Waves on the surface of the Orion molecular cloud

Massive stars influence their parental molecular cloud, and it has long been suspected that the development of hydrodynamical instabilities can compress or fragment the cloud. Identifying such instabilities has proved difficult. It has been suggested that elongated structures (such as the `pillars of creation') and other shapes arise because of instabilities, but alternative explanations are available. One key signature of an instability is a wave-like structure in the gas, which has hitherto not been seen. Here we report the presence of `waves' at the surface of the Orion molecular cloud near where massive stars are forming. The waves seem to be a Kelvin-Helmholtz instability that arises during the expansion of the nebula as gas heated and ionized by massive stars is blown over pre-existing molecular gas.Comment: Preprint of publication in Natur

Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma

Evidence for D1 Dopamine Receptor Activation by a Paracrine Signal of Dopamine in Tick Salivary Glands

Ticks that feed on vertebrate hosts use their salivary secretion, which contains various bioactive components, to manipulate the host's responses. The mechanisms controlling the tick salivary gland in this dynamic process are not well understood. We identified the tick D1 receptor activated by dopamine, a potent inducer of the salivary secretion of ticks. Temporal and spatial expression patterns examined by immunohistochemistry and reverse transcription polymerase chain reaction suggest that the dopamine produced in the basal cells of salivary gland acini is secreted into the lumen and activates the D1 receptors on the luminal surface of the cells lining the acini. Therefore, we propose a paracrine function of dopamine that is mediated by the D1 receptor in the salivary gland at an early phase of feeding. The molecular and pharmacological characterization of the D1 receptor in this study provides the foundation for understanding the functions of dopamine in the blood-feeding of ticks

Observation of discrete time-crystalline order in a disordered dipolar many-body system

Understanding quantum dynamics away from equilibrium is an outstanding challenge in the modern physical sciences. It is well known that out-of-equilibrium systems can display a rich array of phenomena, ranging from self-organized synchronization to dynamical phase transitions. More recently, advances in the controlled manipulation of isolated many-body systems have enabled detailed studies of non-equilibrium phases in strongly interacting quantum matter. As a particularly striking example, the interplay of periodic driving, disorder, and strong interactions has recently been predicted to result in exotic "time-crystalline" phases, which spontaneously break the discrete time-translation symmetry of the underlying drive. Here, we report the experimental observation of such discrete time-crystalline order in a driven, disordered ensemble of $\sim 10^6$ dipolar spin impurities in diamond at room-temperature. We observe long-lived temporal correlations at integer multiples of the fundamental driving period, experimentally identify the phase boundary and find that the temporal order is protected by strong interactions; this order is remarkably stable against perturbations, even in the presence of slow thermalization. Our work opens the door to exploring dynamical phases of matter and controlling interacting, disordered many-body systems.Comment: 6 + 3 pages, 4 figure

The N-terminal intrinsically disordered domain of mgm101p is localized to the mitochondrial nucleoid.

The mitochondrial genome maintenance gene, MGM101, is essential for yeasts that depend on mitochondrial DNA replication. Previously, in Saccharomyces cerevisiae, it has been found that the carboxy-terminal two-thirds of Mgm101p has a functional core. Furthermore, there is a high level of amino acid sequence conservation in this region from widely diverse species. By contrast, the amino-terminal region, that is also essential for function, does not have recognizable conservation. Using a bioinformatic approach we find that the functional core from yeast and a corresponding region of Mgm101p from the coral Acropora millepora have an ordered structure, while the N-terminal domains of sequences from yeast and coral are predicted to be disordered. To examine whether ordered and disordered domains of Mgm101p have specific or general functions we made chimeric proteins from yeast and coral by swapping the two regions. We find, by an in vivo assay in S.cerevisiae, that the ordered domain of A.millepora can functionally replace the yeast core region but the disordered domain of the coral protein cannot substitute for its yeast counterpart. Mgm101p is found in the mitochondrial nucleoid along with enzymes and proteins involved in mtDNA replication. By attaching green fluorescent protein to the N-terminal disordered domain of yeast Mgm101p we find that GFP is still directed to the mitochondrial nucleoid where full-length Mgm101p-GFP is targeted

Interpretation of ambiguous situations: evidence for a dissociation between social and physical threat in Williams syndrome

There is increasing evidence that Williams syndrome (WS) is associated with elevated anxiety that is non-social in nature, including generalised anxiety and fears. To date very little research has examined the cognitive processes associated with this anxiety. In the present research, attentional bias for non-social threatening images in WS was examined using a dot-probe paradigm. Participants were 16 individuals with WS aged between 13 and 34 years and two groups of typically developing controls matched to the WS group on chronological age and attentional control ability respectively. The WS group exhibited a significant attention bias towards threatening images. In contrast, no bias was found for group matched on attentional control and a slight bias away from threat was found in the chronological age matched group. The results are contrasted with recent findings suggesting that individuals with WS do not show an attention bias for threatening faces and discussed in relation to neuroimaging research showing elevated amygdala activation in response to threatening non-social scenes in WS

Perioperative Quality Initiative (POQI) consensus statement on fundamental concepts in perioperative fluid management: fluid responsiveness and venous capacitance

Background: Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state. Methods: The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting. Discussion: We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties

Centre of pressure characteristics in normal, planus and cavus feet

Background The aim of this study was to compare centre of pressure (COP) characteristics between healthy adults with normal, planus or cavus feet who were allocated to groups based on reliable foot posture measurement techniques. Methods Ninety-two healthy adult participants (aged 18 to 45) were recruited and classified as either normal (n = 35), pes planus (n = 31) or pes cavus (n = 26) based on Foot Posture Index, Arch Index and normalised navicular height truncated measurements. Barefoot walking trials were conducted using an emed®-x 400 plantar pressure system (Novel GmbH, Munich, Germany). Average, maximum, minimum and range (difference between maximum and minimum) values were calculated for COP velocity and lateral-medial force index during loading response, midstance, terminal stance and pre-swing phases of stance. The COP excursion index was also calculated. One-way analyses of variance were used to compare the three foot posture groups. Results The cavus foot exhibited the slowest average and minimum COP velocity during terminal stance, but this pattern was reversed during pre-swing, when the cavus foot exhibited the fastest maximum COP velocity. The planus foot exhibited the smallest lateral medial force index range during terminal stance. There were no differences between the groups for COP excursion index. Conclusion These findings indicate that there are differences in COP characteristics between foot postures, which may represent different mechanisms for generating force to facilitate forward progression of the body during the propulsive phases of gait

The U.S. Environmental Protection Agency Particulate Matter Health Effects Research Centers Program: a midcourse report of status, progress, and plans.

In 1998 Congress mandated expanded U.S. Environmental Protection Agency (U.S. EPA) health effects research on ambient air particulate matter (PM) and a National Research Council (NRC) committee to provide research oversight. The U.S. EPA currently supports intramural and extramural PM research, including five academically based PM centers. The PM centers in their first 2.5 years have initiated research directed at critical issues identified by the NRC committee, including collaborative activities, and sponsored scientific workshops in key research areas. Through these activities, there is a better understanding of PM health effects and scientific uncertainties. Future PM centers research will focus on long-term effects associated with chronic PM exposures. This report provides a synopsis of accomplishments to date, short-term goals (during the next 2.5 years) and longer-term goals. It consists of six sections: biological mechanisms, acute effects, chronic effects, dosimetry, exposure assessment, and the specific attributes of a coordinated PM centers program

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures