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Adrenal Cushing's syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a Cushing's driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAcW196G is unexpectedly distinct from other described Cushing's variants, exhibiting retained association with type I regulatory subunits (RI) and their corresponding A kinase anchoring proteins (AKAPs). Molecular dynamics simulations predict that substitution of tryptophan-196 with glycine creates a 653-cubic angstrom cleft between the catalytic core of PKAcW196G and type II regulatory subunits (RII), but only a 395-cubic angstrom cleft with RI. Endocrine measurements show that overexpression of RIa or redistribution of PKAcW196G via AKAP recruitment counteracts stress hormone overproduction. We conclude that a W196G mutation in the kinase catalytic core skews R subunit selectivity and biases AKAP association to drive Cushing's syndrome. [ABSTRACT FROM AUTHOR]

The width of the ITCZ affects tropical rainfall, Earth's albedo, large-scale circulation and climate sensitivity; yet we do not understand what controls it. To better understand the ITCZ width and its effects on global climate, we present a protocol to force changes in ITCZ width in climate models. Starting from an aquaplanet configuration with a slab ocean, adding surface heat fluxes in the deep tropics forces the ITCZ to narrow, and subtracting them causes it to widen. The protocol successfully generates changes in ITCZ width in four climate models; within each model, ITCZ width responds linearly to forcing magnitude and sign. Comparing across the four climate models, a response to varying ITCZ width that is remarkably consistent among models is the ITCZ strength, which is greater the narrower the ITCZ. On the other hand, the effect of varying ITCZ width on climate sensitivity is divergent among our four models, varying even in sign. These results indicate that idealized model experiments have the potential to increase our understanding of ITCZ width. [ABSTRACT FROM AUTHOR]

One of the limiting factors to developing plasma thrusters on alternative propellants is the cost associated with changing the diagnostic tools, which are often propellant-dependent. For laser induced fluorescence (LIF), which is typically used for ion velocity distribution measurements to determine ion trajectories and potential profiles, either new lasers need to be bought, which are tuned to the wavelength of the new element's excitation level, or a costly tunable laser is required. A method to use existing LIF setups designed for xenon on any propellant has been demonstrated on a Hall thruster operating on krypton. In the demonstration test, a small amount of xenon (0.01%–4%) was mixed with the main krypton propellant for use as a diagnostic tracer, and xenon ion velocities were measured while also monitoring changes in the mean discharge current and oscillations. High signal-to-noise ratios in LIF data acquired along the channel centerline were obtained with tracer gas fractions ≤1% that negligibly affected the thruster operation. These results and comparison of the emission spectra of xenon and other common propellants suggest that the tracer LIF method should be broadly applicable to LIF measurements in Hall thrusters operating on alternative propellants. [ABSTRACT FROM AUTHOR]

Uncertainty in the response of clouds to global warming remains a significant barrier to reducing uncertainty in climate sensitivity. A key question is the extent to which the dynamic component—that which is due to changes in circulation rather than changes in the thermodynamic properties of clouds—contributes to the total cloud feedback. Here, simulations with a range of cloud‐resolving models are analyzed to quantify the impact of circulation changes on tropical cloud feedbacks. The dynamic component of the cloud feedback is substantial for some models and is controlled both by sea surface temperature (SST) induced changes in circulation and nonlinearity in the climatological relationship between clouds and circulation. We find notable inter‐model differences in the extent to which ascending regions narrow or expand in response to a change in SST, which we link to differences in the longwave and shortwave dynamic components across models. The diversity of changes in ascent area is coupled to intermodel differences in non‐radiative diabatic heating in ascending regions. Plain Language Summary: Clouds influence Earth's energy balance by absorbing and reflecting solar and terrestrial radiation. The response of clouds to warming remains a key source of uncertainty in understanding how the climate system will evolve. In particular, how the influence of clouds on radiation is coupled to the atmospheric circulation is an open question. In this study, idealized simulations of the tropics at high spatial resolution (3 km) are analyzed to probe how changes in circulation impact clouds in a warming climate. It is found that, across a range of models, the degree to which circulation changes influence clouds depends on how the area of the region with ascending air responds to warming. Key Points: Influence of circulation changes on cloud feedbacks is substantial in some cloud‐resolving modelsComponent of cloud feedback associated with circulation changes is coupled to ascent areaIntermodel spread in response of ascent area linked to non‐radiative diabatic heating [ABSTRACT FROM AUTHOR]

Pseudokinases, so named because they lack one or more conserved canonical amino acids that define their catalytically active relatives, have evolved a variety of biological functions in both prokaryotic and eukaryotic organisms. Human PSKH2 is closely related to the canonical kinase PSKH1, which maps to the CAMK family of protein kinases. Primates encode PSKH2 in the form of a pseudokinase, which is predicted to be catalytically inactive due to loss of the invariant catalytic Asp residue. Although the biological role(s) of vertebrate PSKH2 proteins remains unclear, we previously identified specieslevel adaptions in PSKH2 that have led to the appearance of kinase or pseudokinase variants in vertebrate genomes alongside a canonical PSKH1 paralog. In this paper we confirm that, as predicted, PSKH2 lacks detectable protein phosphotransferase activity, and exploit structural informatics, biochemistry and cellular proteomics to begin to characterise vertebrate PSKH2 orthologues. AlphaFold 2-based structural analysis predicts functional roles for both the PSKH2 N- and C-regions that flank the pseudokinase domain core, and cellular truncation analysis confirms that the N-terminal domain, which contains a conserved myristoylation site, is required for both stable human PSKH2 expression and localisation to a membrane-rich subcellular fraction containing mitochondrial proteins. Using mass spectrometry-based proteomics, we confirm that human PSKH2 is part of a cellular mitochondrial protein network, and that its expression is regulated through client-status within the HSP90/Cdc37 molecular chaperone system. HSP90 interactions are mediated through binding to the PSKH2 C-terminal tail, leading us to predict that this region might act as both a cis and trans regulatory element, driving outputs linked to the PSKH2 pseudokinase domain that are important for functional signalling. [ABSTRACT FROM AUTHOR]

Summary: A 3‐year‐old Thoroughbred filly presented with a several‐month history of weight loss, polydipsia and polyuria, intermittent diarrhoea and behavioural changes and intermittently uncoordinated gait. Neurological examination revealed hyperexcitability, bilaterally reduced pupillary light reflexes and quadrilateral ataxia with proprioceptive deficits more obvious in the forelimbs than in the hindlimbs. A multifocal neurological lesion was suspected. The laboratory finding of a persistent hyperchloraemia and an apparent negative anion gap prompted measurement of serum bromide concentration and subsequently confirmed bromide intoxication. Further questioning of the trainer revealed that the filly had been administered oral potassium bromide for behavioural modification over several months. Clinical signs of bromide intoxication resolved within 20 days following the last bromide administration, without specific medical intervention. This case report describes the risk of inadvertent bromide overdosing in horses and highlights the need for control of bromide use in the equine industry. [ABSTRACT FROM AUTHOR]

The impact of sputtering yield model uncertainty on the predicted erosion of a meshed reflector wire exposed to a Hall effect thruster plume is investigated. Quantifying this uncertainty is critical for making informed assessments of reflector lifetime. The erosion is modeled by assuming known ion current density and energy distribution at the location of the wire. The wire surface is then discretized, and wear is evaluated incrementally over time. The confidence in model predictions is quantified where the major source of uncertainty is assumed to stem from the material sputtering yield. The model is run to simulate reflector erosion after 10 h of exposure to a 3 kW class Hall thruster operating at 300 V. The simulated results then are compared to experimental measurements from a dedicated wear test performed on a series of mesh coupon samples. The experimental results are shown to fall largely within the 95% credible intervals from model predictions, though the uncertainty in the maximum predicted erosion is found to be up to 190% of the maximum predicted erosion. These results are discussed in the context of predicting lifetime of reflectors on orbit and the need for margin in this component design. [ABSTRACT FROM AUTHOR]

