Untangling the Conceptual Isssues Raised in Reydon and Scholz’s Critique of Organizational Ecology and Darwinian Populations

Reydon and Scholz raise doubts about the Darwinian status of organizational ecology by arguing that Darwinian principles are not applicable to organizational populations. Although their critique of organizational ecology’s typological essentialism is correct, they go on to reject the Darwinian status of organizational populations. This paper claims that the distinction between replicators and interactors, raised in modern philosophy of biology but not discussed by Reydon and Scholz, points the way forward for organizational ecologists. It is possible to conceptualise evolving Darwinian populations providing the inheritance mechanism is appropriately specified. By this approach, adaptation and selection are no longer dichotomised, and the evolutionary significance of knowledge transmission is highlightedPeer reviewe

Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions

Positive selection in the two-domain type 1 pilus adhesin FimH enhances Escherichia coli fitness in urinary tract infection (UTI). We report a comprehensive atomic-level view of FimH in two-state conformational ensembles in solution, composed of one low-affinity tense (T) and multiple high-affinity relaxed (R) conformations. Positively selected residues allosterically modulate the equilibrium between these two conformational states, each of which engages mannose through distinct binding orientations. A FimH variant that only adopts the R state is severely attenuated early in a mouse model of uncomplicated UTI but is proficient at colonizing catheterized bladders in vivo or bladder transitional-like epithelial cells in vitro. Thus, the bladder habitat has barrier(s) to R state–mediated colonization possibly conferred by the terminally differentiated bladder epithelium and/or decoy receptors in urine. Together, our studies reveal the conformational landscape in solution, binding mechanisms, and adhesive strength of an allosteric two-domain adhesin that evolved “moderate” affinity to optimize persistence in the bladder during UTI

Deceased donor organ procurement injuries in the United States

AIM: To determine the incidence of surgical injury during deceased donor organ procurements. METHODS: Organ damage was classified into three tiers, from 1-3, with the latter rendering the organ non-transplantable. For 12 consecutive months starting in January of 2014, 36 of 58 organ procurement organization's (OPO)'s prospectively submitted quality data regarding organ damage (as reported by the transplanting surgeon and confirmed by the OPO medical director) seen on the procured organ. RESULTS: These 36 OPOs recovered 5401 of the nations's 8504 deceased donors for calendar year 2014. A total of 19043 organs procured were prospectively analyzed. Of this total, 59 organs sustained damage making them non-transplantable (0 intestines; 4 pancreata; 5 lungs; 6 livers; 43 kidneys). The class 3 damage was spread over 22 (of 36) reporting OPO's. CONCLUSION: While damage to the procured organ is rare with organ loss being approximately 0.3% of procured organs, loss of potential transplantable organs does occur during procurement

Monitoring and Pay: An Experiment on Employee Performance under Endogenous Supervision

We present an experimental test of a shirking model where monitoring intensity is endogenous and effort a continuous variable. Wage level, monitoring intensity and consequently the desired enforceable effort level are jointly determined by the maximization problem of the firm. As a result, monitoring and pay should be complements. In our experiment, between and within treatment variation is qualitatively in line with the normative predictions of the model under standard assumptions. Yet, we also find evidence for reciprocal behavior. Our data analysis shows, however, that it does not pay for the employer to solely rely on the reciprocity of employees

N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington\u27s disease

Huntington\u27s disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington\u27s disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy

Controls on boundary layer ventilation: Boundary layer processes and large-scale dynamics

Midlatitude cyclones are important contributors to boundary layer ventilation. However, it is uncertain how efficient such systems are at transporting pollutants out of the boundary layer, and variations between cyclones are unexplained. In this study 15 idealized baroclinic life cycles, with a passive tracer included, are simulated to identify the relative importance of two transport processes: horizontal divergence and convergence within the boundary layer and large-scale advection by the warm conveyor belt. Results show that the amount of ventilation is insensitive to surface drag over a realistic range of values. This indicates that although boundary layer processes are necessary for ventilation they do not control the magnitude of ventilation. A diagnostic for the mass flux out of the boundary layer has been developed to identify the synoptic-scale variables controlling the strength of ascent in the warm conveyor belt. A very high level of correlation (R-2 values exceeding 0.98) is found between the diagnostic and the actual mass flux computed from the simulations. This demonstrates that the large-scale dynamics control the amount of ventilation, and the efficiency of midlatitude cyclones to ventilate the boundary layer can be estimated using the new mass flux diagnostic. We conclude that meteorological analyses, such as ERA-40, are sufficient to quantify boundary layer ventilation by the large-scale dynamics

