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Artificial intelligence (AI) promises to reshape scientific inquiry and enable breakthrough discoveries in areas such as energy storage, quantum computing, and biomedicine. Scanning transmission electron microscopy (STEM), a cornerstone of the study of chemical and materials systems, stands to benefit greatly from AI-driven automation. However, present barriers to low-level instrument control, as well as generalizable and interpretable feature detection, make truly automated microscopy impractical. Here, we discuss the design of a closed-loop instrument control platform guided by emerging sparse data analytics. We demonstrate how a centralized controller, informed by machine learning combining limited $a$ $priori$ knowledge and task-based discrimination, can drive on-the-fly experimental decision-making. This platform unlocks practical, automated analysis of a variety of material features, enabling new high-throughput and statistical studies., 28 pages, 3 figures

Unlike humans, the zebrafish can repair and regenerate its heart following injury. Understanding the molecular and physiological mechanisms of heart regeneration is critical in developing pro-regenerative strategies for clinical application. The cardiac lymphatic and non-lymphatic vasculature both respond to injury in zebrafish and are instrumental in driving optimal repair and regeneration. However, progress has been impeded by an inability to obtain high resolution images to clearly visualize and thus to fully understand the vascular responses in the injured heart and how this might intersect with successful repair and regeneration in humans.In this chapter, we describe a chemical clearing approach using Clear Unobstructed Brain/Body Imaging Cocktails and Computational analysis (CUBIC), for obtaining high resolution images of the adult zebrafish heart. This approach permits three-dimensional reconstruction of cardiac vasculature throughout the entire organ. By applying CUBIC methodology to tissues from transgenic zebrafish reporter lines or in conjunction with immunofluorescent staining, optical slices can be be generated, negating the need for standard tissue processing and sectioning procedures and yielding higher resolution images. The resultant images enable a holistic view of the coronary blood and lymphatic vasculature during heart injury and regeneration. Herein, we describe our protocol for visualizing vessels in the adult zebrafish heart using these approaches.

Ocean thermal expansion is a large contributor to observed sea level rise, which is expected to continue into the future. However, large uncertainties exist in sea level projections among climate models, partially due to intermodel differences in ocean heat uptake and redistribution of buoyancy. Here, the mechanisms of vertical ocean heat and salt transport are investigated in quasi-steady-state model simulations using the Australian Community Climate and Earth-System Simulator Ocean Model (ACCESS-OM2). New insights into the net effect of key physical processes are gained within the superresidual transport (SRT) framework. In this framework, vertical tracer transport is dominated by downward fluxes associated with the large-scale ocean circulation and upward fluxes induced by mesoscale eddies, with two distinct physical regimes. In the upper ocean, where high-latitude water masses are formed by mixed layer processes, through cooling or salinification, the SRT counteracts those processes by transporting heat and salt downward. In contrast, in the ocean interior, the SRT opposes dianeutral diffusion via upward fluxes of heat and salt, with about 60% of the vertical heat transport occurring in the Southern Ocean. Overall, the SRT is largely responsible for removing newly formed water masses from the mixed layer into the ocean interior, where they are eroded by dianeutral diffusion. Unlike the classical advective–diffusive balance, dianeutral diffusion is bottom intensified above rough bottom topography, allowing an overturning cell to develop in alignment with recent theories. Implications are discussed for understanding the role of vertical tracer transport on the simulation of ocean climate and sea level.

Acquiring environmental information is vital for organisms as it informs about the location of resources, mating partners, and predators. The freshwater crustaceanDaphniadetects predator specific chemical cues released by its predators and subsequently develops defensive morphological features that reduce the predation risk. The detection of such chemical information is generally processed via distinct chemoreceptors that are located on chemoreceptor cells. Lately an ancestral type of ionotropic receptors (IRs) has been identified in crustaceans. IRs and the putative co-receptors IR25a and IR93a are postulated to be involved in chemoreception However, functional roles have not been assessed. Here, using threeDaphniaspecies as model, we report that the two co-receptors are expressed within the chemosensory antennules and gene expression is increased with predator perception. Importantly, RNA interference mediated knock-down of the two IRs impedes species-specific defense expression in the threeDaphniaspecies. Our results suggest that (albeit not testing the enigmatic receptor protein directly), the reduction of two associated proteins has impaired the functional aggregation of the postulated chemoreceptor complex. This in turn has hampered the perception of environmentally relevant chemical cues resulting in a substantial reduction of defensive morphological features.