Two sets of carbohydrate‐NHC hybrid iridium complexes were synthesised in order to combine properties of carbohydrates and triazolylidene (trz) ligands in organometallic catalysis. One set features a direct trz linkage to the anomeric carbohydrate carbon, while the second set is comprised of an ethyl linker between the two functional units. Deprotection of the carbohydrate afforded hybrid complexes that efficiently catalyse the direct hydrogenation of ketones in water. The catalytic activity of the hybrid complexes was influenced by the pH of the aqueous medium and surpassed the activity of carbohydrate‐free or acetyl‐protected analogues (>90 % vs 13 % yield). While no enantiomeric induction was observed for the ethyl‐linked hybrids, a moderate enantiomeric excess (ee) was induced by the directly linked systems. Moreover, these carbohydrate‐trz hybrid complexes displayed mixed inhibitory activity towards a glycosidase from H. orenii that contain a glucose binding site. [ABSTRACT FROM AUTHOR]

In autism research, the impact of the hidden curriculum within higher education remains neglected. The published experiences of undergraduate and postgraduate students with Autism Spectrum Disorder indicate that social issues present a universal problem for this demographic. By being less able to take advantage of the social aspects of their courses, such as interactions with peers and supervisors, autistic students could be left at a disadvantage in their current studies and beyond. Opening formal research questions into the impact of the hidden curriculum on the learning experience of autistic students in higher education are required to highlight this issue. Investigating the most effective forms of hidden curriculum access could provide better insight into how support can be personalised to the needs of these students. [ABSTRACT FROM AUTHOR]

2,2,5,5-tetramethyloxolane (TMO) has recently been identified and demonstrated as a safer solvent to replace toluene, THF, and hydrocarbons in a handful of applications. Herein, several bio-based routes to TMO are presented and assessed for greenness, assisted by the CHEM21 Metrics Toolkit and BioLogicTool plots. Using glucose as a common starting point, two chemocatalytic routes and two biochemical routes to TMO were identified and the pathways compared using the aforementioned tools. In addition, bio-based TMO was synthesised via one of these routes; from methyl levulinate supplied by Avantium, a by-product of the sugar dehydration step during the production of 2,5-furandicarboxylic acid. First, methyl levulinate underwent triple methylation using methyl magnesium chloride (MeMgCl) to yield 2,5-dimethylhexane-2,5-diol (DHL) in high yields of 89.7%. Then DHL was converted to high purity TMO (>98.5%) by cyclodehydration using H-BEA zeolites based on the previously reported approach. Bio-based content of this TMO was confirmed by ASTM D6866-20 Method B and found to have 64% bio-based carbon, well above the threshold of 25% set by CEN/TC 411 standards and matching the anticipated content. This study represents the first demonstration of a bio-based synthesis of TMO and confirmation of bio-content by accepted standards. [ABSTRACT FROM AUTHOR]

Background: Left‐sided cardiac volume overload (LCVO) can cause fluid accumulation in lung tissue changing the distribution of ventilation, which can be evaluated by electrical impedance tomography (EIT). Objectives: To describe and compare EIT variables in horses with naturally occurring compensated and decompensated LCVO and compare them to a healthy cohort. Animals: Fourteen adult horses, including university teaching horses and clinical cases (healthy: 8; LCVO: 4 compensated, 2 decompensated). Methods: In this prospective cohort study, EIT was used in standing, unsedated horses and analyzed for conventional variables, ventilated right (VAR) and left (VAL) lung area, linear‐plane distribution variables (avg‐max VΔZLine, VΔZLine), global peak flows, inhomogeneity factor, and estimated tidal volume. Horses with decompensated LCVO were assessed before and after administration of furosemide. Variables for healthy and LCVO‐affected horses were compared using a Mann‐Whitney test or unpaired t‐test and observations from compensated and decompensated horses are reported. Results: Compared to the healthy horses, the LCVO cohort had significantly less VAL (mean difference 3.02; 95% confidence interval.77‐5.2; P =.02), more VAR (−1.13; −2.18 to −.08; P =.04), smaller avg‐max VΔZLLine (2.54; 1.07‐4.00; P =.003) and VΔZLLine (median difference 5.40; 1.71‐9.09; P =.01). Observation of EIT alterations were reflected by clinical signs in horses with decompensated LCVO and after administration of furosemide. Conclusions and Clinical Importance: EIT measurements of ventilation distribution showed less ventilation in the left lung of horses with LCVO and might be useful as an objective assessment of the ventilation effects of cardiogenic pulmonary disease in horses. [ABSTRACT FROM AUTHOR]

Background: Social anxiety disorder (SAD) is a chronic and disabling psychiatric disorder associated with low levels of help-seeking. To date, however, scarce research has examined the epidemiology of SAD in veterans. This study examined the prevalence, comorbidities and incremental burden of SAD in relation to suicidality and functioning in a representative sample of U.S. military veterans.Methods: A nationally representative sample of 3,157 U.S. veterans completed a web survey containing measures of SAD symptoms, trauma history, psychiatric history and functioning. Multivariable analyses were conducted to examine associations between SAD and psychiatric comorbidities, suicidality and functioning.Results: A total 9.5% (n = 272) of the sample screened positive for lifetime SAD. Veterans with SAD were more likely than those without SAD to be younger, female, single, racial/ethnic minorities and to have experienced childhood abuse. They also had substantially elevated rates of comorbid psychiatric disorders, particularly lifetime major depression (odds ratio [OR]=5.8) and posttraumatic stress disorder (OR=3.1), as well as current suicidal ideation (OR=3.3). Veterans with SAD scored lower on measures of functioning, particularly social, emotional and mental health functioning (d's=0.21-0.34).Limitations: Data were collected cross-sectionally using self-report.Conclusions: SAD in U.S. veterans is prevalent and associated with psychiatric comorbidities, functional impairment and a more than 3-fold greater risk for suicidal ideation . Given that SAD is associated with low treatment seeking and engagement, it may be undetected and undertreated relative to other psychiatric morbidities. These results underscore the importance of screening, monitoring and treating SAD in this population along with other prevalent mental disorders. [ABSTRACT FROM AUTHOR]

Following the environmental problems caused by non-degradable plastics there is a need to synthesise greener and more sustainable polymers. In this work we describe, for the first time, the facile enzyme-catalysed synthesis of linear polyesters using dimethyl malonate as the diester. These polymers, containing a different aliphatic diol component (C4, C6 or C8), were synthesised in solventless conditions using immobilized Candida antarctica lipase B as the biocatalyst. The potential of enzymes for catalysing this reaction is compared with the unsuccessful antimony- and titanium-catalysed synthesis (T > 150 °C). The application of the synthesized polymers as effective metal chelators in biphasic, green solvent systems was also described, together with the characterisation of the synthesised materials. [ABSTRACT FROM AUTHOR]

We document substantial rigidity in household electricity demand in response to large price shocks. We partnered with an electricity retailer to run a field experiment in which randomly-selected households received discounts of up to 50% on their total electricity bill or up to 95% off their per unit cost of electricity for a full month. We show that the quantity of electricity consumed was unaffected by these discounts. Exploiting rich billing, smart meter, and survey data, we document responses that are much more inelastic than previously observed in scenarios that raise prices for a few hours or raise or lower prices for indefinitely-long periods of time. Our results hold even among subgroups that we ex-ante believed were most likely to respond. [ABSTRACT FROM AUTHOR]

Sulfated carbohydrate metabolism is a fundamental process, which occurs in all domains of life. Carbohydrate sulfatases are enzymes that remove sulfate groups from carbohydrates and are essential to the depolymerisation of complex polysaccharides. Despite their biological importance, carbohydrate sulfatases are poorly studied and challenges remain in accurately assessing the enzymatic activity, specificity and kinetic parameters. Most notably, the separation of desulfated products from sulfated substrates is currently a time-consuming process. In this paper, we describe the development of rapid capillary electrophoresis coupled to substrate fluorescence detection as a high-throughput and facile means of analysing carbohydrate sulfatase activity. The approach has utility for the determination of both kinetic and inhibition parameters and is based on existing microfluidic technology coupled to a new synthetic fluorescent 6S-GlcNAc carbohydrate substrate. Furthermore, we compare this technique, in terms of both time and resources, to high-performance anion exchange chromatography and NMR-based methods, which are the two current 'gold standards' for enzymatic carbohydrate sulfation analysis. Our study clearly demonstrates the advantages of mobility shift assays for the quantification of near real-time carbohydrate desulfation by purified sulfatases, and will support the search for small molecule inhibitors of these disease-associated enzymes. [ABSTRACT FROM AUTHOR]