Association of coronary vessel characteristics with outcome in patients with percutaneous coronary interventions with incomplete revascularization

© 2017 American Medical Association. All rights reserved. IMPORTANCE Many studies have compared outcomes for incomplete revascularization (IR) among patients undergoing percutaneous coronary interventions (PCI), but little is known about whether outcomes are related to the nature of the IR. OBJECTIVE To determine whether some coronary vessel characteristics are associated with worse outcomes in patients with PCI with IR. DESIGN, SETTING, AND PARTICIPANTS New York\u27s PCI registrywas used to examine mortality (median follow-up, 3.4 years) as a function of the number of vessels that were incompletely revascularized, the stenosis in those vessels, and whether the proximal left anterior descending artery was incompletely revascularized after controlling for other factors associated with mortality for patients with and without ST-elevationmyocardial infarction (STEMI). This was a multicenter study (all nonfederal PCI hospitals in New York State) that included 41 639 New York residents with multivessel coronary artery disease undergoing PCI in New York State between January 1, 2010, and December 31, 2012. EXPOSURES Percutaneous coronary interventions, with complete and incomplete revascularization. MAIN OUTCOMES AND MEASURES Medium-term mortality. RESULTS For patients with STEMI, the mean age was 62.8 years; 26.2%were women, 11.9% were Hispanic, and 81.5%were white. For other patients, the mean age was 66.6 years, 29.1%were women, 11.3%were Hispanic, and 79.1%were white. Incomplete revascularization was very common (78%among patients with STEMI and 71%among other patients). Patients with IR in a vessel with at least 90% stenosis were at higher risk than other patients with IR. This was not significant among patients with STEMI (17.18%vs 12.86%; adjusted hazard ratio [AHR], 1.16; 95%CI, 0.99-1.37) and significant among patients without STEMI (17.71% vs 12.96%; AHR, 1.15; 95%CI, 1.07-1.24). Similarly, patients with IR in 2 or more vessels had higher mortality than patients with completely revascularization and higher mortality than other patients with IR among patients with STEMI (20.37%vs 14.39%; AHR, 1.35; 95%CI, 1.15-1.59) and among patients without STEMI (20.10% vs 12.86%; AHR, 1.17; 95% CI, 1.09-1.59). Patients with proximal left anterior descending artery vessel IR had higher mortality than other patients with IR (20.09% vs 14.67%; AHR, 1.31; 95%CI, 1.04-1.64 for patients with STEMI and 20.78%vs 15.62%; AHR, 1.11; 95%CI, 1.01-1.23 for patients without STEMI). More than 20%of all PCI patients had IR of 2 or more vessels and more than 30% had IR with more than 90% stenosis. CONCLUSIONS AND RELEVANCE Patients with IR are at higher risk of mortality if they have IR with at least 90% stenosis, IR in 2 or more vessels, or proximal left anterior descending IR

A functional genetic screen defines the AKT-induced senescence signaling network

Exquisite regulation of PI3K/AKT/mTORC1 signaling is essential for homeostatic control of cell growth, proliferation, and survival. Aberrant activation of this signaling network is an early driver of many sporadic human cancers. Paradoxically, sustained hyperactivation of the PI3K/AKT/mTORC1 pathway in nontransformed cells results in cellular senescence, which is a tumor-suppressive mechanism that must be overcome to promote malignant transformation. While oncogene-induced senescence (OIS) driven by excessive RAS/ERK signaling has been well studied, little is known about the mechanisms underpinning the AKT-induced senescence (AIS) response. Here, we utilize a combination of transcriptome and metabolic profiling to identify key signatures required to maintain AIS. We also employ a whole protein-coding genome RNAi screen for AIS escape, validating a subset of novel mediators and demonstrating their preferential specificity for AIS as compared with OIS. As proof of concept of the potential to exploit the AIS network, we show that neurofibromin 1 (NF1) is upregulated during AIS and its ability to suppress RAS/ERK signaling facilitates AIS maintenance. Furthermore, depletion of NF1 enhances transformation of p53-mutant epithelial cells expressing activated AKT, while its overexpression blocks transformation by inducing a senescent-like phenotype. Together, our findings reveal novel mechanistic insights into the control of AIS and identify putative senescence regulators that can potentially be targeted, with implications for new therapeutic options to treat PI3K/AKT/mTORC1-driven cancers.Peer reviewe