing or stress responses to regulate toxin production, will readily evolve as they outcompete constitutive toxin production. Amongst regulated strategies, we show that a particularly successful strategy is to upregulate toxin production in response to an incoming competitor’s toxin, which can be achieved via stress responses that detect cell damage (competition sensing). Mirroring classical game theory, our work suggests a fundamental advantage to reciprocation. However, in contrast to classical results, we argue that reciprocation in bacteria serves not to promote peaceful outcomes but to enable efficient and effective attacks.
Crumbs (Crb in Drosophila; CRB1-3 in mammals) is a transmembrane determinant of epithelial cell polarity and a regulator of Hippo signalling. Crb is normally localized to apical cell-cell contacts, ...just above adherens junctions, but how apical trafficking of Crb is regulated in epithelial cells remains unclear. We use the Drosophila follicular epithelium to demonstrate that polarized trafficking of Crb is mediated by transport along microtubules by the motor protein Dynein and along actin filaments by the motor protein Myosin-V (MyoV). Blocking transport of Crb-containing vesicles by Dynein or MyoV leads to accumulation of Crb within Rab11 endosomes, rather than apical delivery. The final steps of Crb delivery and stabilisation at the plasma membrane requires the exocyst complex and three apical FERM domain proteins – Merlin, Moesin and Expanded – whose simultaneous loss disrupts apical localization of Crb. Accordingly, a knock-in deletion of the Crb FERM-binding motif (FBM) also impairs apical localization. Finally, overexpression of Crb challenges this system, creating a sensitized background to identify components involved in cytoskeletal polarization, apical membrane trafficking and stabilisation of Crb at the apical domain.
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•Crumbs is transported apically along microtubules and actin filaments.•Dynein is the key microtubule motor protein transporting Crumbs.•Myosin V is the key F-actin motor protein transporting Crumbs.•Crumbs polarises the cytoskeleton, which then directs further Crumbs delivery.
How epithelial cells polarize is a fascinating unsolved problem in biology. A key determinant of epithelial polarity is the transmembrane protein Crumbs, which localises specifically to the apical domain of epithelial cells and then helps direct the apical-basal polarization of the entire epithelial cell. How Crumbs itself becomes localized apically is still poorly understood. Here we define a key role for two motor proteins which can transport Crumbs apically along microtubules and actin filaments, respectively. Thus, a polarised cytoskeleton directs Crumbs delivery, which then helps define the apical-basal axis, which feeds back to polarize the cytoskeleton - a positive feedback loop.
Acute gastrointestinal (GI) bleeding is common and necessitates rapid diagnosis and treatment. Bleeding can occur anywhere throughout the GI tract and may be caused by many types of disease. The ...variety of enteric diseases that cause bleeding and the tendency for bleeding to be intermittent may make it difficult to render a diagnosis. The workup of GI bleeding is frequently prolonged and expensive, with examinations commonly needing to be repeated. The use of computed tomography (CT) for evaluation of acute GI bleeding is gaining popularity because it can be used to rapidly diagnose active bleeding and nonbleeding bowel disease. The CT examinations used to evaluate acute GI bleeding include CT angiography and multiphase CT enterography. Understanding the clinical evaluation of acute GI bleeding, including the advantages and limitations of endoscopic evaluation, is necessary for the appropriate selection of patients who may benefit from CT. Multiphase CT enterography is used primarily to evaluate stable patients who have undergone upper and lower endoscopy without identification of a bleeding source. CT angiography is used to examine stable and unstable patients who respond to resuscitation, are believed to be actively bleeding, and are considered unlikely to have an upper GI source of hemorrhage. In the emergent setting, CT may yield critical information regarding the presence, location, and cause of active bleeding-data that can guide the choice of subsequent therapy. Recent developments in the use of and techniques for performing CT angiography have made it a potential first-line tool for evaluating acute GI bleeding.
RSNA, 2018.
The hormone cytokinin (CK) controls root length in Arabidopsis thaliana by defining where dividing cells, derived from stem cells of the root meristem, start to differentiate 1–6. However, the ...regulatory inputs directing CK to promote differentiation remain poorly understood. Here, we show that the HD-ZIPIII transcription factor PHABULOSA (PHB) directly activates the CK biosynthesis gene ISOPENTENYL TRANSFERASE 7 (IPT7), thus promoting cell differentiation and regulating root length. We further demonstrate that CK feeds back to repress both PHB and microRNA165, a negative regulator of PHB. These interactions comprise an incoherent regulatory loop in which CK represses both its activator and a repressor of its activator. We propose that this regulatory circuit determines the balance of cell division and differentiation during root development and may provide robustness against CK fluctuations.
► PHB and PHV regulate root growth by controlling cell differentiation via CK ► Direct activation of IPT7 underlies PHB function in root meristem differentiation ► Regulatory feedbacks between CK and PHB may confer robustness against CK fluctuations
Virtual care in cancer care existed in a limited fashion globally before the COVID-19 pandemic, mostly driven by geographic constraints. The pandemic has required dramatic shifts in health care ...delivery, including cancer care. We conducted a systematic review of comparative studies evaluating virtual versus in-person care in patients with cancer. Embase, APA PsycInfo, Ovid MEDLINE, and the Cochrane Library were searched for literature from January 2015 to 6 August 2020. We adhered to PRISMA guidelines and used the modified GRADE approach to evaluate the data. We included 34 full-text publications of 10 randomized controlled trials, 13 non-randomized comparative studies, and 5 ongoing randomized controlled trials. Evidence was divided into studies that provide psychosocial or genetic counselling and those that provide or assess medical and supportive care. The limited data in this review support that in the general field of psychological counselling, virtual or remote counselling can be equivalent to in-person counselling. In the area of genetic counselling, telephone counselling was more convenient and noninferior to usual care for all outcomes (knowledge, decision conflict, cancer distress, perceived stress, genetic counseling satisfaction). There are few data for clinical outcomes and supportive care. Future research should assess the role of virtual care in these areas. Protocol registration: PROSPERO CRD42020202871.
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