An analytical model for the dependence of the cathode coupling voltage in a Hall thruster on facility pressure is derived and investigated. The expression for the coupling voltage is determined by performing a line integral of the generalized Ohm's law from the cathode emitter to the thruster's main plume. The effects of pressure as well as non-classical resistance due to ion acoustic turbulence are included. The resulting model is applied to datasets from 12 different Hall thruster configurations and is shown in all cases to match the trends in the data within experimental uncertainty. The model in turn is used to extrapolate the experimental datasets to on-orbit conditions, and the confidence in these predictions is quantified through the lens of Bayesian parameter estimation. The derived model is discussed in the context of the underlying assumptions as well as previous models that have been proposed for this facility effect. [ABSTRACT FROM AUTHOR]

Monsoons are summertime circulations shaping climates and societies across the tropics and subtropics. Here the radiative effects controlling an axisymmetric monsoon and its response to climate change are investigated using aquaplanet simulations. The influences of clouds, water vapor, and CO2 on the axisymmetric monsoon are decomposed using the radiation-locking technique. Seasonal variations in clouds and water vapor strongly modulate the axisymmetric monsoon, reducing net precipitation by approximately half. Warming and moistening of the axisymmetric monsoon by seasonal longwave cloud and water vapor effects are counteracted by a strong shortwave cloud effect. The shortwave cloud effect also expedites onset of the axisymmetric monsoon by approximately two weeks, whereas longwave cloud and water vapor effects delay onset. A conceptual model relates the timing of monsoon onset to the efficiency of surface cooling. In climate change simulations CO2 forcing and the water vapor feedback have similar influences on the axisymmetric monsoon, warming the surface and moistening the region. In contrast, clouds have a negligible effect on surface temperature yet dominate the monsoon circulation response. A new perspective for understanding how cloud radiative effects shape the monsoon circulation response to climate change is introduced. The radiation-locking simulations and analyses advance understanding of how radiative processes influence an axisymmetric monsoon, and establish a framework for interpreting monsoon--radiation coupling in observations, in state-of-the-art models, and in different climate states. [ABSTRACT FROM AUTHOR]

Pseudoenzymes are present within many, but not all, known enzyme families and lack one or more conserved canonical amino acids that help define their catalytically active counterparts. Recent findings in the pseudokinase field confirm that evolutionary repurposing of the structurally defined bilobal protein kinase fold permits distinct biological functions to emerge, many of which rely on conformational switching, as opposed to canonical catalysis. In this analysis, we evaluate progress in evaluating several members of the 'dark' pseudokinome that are pertinent to help drive this expanding field. Initially, we discuss how adaptions in erythropoietin‐producing hepatocellular carcinoma (Eph) receptor tyrosine kinase domains resulted in two vertebrate pseudokinases, EphA10 and EphB6, in which co‐evolving sequences generate new motifs that are likely to be important for both nucleotide binding and catalysis‐independent signalling. Secondly, we discuss how conformationally flexible Tribbles pseudokinases, which have radiated in the complex vertebrates, control fundamental aspects of cell signalling that may be targetable with covalent small molecules. Finally, we show how species‐level adaptions in the duplicated canonical kinase protein serine kinase histone (PSKH)1 sequence have led to the appearance of the pseudokinase PSKH2, whose physiological role remains mysterious. In conclusion, we show how the patterns we discover are selectively conserved within specific pseudokinases, and that when they are modelled alongside closely related canonical kinases, many are found to be located in functionally important regions of the conserved kinase fold. Interrogation of these patterns will be useful for future evaluation of these, and other, members of the unstudied human kinome. [ABSTRACT FROM AUTHOR]

Abundant sugars of five and six carbon atoms are promising candidates for the production of valuable platform chemicals. Here, we describe the catalytic dehydrogenation of several pentoses and hexoses into their corresponding sugar acids with the concomitant formation of molecular hydrogen. This biomass transformation is promoted by highly active and selective catalysts based on iridium(III) complexes containing a triazolylidene (trz) as ligand. Monosaccharides are converted into sugar acids in an easy and sustainable manner using only catalyst and water, and in contrast to previously reported procedures, in the absence of any additive. The reaction is therefore very clean, and highly selective, which avoids the tedious purification and product separation. Mechanistic investigations using 1H NMR and UV‐vis spectroscopies and ESI mass spectrometry (ESI‐MS) indicate the formation of an unprecedented diiridium‐hydride as dormant species that correspond to the catalyst resting state. [ABSTRACT FROM AUTHOR]

Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication in metazoan organisms. Catalytic activity and protein turnover of PLK4 are tightly coupled in human cells, since changes in PLK4 concentration and catalysis have profound effects on centriole duplication and supernumerary centrosomes, which are associated with aneuploidy and cancer. Recently, PLK4 has been targeted with a variety of small molecule kinase inhibitors exemplified by centrinone, which rapidly induces inhibitory effects on PLK4 and leads to on-target centrosome depletion. Despite this, relatively few PLK4 substrates have been identified unequivocally in human cells, and PLK4 signalling outside centriolar networks remains poorly characterised. We report an unbiased mass spectrometry (MS)- based quantitative analysis of cellular protein phosphorylation in stable PLK4-expressing U2OS human cells exposed to centrinone. PLK4 phosphorylation was itself sensitive to brief exposure to the compound, resulting in PLK4 stabilisation. Analysing asynchronous cell populations, we report hundreds of centrinone-regulated cellular phosphoproteins, including centrosomal and cell cycle proteins and a variety of likely 'non-canonical' substrates. Surprisingly, sequence interrogation of ~300 significantly down-regulated phosphoproteins reveals an extensive network of centrinone-sensitive [Ser/Thr]Pro phosphorylation sequence motifs, which based on our analysis might be either direct or indirect targets of PLK4. In addition, we confirm that NMYC and PTPN12 are PLK4 substrates, both in vitro and in human cells. Our findings suggest that PLK4 catalytic output directly controls the phosphorylation of a diverse set of cellular proteins, including Prodirected targets that are likely to be important in PLK4-mediated cell signalling. [ABSTRACT FROM AUTHOR]

Objective: The objective of the present study was to determine whether or not the effects of peripheral nerve block can be reversed by flushing normal saline down a peripheral nerve block catheter following the completion of arteriovenous (AV) fistula surgery. Methods: In the present study, 38 patients undergoing AV fistula surgery were recruited, and a brachial plexus block with a peripheral nerve catheter was established. Following surgery, the patients were randomised to either the control group or the washout group, where 10 mL of normal saline was flushed down the peripheral nerve catheter at 15-minute intervals for 1 h while the patients were in the postoperative recovery room. An observer blinded to the patient group allocation assessed motor and sensory functions in all patients at 15-minute intervals for 1 h, and pain scores were recorded. Results: There was no difference in time to resolution of motor or sensory block in the two groups. The median changes in the motor score were 1.5 out of 10 for the control group and 2 for the washout group (p=0.95). The median changes in the sensory score were 3 out of 10 for the control group and 1 for the washout group (p=0.14). There were no differences in pain scores over the study period in either group (p=0.44). Conclusion: We were unable to show any useful improvement in block resolution with normal saline washout of supraclavicular or infraclavicular brachial plexus blocks following AV fistula surgery. [ABSTRACT FROM AUTHOR]

TEG6s® is a new device introduced by the Haemonetics Corporation and designed to provide the same information as TEG® 5000 (Haemonetics Corporation, Braintree, MA, USA) but with much greater ease of use. We tested whether using citrated TEG6s gave reaction time, maximum amplitude and percentage of clot that had lysed at 30 minutes values similar to a non-citrated TEG5000, to allow clinical interchangeability using our current thrombelastography management algorithm for cardiac surgery. We also examined the agreement between the alpha-angle and functional fibrinogen maximum amplitude in our cardiac surgical patients. In total, 243 paired arterial blood samples in 99 patients were tested, using TEG5000 (non-citrated) and TEG6s (citrated) after induction of anaesthesia (prior to heparin administration), following protamine administration at the end of the cardiac bypass and whenever a TEG5000 was requested after this by the attending anaesthetist. Bland–Altman plots and Lin's concordance coefficient were used to compare agreement whereas modified Bland–Altman plots and McNemar's test were used to illustrate the differences in management recommendations between the two thrombelastography devices. All 243 samples were compared for reaction time and alpha-angle; 239 samples were compared for maximum amplitude; 136 samples were compared for the percentage of clot that had lysed at 30 minutes; 16 samples were compared for functional fibrinogen maximum amplitude. Lin's concordance coefficient for these parameters was: reaction time 0.63, alpha-angle 0.39, maximum amplitude 0.5, percentage of clot that had lysed at 30 minutes 0.09 and functional fibrinogen maximum amplitude 0.31. Differences between the two devices became more marked at more abnormal values. Significant differences in median values, suggesting a fixed bias, were found for maximum amplitude and functional fibrinogen maximum amplitude. Differences in treatment recommendation could only be calculated for reaction time and maximum amplitude. Maximum amplitude was found to have a significant difference in treatment recommendation between the two devices using our current thrombelastography management algorithm for cardiac surgery with TEG6s recommending treatment in 11.5% more patients than TEG5000. Using the TEG6s with our current TEG5000–based thrombelastography management algorithm for cardiac surgery would result in a change in treatment recommendation in at least 10% of our cardiac surgical patients. Agreement between the two thrombelastography devices appears to decrease with increasing patient coagulopathy. New algorithms will need to be developed and tested to validate TEG6s for cardiac surgical patients in our institution. [ABSTRACT FROM AUTHOR]

Background: Cue Exposure Therapy (CET) has shown efficacy for treating alcohol use disorders (AUDs). Exposure therapy is highly effective for treating anxiety. Both techniques involve repeated, controlled exposures to alcohol or fear-related stimuli. Objectives: We considered the mechanisms of CET for AUDs by comparing it to exposure therapy for anxiety. Method: We conducted a narrative review contrasting theoretical literature examining the mechanisms of CET versus exposure therapy for anxiety. We reviewed RCTs and acute laboratory paradigms examining CET for AUDs. We considered common areas of emerging research, including the use of d-Cycloserine (DCS) and virtual reality (VR). Results: We found evidence that exposure therapy and CET at least partially achieve their effects through extinction learning. We found evidence that CET for AUDs is effective, with comparable benefits to other effective psychosocial treatments. DCS and VR have shown some limited success for augmenting CET for AUDs, so further research is needed to determine their value. Conclusions: There are theoretical and practical similarities between exposure to fear cues and cues of addiction, especially regarding extinction learning. However, these processes are also unique, particularly regarding the differing motivational properties of fear versus reward-related stimuli. We propose that unlike exposure for anxiety, CET takes effect by increasing self-control with each unreinforced exposure. We consider reasons for CET's limited use for AUDs, including its lower acceptability to clients and clinicians. We also note the limited evidence for CET for other substance use disorders, highlighting the need for continued investigation into its mechanisms and efficacy. [ABSTRACT FROM AUTHOR]

The dynamical processes controlling the width of the intertropical convergence zone (ITCZ) are investigated using idealized and CMIP5 simulations. ITCZ width is defined in terms of boundary layer vertical velocity. The tropical boundary layer is approximately in Ekman balance, suggesting that wind stress places a strong constraint on ITCZ width. A scaling based on Ekman balance predicts that ITCZ width is proportional to the wind stress and inversely proportional to its meridional gradient. A toy model of an Ekman boundary layer illustrates the effects of wind stress perturbations on ITCZ width. A westerly wind perturbation widens the ITCZ whereas an easterly perturbation narrows the ITCZ. Multiplying the wind stress by a constant factor does not shift the ITCZ edge, but ITCZ width is sensitive to the latitude of maximum wind stress. Scalings based on Ekman balance cannot fully capture the behavior of ITCZ width across simulations, suggesting that non-Ekman dynamical processes need to be accounted for. An alternative scaling based on the full momentum budget explains variations in ITCZ width and highlights the importance of horizontal and vertical momentum advection. Scalings are also introduced linking ITCZ width to surface temperature. An extension to Lindzen–Nigam theory predicts that ITCZ width scales with the latitude where the Laplacian of SST is zero. The supercriticality theory of Emanuel is also invoked to show that ITCZ width is dynamically linked to boundary layer moist entropy gradients. The results establish a dynamical understanding of ITCZ width that can be applied to interpret persistent ITCZ biases in climate models and the response of tropical precipitation to climate change. [ABSTRACT FROM AUTHOR]

Three Ru complexes containing carbohydrate/N-heterocyclic carbene hybrid ligands were synthesized that were comprised of a triazolylidene coordination site and a directly linked per-acetylated glucosyl (5Glc) or galactosyl unit (5Gal), or a glycosyl unit linked through an ethylene spacer (6). Electrochemical and UV-vis analysis indicate only minor perturbation of the electronic configuration of the metal center upon carbohydrate installation. Deprotection of the carbohydrate was accomplished under basic conditions to afford complexes that were stable in solution over several hours, but decomposed in the solid state. Complexes 5 and 6 were used as pre-catalysts for transfer hydrogenation of ketones under basic conditions, i.e. conditions that lead to in situ deprotection of the carbohydrate entity. The carbohydrate directly influences the catalytic activity of the metal center. Remotely linked carbohydrates (complex 6) induce significantly lower catalytic activity than directly linked carbohydrates (complexes 5Glc, 5Gal), while unfunctionalized triazolylidenes are an order of magnitude more active. These observations and substrate variations strongly suggest that substrate bonding is rate-limiting for transfer hydrogenation in these hybrid carbohydrate/triazolylidene systems. [ABSTRACT FROM AUTHOR]

Presents an excerpt of the essay titled 'Debating the Reformation in the Humanities Classroom,' by professor Joseph P. Byrne of Belmont University in Nashville, Tennessee. Analysis of the humanities curriculum offered by the university; Requirement of term projects for the completion of the course; Organization of a debate over issues related to humanities studies.

With increased awareness of environmental issues caused by traditional petrochemical processes, both academia and industry are making enormous efforts towards the development of sustainable practices using renewable biomass as a feedstock. In this work, the biocatalyzed synthesis of polyesters derived from renewable monomers was performed in safer, bio-derivable organic solvents. Candida antarctica lipase B (CaLB), an enzyme belonging to the Ser-hydrolase family (adsorbed on methacrylic resin, also known as Novozym 435) was tested for its performance in the synthesis of adipate- and furandicarboxylate-based polyesters. In addition, the traditional solvents toluene and tetrahydrofuran were compared with a series of green solvents, 2,2,5,5-tetramethyloxolane, 2-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran and pinacolone for the enzymatic polymerizations. We can conclude that the monomer conversions and molecular masses of the obtained polyesters in all the tested alternative solvents were suitable, and in some cases superior, with CaLB immobilized via physisorption on acrylic resin being the optimal biocatalyst for all reactions. Strikingly, it was found that for the majority of the new solvents, lower reaction temperatures gave comparable monomer conversions and polymers with similar molecular weights whilst pinacolone yielded better polymers with Mn ＞ 2000 Da and conversions of over 80%. [ABSTRACT FROM AUTHOR]

Objective: The authors examined the effect of patient treatment preference on the differential effectiveness of prolonged exposure and sertraline for the treatment of posttraumatic stress disorder (PTSD).Method: In a doubly randomized preference trial, 200 patients with PTSD viewed standardized treatment rationales prior to randomization. Patients were first randomized to choice of treatment or no choice. Those assigned to no choice were then randomized to prolonged exposure or sertraline. Acute treatment was 10 weeks, with 24-month follow-up. Interviewer-rated PTSD symptom severity was the main outcome measure, and depression, anxiety, and functioning were assessed as additional outcomes.Results: Patients preferred prolonged exposure over sertraline (number needed to benefit [NNTB]=4.5). Using intent-to-treat analyses (N=200), both prolonged exposure and sertraline showed large gains that were maintained over 24 months. Although no differential effect was observed on interviewer-rated PTSD severity, there was a significant benefit of prolonged exposure over sertraline on interview-rated loss of PTSD diagnosis (NNTB=7.0), responder status (NNTB=5.7), and self-reported PTSD, depression, and anxiety symptoms and functioning (effect sizes, 0.35-0.44). Patients who received their preferred treatment were more likely to be adherent, lose their PTSD diagnosis (NNTB=3.4), achieve responder status (NNTB=3.4), and have lower self-reported PTSD, depression, and anxiety symptoms (effect sizes, 0.40-0.72).Conclusions: Prolonged exposure and sertraline confer significant benefits for PTSD, with some evidence of an advantage for prolonged exposure. Giving patients with PTSD their preferred treatment also confers important benefits, including enhancing adherence. [ABSTRACT FROM AUTHOR]

Highlights • We used latent class analysis to identify typologies of DSM-5 PTSD in U.S. veterans • A three-class solution was determined, described as Dysphoric, Threat and High Symptom • Threat had greater intrusions and avoidance; Dysphoric had greater negative affect • The High Symptom typology had high probabilities of all symptoms • The three typologies were differentially linked to clinical and trauma characteristics Abstract Posttraumatic stress disorder (PTSD) is a heterogeneous condition that can be characterized by unique typologies of symptoms. To date, no study has examined predominant PTSD typologies using DSM-5 criteria. We used latent class analysis (LCA) to identify typologies of DSM-5 PTSD symptoms in 158 U.S. veterans who screened positive for this condition. A three-class solution provided the best fit to the data, described as Dysphoric (36.2%), High Symptom (34.0%) and Threat (29.8%). The Threat class had higher probabilities of intrusions and avoidance compared to the Dysphoric class; the Dysphoric class had higher probabilities of negative affect, anhedonia and externalizing behavior relative to Threat; the High Symptom class had high probabilities of all symptoms. Compared to the Threat class, the Dysphoric class was more likely to have a lifetime history of major depressive, alcohol and drug use disorders; the High Symptom class was more likely to have a lifetime history of alcohol, drug, and nicotine use disorder, current generalized anxiety, or to have attempted or currently contemplated suicide. The High Symptom class reported greater mental, physical and cognitive impairment and lower quality of life. These findings underscore the importance of a personalized approach to the assessment and treatment of DSM-5 PTSD. [ABSTRACT FROM AUTHOR]

Aims Third wave therapies have shown efficacy for treating emotional disorders and potential for treating substance use disorders. There is developing interest in whether they can more specifically be used for treating alcohol use disorders (AUDs). We were interested in whether third wave therapies have value alongside current evidence-based psychosocial treatments for AUDs. Method We conducted systematic reviews of third wave therapies for AUDs. We searched PsycINFO, Embase and Medline for peer reviewed journal articles where mindfulness or Acceptance and Commitment Therapy (ACT) were used to treat adults with AUDs or alcohol use that caused impairment. Results We identified 11 studies where mindfulness was used for treating AUDs and 6 where ACT was used for AUDs. The studies identified included RCTs, non-randomized controlled studies and uncontrolled studies. We found preliminary support that both third wave therapies are better than no treatment, treatments of minimal efficacy, as well as some evidence they are comparable to effective psychosocial treatments for AUDs. Conclusions We conclude ACT and mindfulness provide an alternative to existing treatments, particularly for patients who have not responded to, or have disengaged from, standard treatments. We also found some evidence ACT and mindfulness are useful for comorbid mental health conditions. Yet while these results are promising, further research is needed to determine their utility, ideally employing randomized-controlled designs, larger clinical samples and longer follow-ups. Furthermore, few studies in this review directly compared third wave therapies to first line treatments, making it difficult to determine their relative efficacy. [ABSTRACT FROM AUTHOR]

It is vital that new mothers quickly and accurately recognize their child's facial expressions. There is evidence that during pregnancy women develop enhanced processing of facial features associated with infancy and distress, as these cues signal vulnerability and are therefore biologically salient. In this study, 51 pregnant women at 17-36 weeks gestation watched neutral infant and adult faces gradually morph into either happy or sad expressions. We measured the speed and accuracy with which participants were able to recognize facial affect (happy vs. sad) across facial ages (infant vs. adult). Participants were faster and more accurate at recognizing happy versus sad faces and adult versus infant faces. We discuss how prior exposure to a certain face type may explain faster recognition. We also consider these results in the context of evidence indicating positive affect is recognized more quickly, but associated with slower attention and detection. [ABSTRACT FROM AUTHOR]

The NF-κB transcription factors are known to be extensively phosphorylated, with dynamic site-specific modification regulating their ability to dimerize and interact with DNA. p50, the proteolytic product of p105 (NF-κB1), forms homodimers that bind DNA but lack intrinsic transactivation function, functioning as repressors of transcription from κB promoters. Here, we examine the roles of specific phosphorylation events catalysed by either protein kinase A (PKAc) or Chk1, in regulating the functions of p50 homodimers. LC-MS/MS analysis of proteolysed p50 following in vitro phosphorylation allows us to define Ser328 and Ser337 as PKAc- and Chk1-mediated modifications, and pinpoint an additional four Chk1 phosphosites: Ser65, Thr152, Ser242 and Ser248. Native mass spectrometry (MS) reveals Chk1- and PKAc-regulated disruption of p50 homodimer formation through Ser337. Additionally, we characterise the Chk1-mediated phosphosite, Ser242, as a regulator of DNA binding, with a S242D p50 phosphomimetic exhibiting a > 10-fold reduction in DNA binding affinity. Conformational dynamics of phosphomimetic p50 variants, including S242D, are further explored using ion-mobility MS (IM-MS). Finally, comparative theoretical modelling with experimentally observed p50 conformers, in the absence and presence of DNA, reveals that the p50 homodimer undergoes conformational contraction during electrospray ionisation that is stabilised by complex formation with κB DNA.ᅟ [ABSTRACT FROM AUTHOR]

The oomycetes are a class of microscopic, filamentous eukaryotes within the stramenopiles–alveolates–rhizaria eukaryotic supergroup. They include some of the most destructive pathogens of animals and plants, such as Phytophthora infestans, the causative agent of late potato blight. Despite the threat they pose to worldwide food security and natural ecosystems, there is a lack of tools and databases available to study oomycete genetics and evolution. To this end, we have developed the Oomycete Gene Order Browser (OGOB), a curated database that facilitates comparative genomic and syntenic analyses of oomycete species. OGOB incorporates genomic data for 20 oomycete species including functional annotations and a number of bioinformatics tools. OGOB hosts a robust set of orthologous oomycete genes for evolutionary analyses. Here, we present the structure and function of OGOB as well as a number of comparative genomic analyses we have performed to better understand oomycete genome evolution. We analyze the extent of oomycete gene duplication and identify tandem gene duplication as a driving force of the expansion of secreted oomycete genes. We identify core genes that are present and microsyntenically conserved (termed syntenologs) in oomycete lineages and identify the degree of microsynteny between each pair of the 20 species housed in OGOB. Consistent with previous comparative synteny analyses between a small number of oomycete species, our results reveal an extensive degree of microsyntenic conservation amongst genes with housekeeping functions within the oomycetes. OGOB is available at https://ogob.ie. [ABSTRACT FROM AUTHOR]

A “top down” approach to the development of sustainable, greener, low-polarity solvents is presented. Methyl butyrate, ethyl isobutyrate, methyl pivalate and pinacolone were identified as potential target solvents from trends in Hansen solubility parameters and known physical properties. Solubility, flammability and physical properties were determined which showed their potential to replace traditional, hazardous, volatile, non-polar solvents such as toluene. Each new candidate then demonstrated their suitability to replace these traditional solvents in solubility tests, despite being esters and ketones, each candidate demonstrated their similarity to traditional volatile non-polar solvents in terms of their solubility properties by their ability to dissolve natural rubber, a particularly low-polarity solute. This was reinforced by their performance in a model Menschutkin reaction and a radical-initiated polymerisation for the production of pressure-sensitive adhesives, where their performance was found to be similar to that of toluene. Importantly, a preliminary toxicity test (Ames test) suggested non-mutagenicity in all candidates. Each of the four candidates can be synthesised via a catalytic route from potentially renewable resources, thus enhancing their green credentials. [ABSTRACT FROM AUTHOR]