Titin-truncating variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy. TTNtv occur in ~1% of the general population and causes subclinical cardiac remodeling in asymptomatic carriers. In rat models with either proximal or distal TTNtv, we previously showed altered cardiac metabolism at baseline and impaired cardiac function in response to stress. However, the molecular mechanism(s) underlying these effects remains unknown. In the current study, we used rat models of TTNtv to investigate the effect of TTNtv on autophagy and mitochondrial function, which are essential for maintaining cellular metabolic homeostasis and cardiac function. In both the proximal and distal TTNtv rat models, we found increased levels of LC3B-II and p62 proteins, indicative of diminished autophagic degradation. The accumulation of autophagosomes and p62 protein in cardiomyocytes was also demonstrated by electron microscopy and immunochemistry, respectively. Impaired autophagy in the TTNtv heart was associated with increased phosphorylation of mTOR and decreased protein levels of the lysosomal protease, cathepsin B. In addition, TTNtv hearts showed mitochondrial dysfunction, as evidenced by decreased oxygen consumption rate in cardiomyocytes, increased levels of reactive oxygen species and mitochondrial protein ubiquitination. We also observed increased acetylation of mitochondrial proteins associated with decreased NAD+/NADH ratio in the TTNtv hearts. mTORC1 inhibitor, rapamycin, was able to rescue the impaired autophagy in TTNtv hearts. In summary, TTNtv leads to impaired autophagy and mitochondrial function in the heart. These changes not only provide molecular mechanisms that underlie TTNtv-associated ventricular remodeling but also offer potential targets for its intervention.

Coupled general circulation models (GCM), and their atmospheric, oceanic, land, and sea‐ice components have many parameters. Some parameters determine the numerics of the dynamical core, while others are based on our current understanding of the physical processes being simulated. Many of these parameters are poorly known, often globally defined, and are subject to pragmatic choices arising from a complex interplay between grid resolution and inherent model biases. To address this problem, we use an ensemble transform Kalman filter, to estimate spatiotemporally varying maps of ocean albedo and shortwave radiation e‐folding length scale in a coupled climate GCM. These parameters are designed to minimize the error between short term (3–28 days) forecasts of the climate model and a network of real world atmospheric, oceanic, and sea‐ice observations. The data assimilation system has an improved fit to observations when estimating ocean albedo and shortwave e‐folding length scale either individually or simultaneously. However, only individually estimated maps of shortwave e‐folding length scale are also shown to systematically reduce bias in longer multiyear climate forecasts during an out‐of‐sample period. The bias of the multiyear forecasts is reduced for parameter maps determined from longer DA cycle lengths.

A database of micronuclei counts for historical negative control data from rat in vivo micronuclei tests performed in 10 different laboratories was established. Data were available from over 4000 negative control rats from 10 laboratories. The mean frequency of micronucleated cells (MN)/1000 cells ranged from 0.44 to 2.22, a 5-fold range. Overall there were no major sex or strain differences in frequency, although there were some small but statistically significant differences within laboratories. There was appreciable variability between experiments compared with variability within experiments in some laboratories. No specific factor was identified which could explain this variability although it was noted that many different vehicles were used in the experiments. It is hoped that these data will help laboratories beginning studies with the rat micronucleus assay and those involved in the assessment of micronucleus assay results.

Readily exchangeable water molecules are commonly found in the active sites of oxidoreductases, yet the overwhelming majority of studies on small-molecule mimics of these enzymes entirely ignores the contribution of water to the reactivity. Studies of how these enzymes can continue to function in spite of the presence of highly oxidizing species are likewise limited. The mononuclear MnII complex with the potentially hexadentate ligand N-(2-hydroxy-5-methylbenzyl)-N,N′,N′-tris(2-pyridinylmethyl)-1,2-ethanediamine (LOH) was previously found to act as both a H2O2-responsive MRI contrast agent and a mimic of superoxide dismutase (SOD). Here, we studied this complex in aqueous solutions at different pH values in order to determine its (i) acid–base equilibria, (ii) coordination equilibria, (iii) substitution lability and operative mechanisms for water exchange, (iv) redox behavior and ability to participate in proton-coupled electron transfer (PCET) reactions, (v) SOD activity and reductive activity toward bot...

ZusammenfassungVeränderungen im Knochenstoffwechsel nach soliden Organtransplantationen, insbesondere nach Nierentransplantation, der mit über 2000 Transplantationen pro Jahr häufigsten Form, stellen immer wieder eine Herausforderung für den klinisch tätigen Osteologen dar. Die Besonderheiten der Transplantationsosteopathie (TO) liegen zum einem in der multifaktoriellen Pathogenese (u. a. Medikamente, vor Transplantation bestehende Knochenstörungen, hormonelle und weitere Faktoren) und zum anderen in den eingeschränkten Leitlinien, da nur eine geringe Zahl an evidenzbasierten Studien berücksichtigt werden können. In diesem Übersichts-artikel wird auf die aktuellen Aspekte bezüglich der Ursachen, Leitlinien, Diagnostik und der Therapiemöglichkeiten eingegangen. Im Speziellen soll dabei die Bedeutung der Knochenbiopsie und der Osteodensitometrie als diagnostische Tools und die Behandlung der frakturgefährdeten Patienten im ersten Jahr nach der Transplantation hervorgehoben werden.

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival.

Digital elevation models (DEMs) of river channel bathymetries are developed by interpolating elevations between data collected at discrete points or along transects. The accuracy of interpolated bathymetries depends on measurement error, the density and distribution of point data, and the interpolation method. Whereas point measurement errors can be minimized by selecting the most efficient equipment, the effect of data density and interpolation method on river bathymetry is relatively unknown. Thus, this study focuses on transect-based collection methods and investigates the effects of transect location, the spacing between transects, and interpolation methods on the accuracy of interpolated bathymetry. This is accomplished by comparing four control bathymetries generated from accurate and high resolution, sub-meter scale data to bathymetries interpolated from transect data extracted from the control bathymetries using two transect locating methods and four interpolation methods. The transect locating methods are a morphologically-spaced and an equally-spaced model. The four interpolation methods are Ordinary Kriging, Delaunay Triangulation, and Simple Linear, which are applied in curvilinear coordinates (Delaunay Triangulation is also applied in Cartesian coordinates), and Natural Neighbor only in Cartesian Coordinates. The bathymetric data were obtained from morphologically simple and complex reaches of a large (average bankfull width = 90 m) and a small (average bankfull width = 17 m) river. The accuracy of the developed DEMs is assessed using statistical analysis of the differences between the control and interpolated bathymetries and hydraulic parameters assessed from bankfull water surface elevations. Results indicate that DEM accuracy is not influenced by the choice of transect location method (with same averaged cross-section spacing) or a specific interpolation method, but rather by the coordinate system for which the interpolation method is applied and the spacing between transects. They also show negligible differences between the mean depths and surface areas calculated from bathymetries with dense or coarse spacing. Copyright © 2016 John Wiley & Sons, Ltd.

Following an explosion of molecular and cellular research in the last 50 years, the study of specific molecular targets in the context of heart failure has generated much excitement. With the incidence of heart failure rising worldwide, new pharmacological agents are eagerly anticipated as a key tool with the potential for significant impact. In this regard, the results of the keenly awaited Does Cyclosporine Improve Clinical Outcome in ST Elevation Myocardial Infarction Patients (CIRCUS) trial have just been made available. Despite a substantial programme of supporting experimental and preclinical evidence however, the results have proved negative. This is of great disappointment to the clinical and scientific community. Here, this is discussed in the context of previous studies and future directions explored.