Protein tyrosine sulfation is a post-translational modification best known for regulating extracellular protein-protein interactions. Tyrosine sulfation is catalysed by two Golgi-resident enzymes termed tyrosylprotein sulfotransferases (TPSTs) 1 and 2, which transfer sulfate from the cofactor PAPS (30-phosphoadenosine 50-phosphosulfate) to a contextdependent tyrosine in a protein substrate. A lack of quantitative tyrosine sulfation assays has hampered the development of chemical biology approaches for the identification of small-molecule inhibitors of tyrosine sulfation. In the present paper, we describe the development of a non-radioactive mobility-based enzymatic assay for TPST1 and TPST2, through which the tyrosine sulfation of synthetic fluorescent peptides can be rapidly quantified. We exploit ligand binding and inhibitor screens to uncover a susceptibility of TPST1 and TPST2 to different classes of small molecules, including the anti-angiogenic compound suramin and the kinase inhibitor rottlerin. By screening the Published Kinase Inhibitor Set, we identified oxindole-based inhibitors of the Ser/Thr kinase RAF (rapidly accelerated fibrosarcoma) as low-micromolar inhibitors of TPST1 and TPST2. Interestingly, unrelated RAF inhibitors, exemplified by the dual BRAF/VEGFR2 inhibitor RAF265, were also TPST inhibitors in vitro. We propose that target-validated protein kinase inhibitors could be repurposed, or redesigned, as more-specific TPST inhibitors to help evaluate the sulfotyrosyl proteome. Finally, we speculate that mechanistic inhibition of cellular tyrosine sulfation might be relevant to some of the phenotypes observed in cells exposed to anionic TPST ligands and RAF protein kinase inhibitors. [ABSTRACT FROM AUTHOR]

Sulfation of carbohydrate residues occurs on a variety of glycans destined for secretion, and this modification is essential for efficient matrix-based signal transduction. Heparan sulfate (HS) glycosaminoglycans control physiological functions ranging from blood coagulation to cell proliferation. HS biosynthesis involves membrane-bound Golgi sulfotransferases, including HS 2-O-sulfotransferase (HS2ST), which transfers sulfate from the cofactor PAPS (30-phosphoadenosine 5'-phosphosulfate) to the 2-O position of α-L-iduronate in the maturing polysaccharide chain. The current lack of simple non-radioactive enzyme assays that can be used to quantify the levels of carbohydrate sulfation hampers kinetic analysis of this process and the discovery of HS2ST inhibitors. In the present paper, we describe a new procedure for thermal shift analysis of purified HS2ST. Using this approach, we quantify HS2ST-catalysed oligosaccharide sulfation using a novel synthetic fluorescent substrate and screen the Published Kinase Inhibitor Set, to evaluate compounds that inhibit catalysis. We report the susceptibility of HS2ST to a variety of cell-permeable compounds in vitro, including polyanionic polar molecules, the protein kinase inhibitor rottlerin and oxindole-based RAF kinase inhibitors. In a related study, published back-to-back with the present study, we demonstrated that tyrosyl protein sulfotranferases are also inhibited by a variety of protein kinase inhibitors. We propose that appropriately validated small-molecule compounds could become new tools for rapid inhibition of glycan (and protein) sulfation in cells, and that protein kinase inhibitors might be repurposed or redesigned for the specific inhibition of HS2ST. [ABSTRACT FROM AUTHOR]

In recent decades, the land surface has warmed substantially more than the ocean surface, and relative humidity has fallen over land. Amplified warming and declining relative humidity over land are also dominant features of future climate projections, with implications for climate-change impacts. An emerging body of research has shown how constraints from atmospheric dynamics and moisture budgets are important for projected future land-ocean contrasts, but these ideas have not been used to investigate temperature and humidity records over recent decades. Here we show how both the temperature and humidity changes observed over land between 1979 and 2016 are linked to warming over neighboring oceans. A simple analytical theory, based on atmospheric dynamics and moisture transport, predicts equal changes in moist static energy over land and ocean and equal fractional changes in specific humidity over land and ocean. The theory is shown to be consistent with the observed trends in land temperature and humidity given the warming over ocean. Amplified land warming is needed for the increase in moist static energy over drier land to match that over ocean, and land relative humidity decreases because land specific humidity is linked via moisture transport to the weaker warming over ocean. However, there is considerable variability about the best-fit trend in land relative humidity that requires further investigation and which may be related to factors such as changes in atmospheric circulations and land-surface properties. [ABSTRACT FROM AUTHOR]

The regional climate response to radiative forcing is largely controlled by changes in the atmospheric circulation. it has been suggested that global climate sensitivity also depends on the circulation response, an effect called the "atmospheric dynamics feedback." Using a technique to isolate the influence of changes in atmospheric circulation on top-of-the-atmosphere radiation, the authors calculate the atmospheric dynamics feedback in coupled climate models. Large-scale circulation changes contribute substantially to all-sky and cloud feedbacks in the tropics but are relatively less important at higher latitudes. Globally averaged, the atmospheric dynamics feedback is positive and amplifies the near-surface temperature response to climate change by an average of 8% in simulations with coupled models. A constraint related to the atmospheric mass budget results in the dynamics feedback being small on large scales relative to feedbacks associated with thermodynamic processes. Idealized-forcing simulations suggest that circulation changes at high latitudes are potentially more effective at influencing global temperature than circulation changes at low latitudes, and the implications for past and future climate change are discussed. [ABSTRACT FROM AUTHOR]

Parental reflective functioning (PRF) describes a parent’s capacity for considering both their own and their child’s thoughts, feelings, and behaviors, which can help parents to guide interactions with children. Given the cognitive demands of keeping infants in mind whilst caregiving, we examined the association between aspects of executive function (i.e., working memory and set-shifting) and PRF (employing the Parental Reflective Functioning Questionnaire) in recent mothers. In Study 1 (N = 50), we found that better working memory was associated with higher levels of maternal interest and curiosity in their child’s feelings. In Study 2 (N = 68), we found that visual working memory and set-shifting capacity were also associated with higher levels of maternal interest and curiosity in their child’s thoughts and feelings. Our results provide preliminary support for the association between executive processes and maternal reflective functioning. The implications of these findings and important future directions are discussed, including advancing our understanding of executive processes and PRF to support the broader family system. [ABSTRACT FROM AUTHOR]

Objectives: Traumatic subarachnoid hemorrhage is a common radiographic finding associated with traumatic brain injury. The objective of this investigation is to evaluate the association between hospital-level ICU admission practices and clinically important outcomes for patients with isolated traumatic subarachnoid hemorrhage and mild clinical traumatic brain injury.Design: Multicenter observational cohort.Setting: Trauma centers participating in the American College of Surgeons Trauma Quality Improvement Program spanning January 2012 to March 2014.Patients: A total of 14,146 subjects, 16 years old and older, admitted to 215 trauma centers with isolated traumatic subarachnoid hemorrhage and Glasgow Coma Scale score 13 or greater. Patients with concurrent intracranial injuries, severe injury to other body regions, or tests positive for alcohol or illicit substances were excluded.Intervention: ICU admission.Measurements and Main Results: The primary outcome was need for neurosurgical intervention, defined as insertion of an intracranial monitor/drain or craniectomy/craniotomy. Secondary outcomes describing the clinical course included hospital discharge disposition, in-hospital mortality, and length of stay. Admission to ICU was common within the cohort (44.6%), yet the need for neurosurgical intervention was rare (0.24%). Variability was high between centers and remained so after adjusting for differences in case-mix and hospital-level characteristics (median odds ratio, 4.1). No significant differences in neurosurgical interventions, mortality, or discharge disposition to home under self-care were observed between groups of the highest and lowest ICU admitting hospitals. However, those in highest admitting group "stayed" in hospital 1.13 (95% CI, 1.07-1.20; p < 0.001) times that of the lowest admitting group.Conclusions: Critical care admission for mild traumatic brain injury patients with isolated traumatic subarachnoid hemorrhage is frequent and highly variable despite low probability of requiring neurosurgical intervention. Reevaluation of hospital-level practices may represent an opportunity for resource optimization when managing patients with mild clinical traumatic brain injury and associated isolated traumatic subarachnoid hemorrhage. [ABSTRACT FROM AUTHOR]

Previous studies of the genetic landscape of Ireland have suggested homogeneity, with population substructure undetectable using single-marker methods. Here we have harnessed the haplotype-based method fineSTRUCTURE in an Irish genome-wide SNP dataset, identifying 23 discrete genetic clusters which segregate with geographical provenance. Cluster diversity is pronounced in the west of Ireland but reduced in the east where older structure has been eroded by historical migrations. Accordingly, when populations from the neighbouring island of Britain are included, a west-east cline of Celtic-British ancestry is revealed along with a particularly striking correlation between haplotypes and geography across both islands. A strong relationship is revealed between subsets of Northern Irish and Scottish populations, where discordant genetic and geographic affinities reflect major migrations in recent centuries. Additionally, Irish genetic proximity of all Scottish samples likely reflects older strata of communication across the narrowest inter-island crossing. Using GLOBETROTTER we detected Irish admixture signals from Britain and Europe and estimated dates for events consistent with the historical migrations of the Norse-Vikings, the Anglo-Normans and the British Plantations. The influence of the former is greater than previously estimated from Y chromosome haplotypes. In all, we paint a new picture of the genetic landscape of Ireland, revealing structure which should be considered in the design of studies examining rare genetic variation and its association with traits. [ABSTRACT FROM AUTHOR]

Background: The Glasgow Coma Scale (GCS) is the most widely used measure of traumatic brain injury (TBI) severity. Currently, the arrival GCS motor component (mGCS) score is used in risk-adjustment models for external benchmarking of mortality. However, there is evidence that the highest mGCS score in the first 24 hours after injury might be a better predictor of death. Our objective was to evaluate the impact of including the highest mGCS score on the performance of risk-adjustment models and subsequent external benchmarking results.Study Design: Data were derived from the Trauma Quality Improvement Program analytic dataset (January 2014 through March 2015) and were limited to the severe TBI cohort (16 years or older, isolated head injury, GCS ≤8). Risk-adjustment models were created that varied in the mGCS covariates only (initial score, highest score, or both initial and highest mGCS scores). Model performance and fit, as well as external benchmarking results, were compared.Results: There were 6,553 patients with severe TBI across 231 trauma centers included. Initial and highest mGCS scores were different in 47% of patients (n = 3,097). Model performance and fit improved when both initial and highest mGCS scores were included, as evidenced by improved C-statistic, Akaike Information Criterion, and adjusted R-squared values. Three-quarters of centers changed their adjusted odds ratio decile, 2.6% of centers changed outlier status, and 45% of centers exhibited a ≥0.5-SD change in the odds ratio of death after including highest mGCS score in the model.Conclusions: This study supports the concept that additional clinical information has the potential to not only improve the performance of current risk-adjustment models, but can also have a meaningful impact on external benchmarking strategies. Highest mGCS score is a good potential candidate for inclusion in additional models. [ABSTRACT FROM AUTHOR]

In haploid cells of Ogataea (Hansenula) polymorpha an environmental signal, nitrogen starvation, induces a reversible change in the structure of a chromosome. This process, mating-type switching, inverts a 19-kb DNA region to place either MATa or MATα genes under centromeric repression of transcription, depending on the orientation of the region. Here, we investigated the genetic pathway that controls switching. We characterized the transcriptomes of haploid and diploid O. polymorpha by RNAseq in rich and nitrogen-deficient media, and found that there are no constitutively a-specific or α-specific genes other than the MAT genes themselves. We mapped a switching defect in a sibling species (O. parapolymorpha strain DL-1) by interspecies bulk segregant analysis to a frameshift in the transcription factor EFG1, which in Candida albicans regulates filamentous growth and white-opaque switching. Gene knockout, overexpression and ChIPseq experiments show that EFG1 regulates RME1, which in turn regulates STE12, to achieve mating-type switching. All three genes are necessary both for switching and for mating. Overexpression of RME1 or STE12 is sufficient to induce switching without a nitrogen depletion signal. The homologous recombination genes RAD51 and RAD17 are also necessary for switching. The pathway controlling switching in O. polymorpha shares no components with the regulation of HO in S. cerevisiae, which does not involve any environmental signal, but it shares some components with mating-type switching in Kluyveromyces lactis and with white-opaque phenotypic switching in C. albicans. [ABSTRACT FROM AUTHOR]

Catalytic signaling outputs of protein kinases are dynamically regulated by an array of structural mechanisms, including allosteric interactions mediated by intrinsically disordered segments flanking the conserved catalytic domain. The doublecortin-like kinases (DCLKs) are a family of microtubule-associated proteins characterized by a flexible C-terminal autoregulatory 'tail' segment that varies in length across the various human DCLK isoforms. However, the mechanism whereby these isoform-specific variations contribute to unique modes of autoregulation is not well understood. Here, we employ a combination of statistical sequence analysis, molecular dynamics simulations, and in vitro mutational analysis to define hallmarks of DCLK family evolutionary divergence, including analysis of splice variants within the DCLK1 sub-family, which arise through alternative codon usage and serve to 'supercharge' the inhibitory potential of the DCLK1 C-tail. We identify co-conserved motifs that readily distinguish DCLKs from all other calcium calmodulin kinases (CAMKs), and a 'Swiss Army' assembly of distinct motifs that tether the C-terminal tail to conserved ATP and substrate-binding regions of the catalytic domain to generate a scaffold for autoregulation through C-tail dynamics. Consistently, deletions and mutations that alter C-terminal tail length or interfere with co-conserved interactions within the catalytic domain alter intrinsic protein stability, nucleotide/inhibitor binding, and catalytic activity, suggesting isoform-specific regulation of activity through alternative splicing. Our studies provide a detailed framework for investigating kinome-wide regulation of catalytic output through cis-regulatory events mediated by intrinsically disordered segments, opening new avenues for the design of mechanistically divergent DCLK1 modulators, stabilizers, or degraders. [ABSTRACT FROM AUTHOR]

Cloud feedbacks are the leading cause of uncertainty in climate sensitivity. The complex coupling between clouds and the large‐scale circulation in the tropics contributes to this uncertainty. To address this problem, the coupling between clouds and circulation in the latest generation of climate models is compared to observations. Significant biases are identified in the models. The implications of these biases are assessed by combining observations of the present day with future changes predicted by models to calculate observationally constrained feedbacks. For the dynamic cloud feedback (i.e., due to changes in circulation), the observationally constrained values are consistently larger than the model‐only values. This is due to models failing to capture a nonlinear minimum in cloud brightness for weakly descending regimes. Consequently, while the models consistently predict that these regimes increase in frequency in association with a weakening tropical circulation, they underestimate the positive cloud feedback associated with this increase. Plain Language Summary: Climate models are crucial for understanding the impacts of climate change. Yet there are significant differences between models even for the global mean temperature increase due to a doubling of carbon dioxide concentrations (known as the climate sensitivity). These differences in climate sensitivity are largely due to differences in cloud responses to warming between the models (known as cloud feedbacks). Cloud feedback uncertainty is particularly large for tropical clouds. One reason for this is the two‐way interactions between clouds and the large‐scale circulation. This remains relatively poorly understood and involves processes that occur at a wide range of scales which cannot be captured by climate models. This study examines relationships between clouds and circulation in the tropics in the latest generation of climate models. Cloud feedbacks can be separated into dynamic (changes in circulation) and thermodynamic (changes in cloud for a given circulation regime) components. We use this framework to calculate the cloud feedbacks models would predict if the relationships between clouds and circulation matched observations. This results in an increase in the dynamic component of the cloud feedback which is due to the models' failure to capture the observed nonlinear relationships between clouds and circulation. Key Points: Climate models miss key details of the observed links between tropical clouds and circulation, notably for common weak subsidence regimesUsing observations to constrain thermodynamic and dynamic cloud feedbacks in models increases the dynamic and hence total feedbackThis is due to subtle nonlinear changes in the observed SW cloud radiative effect across circulation regimes that the models predict will change in frequency [ABSTRACT FROM AUTHOR]