Cardiovascular disease remains a leading cause of death and significant burden on healthcare systems worldwide. While interventional and preventative medicine has considerably changed the face of clinical practice, at the molecular level, treatment has not altered in recent decades and is still directed towards alleviating symptoms or mitigating the underlying cause rather than regenerating damaged heart muscle. This is surprising, given the explosion of research in this area in the 1970’s, and the fact that research output has continued to increase exponentially. With the incidence of heart failure on the rise, a trend predicted to continue, it is imperative that treatment strategies are improved. The development and adoption of molecular interventions might therefore present the most fruitful avenue in providing the greatest impact on mortality rates. This commentary aims to reflect on the earliest documented studies of human cardiovascular physiology, to surgical interventions in the 12th, to the first molecular studies in the 20th, to current pharmacological treatments. With this knowledge in mind, the future of molecular approaches in treating heart failure and cardiovascular conditions will be considered.

Reported herein are the magnetic and structural properties as well as solution equilibrium investigation for a pair of iron (II) pyridyl-imidazoline complexes: [Fe(pizMe)Cl2]2 (1) and [Fe(pizMe)3](FeCl4) (2), where pizMe = 2-(2′-pyridinyl)-4,5-dihydro-1-methylimidazole. Dinuclear complex 1 contains high-spin iron (II) centers and a “flat” pizMe ligand (planar at the imidazoline N atom), while the pizMe-containing complex in 2 exhibits characteristics of a low-spin iron (II) center and a pyramidalized pizMe ligand. In solution, the two complexes are present in equilibrium as evinced through NMR and electronic absorption spectral studies. Spin-state switching between 1 and 2 in methanolic solution is a result of ligand lability.

Prospektive 2-Jahresstudie zum Malnutritions-Inflammations-Arteriosklerose (MIA)-Syndrom bei Hamodialysepatienten: Inflammationsassoziierte Malnutrition ist ein signifikanter Mortalitatspradiktor Bei mangelernahrten Dialysepatienten wird das gleichzeitige Auftreten von Inflammation und kardiovaskularen Ereignissen haufig beobachtet und als Malnutritions-Inflammations-Atherosklerose (MIA)-Syndrom bezeichnet. Um dessen Mortalitatsrisiko abzuschatzen, wurde in einer prospektiven, multizentrischen und randomisierten Studie der Zusammenhang zwischen den einzelnen Komponenten des MIA-Syndroms und dem klinischen Endpunkt „Tod“ bei 123 Hamodialysepatienten uber 24 Monate untersucht. Sekundar sollte die Frage geklart werden, wie sich in Abhangigkeit vom Ernahrungsstatus die Dosierung und das Erreichen des Hamoglobinzielwertes unter dem langer wirkenden, die Erythropoese stimulierenden Agens Darbepoetin alfa (DPA) im Vergleich zu rekombinatem humanen Erythropoietin (EPO) in der Anamiebehandlung verandern. Im Vorfeld erfolgte deshalb eine Randomisierung der Patienten auf DPA bzw. EPO und wahrend des gesamten Studienzeitraums ein optimierter Azidoseausgleich. Der Ernahrungsstatus wurde mit dem „Subjective Global Assessment (SGA)-Score“ bestimmt: 73 Patienten waren normal ernahrt (SGA Score A), 50 Patienten mangelernahrt (SGA Score B oder C). Von den 26 verstorbenen Patienten waren zum Todeszeitpunkt 5 als normal ernahrt und 21 als mangelernahrt (19% vs. 81%; p < 0,001) eingruppiert. DPA bzw. EPO hatten keinen Einfluss auf das Uberleben der Patienten. Jedoch hatten die verstorbenen Patienten haufig ein hoheres Inflammationsniveau. Bezuglich des Ernahrungsstatus unterschieden sich weder die Dosierung von DPA bzw. EPO noch die Hamoglobinwerte signifikant voneinander. Diese prospektive Studie zum klinischen Verlauf des MIA-Syndroms uber 2 Jahre zeigt, dass die inflammationsassoziierte Malnutrition ein entscheidender Prognosefaktor fur das Uberleben von Dialysepatienten ist.