Background: Femoral shaft fractures are common in major trauma. Early definitive fixation, within 24 hours, is feasible in most patients and is associated with improved outcomes. Nonetheless, variability might exist between trauma centers in timeliness of fixation. Such variability could impact outcomes and would therefore represent a target for quality improvement. We evaluated variability in delayed fixation (≥24 hours) between trauma centers participating in the American College of Surgeons (ACS) Trauma Quality Improvement Program (TQIP) and measured the resultant association with important clinical outcomes at the hospital level.Methods and Findings: A retrospective cohort study was performed using data derived from the ACS TQIP database. Adults with severe injury who underwent definitive fixation of a femoral shaft fracture at a level I or II trauma center participating in ACS TQIP (2012-2015) were included. Patient baseline and injury characteristics that might affect timing of fixation were considered. A hierarchical logistic regression model was used to identify predictors of delayed fixation. Hospital variability in delayed fixation was measured using 2 approaches. First, the random effects output of the hierarchical model was used to identify outlier hospitals where the odds of delayed fixation were significantly higher or lower than average. Second, the median odds ratio (MOR) was calculated to quantify heterogeneity in delayed fixation between hospitals. Finally, complications (pulmonary embolism, deep vein thrombosis, acute respiratory distress syndrome, pneumonia, decubitus ulcer, and death) and hospital length of stay were compared across quartiles of risk-adjusted delayed fixation. We identified 17,993 patients who underwent definitive fixation at 216 trauma centers. The median injury severity score (ISS) was 13 (interquartile range [IQR] 9-22). Median time to fixation was 15 hours (IQR 7-24 hours) and delayed fixation was performed in 26% of patients. After adjusting for patient characteristics, 57 hospitals (26%) were identified as outliers, reflecting significant practice variation unexplained by patient case mix. The MOR was 1.84, reflecting heterogeneity in delayed fixation across centers. Compared to hospitals in the lowest quartile of delayed fixation, patients treated at hospitals in the highest quartile of delayed fixation suffered 2-fold higher rates of pulmonary embolism (2.6% versus 1.3%; rate ratio [RR] 2.0; 95% CI 1.2-3.2; P = 0.005) and required greater length of stay (7 versus 6 days; RR 1.15; 95% CI 1.1-1.19; P < 0.001). There was no significant difference with respect to mortality (1.3% versus 0.8%; RR 1.6; 95% CI 1.0-2.8; P = 0.066). The main limitations of this study include the inability to classify fractures by severity, challenges related to the heterogeneity of the study population, and the potential for residual confounding due to unmeasured factors.Conclusions: In this large cohort study of 216 trauma centers, significant practice variability was observed in delayed fixation of femoral shaft fractures, which could not be explained by differences in patient case mix. Patients treated at centers where delayed fixation was most common were at significantly greater risk of pulmonary embolism and required longer hospital stay. Trauma centers should strive to minimize delays in fixation, and quality improvement initiatives should emphasize this recommendation in best practice guidelines. [ABSTRACT FROM AUTHOR]

Women are vulnerable to anxiety during pregnancy and postpartum. However, little is known about antenatal anxiety and neural processing of infant-relevant information. In this experiment, the N170, P300, and LPP (late positive potential) event-related potentials were measured from 43 pregnant women as they viewed infant and adult faces, which were either neutral or distressed in expression. Mother's self-reported anxiety levels were also assessed. The N170 was comparable across face conditions and was not associated with anxiety. However, our central finding was that greater levels of antenatal anxiety were associated with a larger LPP, but only for neutral infant faces. Results suggest that antenatal anxiety may result in deeper processing of neutral, emotionally ambiguous, infant faces during pregnancy. These findings are discussed in light of other work indicating an interpretive bias toward threat in response to neutral stimuli in anxiety. [ABSTRACT FROM AUTHOR]

This study examined factors influencing parent willingness to use D-Cycloserine (DCS) for treating child anxiety. N = 222 parents were given information about using DCS to treat anxiety. They were then asked to rate their willingness to allow their child to take DCS/antibiotics for mild anxiety, severe anxiety, or an infection. The associations between willingness to use DCS and parental trait anxiety, demographics, as well as specific concerns regarding the medication, were examined. Parents could also provide written responses regarding their attitudes to DCS, which were analysed for themes. Parents reported concerns regarding potential side-effects from DCS. More severe anxiety was associated with more willingness to consent; however, parents were more willing to use antibiotics to treat an infection than DCS to treat their child's anxiety. The degree of perceived benefit from DCS was most strongly associated with parents’ willingness to use it. Overall, parents expressed mixed views, reporting they would consider using DCS to treat their child; however, they had significant concerns about it. Results suggest providing parents with information explaining how DCS works, its risks and potential benefits may increase its acceptability. [ABSTRACT FROM PUBLISHER]

Climate models simulate a strong land-ocean contrast in the response of near-surface relative humidity to global warming; relative humidity tends to increase slightly over oceans but decrease substantially over land. Surface energy balance arguments have been used to understand the response over ocean but are difficult to apply over more complex land surfaces. Here, a conceptual box model is introduced, involving atmospheric moisture transport between the land and ocean and surface evapotranspiration, to investigate the decreases in land relative humidity as the climate warms. The box model is applied to simulations with idealized and full-complexity (CMIP5) general circulation models, and it is found to capture many of the features of the simulated changes in land humidity. The simplest version of the box model gives equal fractional increases in specific humidity over land and ocean. This relationship implies a decrease in land relative humidity given the greater warming over land than ocean and modest changes in ocean relative humidity, consistent with a mechanism proposed previously. When evapotranspiration is included, it is found to be of secondary importance compared to ocean moisture transport for the increase in land specific humidity, but it plays an important role for the decrease in land relative humidity. For the case of a moisture forcing over land, such as from stomatal closure, the response of land relative humidity is strongly amplified by the induced change in land surface-air temperature, and this amplification is quantified using a theory for the link between land and ocean temperatures. [ABSTRACT FROM AUTHOR]

Background: Many patients with anxiety disorders remain symptomatic after receiving evidence-based treatment, yet research on treatment-resistant anxiety is limited. We evaluated effects of cognitive behavioral therapy (CBT) on outcomes of patients with medication-resistant anxiety disorders using data from the Coordinated Anxiety Learning and Management (CALM) trial.Methods: Primary care patients who met study entry criteria (including DSM-IV diagnosis of generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or social anxiety disorder) despite ongoing pharmacotherapy of appropriate type, dose, and duration were classified as medication resistant (n = 227). Logistic regression was used to estimate effects of CALM's CBT program (CALM-CBT; chosen by 104 of 117 medication-resistant patients randomized to CALM) versus usual care (UC; n = 110) on response [≥ 50% reduction of 12-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptom score] and remission (BSI-12 < 6) at 6, 12, and 18 months. Within-group analyses examined outcomes by treatment choice (CBT vs. CBT plus medication management) and CBT dose.Results: Approximately 58% of medication-resistant CALM-CBT patients responded and 46% remitted during the study. Relative to UC, CALM-CBT was associated with greater response at 6 months (AOR = 3.78, 95% CI 2.02-7.07) and 12 months (AOR = 2.49, 95% CI 1.36-4.58) and remission at 6, 12, and 18 months (AORs = 2.44 to 3.18). Patients in CBT plus medication management fared no better than those in CBT only. Some evidence suggested higher CBT dose produced better outcomes.Conclusions: CBT can improve outcomes for patients whose anxiety symptoms are resistant to standard pharmacotherapy. [ABSTRACT FROM AUTHOR]