Summary The convolution of an input with a response function has been widely used in hydrology as a means to solve various problems analytically. Due to the high computation demand in solving the functions using numerical integration, it is often advantageous to use the discrete convolution instead of the integration of the continuous functions. This approach greatly reduces the amount of the computational work; however, it increases the possibility for mass balance errors. In this study, we analyzed the characteristics of the kernel function for the Hayami convolution solution to the linear diffusion-wave channel routing with distributed lateral inflow. We propose two ways of selection of the discrete kernel function values: using the exact point values or using the center-averaged values. Through a hypothetical example and the applications to Asotin Creek, WA and the Clearwater River, ID, we showed that when the point kernel function values were used in the discrete Hayami convolution (DHC) solution, the mass balance error of channel routing is dependent on the number of time steps on the rising limb of the Hayami kernel function. The mass balance error is negligible when there are more than 1.8 time steps on the rising limb of the kernel function. The fewer time steps on the rising limb, the greater risk of high mass balance errors. When the average kernel function values are used for the DHC solution, however, the mass balance is always maintained, since the integration of the discrete kernel function is always unity.

A trio of Pt-based heterobimetallic lantern complexes of the form [(py)PtM(SAc)4(py)] (M = Co, 1; Ni, 2; Zn, 3) with unusual octahedral coordination of Pt(II) was prepared from a reaction of [PtM(SAc)4] with excess pyridine. These dipyridine lantern complexes could be converted to monopyridine derivatives with gentle heat to give the series [PtM(SAc)4(py)] (M = Co, 4; Ni, 5; Zn, 6). An additional family of the form [PtM(SAc)4(pyNH2)] (M = Co, 7; Ni, 8; Zn, 9) was synthesized from reaction of [PtM(SAc)4(OH2)] or [PtM(SAc)4] with 4-aminopyridine. Dimethylsulfoxide and N,N-dimethylformamide were also determined to react with [PtM(SAc)4] (M = Co, Ni), respectively, to give [PtCo(SAc)4(DMSO)](DMSO), 10, and [PtNi(SAc)4(DMF)](DMF), 11. Structural and magnetic data for these compounds and those for two other previously published families, [PtM(tba)4(OH2)] and [PtM(SAc)4(L)], L = OH2, pyNO2, are used to divide the structures among three distinct categories based on Pt···Pt and Pt···S distances. In general, the weaker donors H2O and pyNO2 seem to favor metallophilicity and antiferromagnetic coupling between 3d metal centers. When Pt···S interactions are favored over Pt···Pt ones, no coupling is observed and the pKa of the pyridine donor correlates with the interlantern S···S distance. UV-vis-NIR electronic and (1)H NMR spectra provide complementary characterization as well.

A series of Pt-based heterobimetallic lantern complexes of the form [PtM(SAc)4(OH2)] (M = Co, 1; Ni, 2; Zn, 3) were prepared using a facile, single-step procedure. These hydrated species were reacted with 3-nitropyridine (3-NO2py) to prepare three additional lantern complexes, [PtM(SAc)4(3-NO2py)] (M = Co, 4; Ni, 5; Zn, 6), or alternatively dried in vacuo to the dehydrated species [PtM(SAc)4] (M = Co, 7; Ni, 8; Zn, 9). The Co- and Ni-containing species exhibit Pt-M bonding in solution and the solid state. In the structurally characterized compounds 1-6, the lantern units form dimers in the solid state via a short Pt···Pt metallophilic interaction. Antiferromagnetic coupling between 3d metal ions in the solid state through noncovalent metallophilic interactions was observed for all the paramagnetic lantern complexes prepared, with J-coupling values of -12.7 cm(-1) (1), -50.8 cm(-1) (2), -6.0 cm(-1) (4), and -12.6 cm(-1) (5). The Zn complexes 3 and 6 also form solid-state dimers, indicating that the formation of short Pt···Pt interactions in these complexes is not predicated on the presence of a paramagnetic 3d metal ion. These contacts and the resultant antiferromagnetic coupling are also not unique to heterobimetallic lantern complexes with axially coordinated H2O or the previously reported thiobenzoate supporting ligand.

Thermal water quality trading is an emerging policy tool that allows thermal polluters to comply with effluent restrictions by paying nearby landowners to plant shade trees. We created a system dynamics model of a hypothetical thermal trading program and conducted scenario analysis to study how weather, climate, and trading behavior might influence program effectiveness. It is likely that neither thermal trading nor conventional regulation can reduce water temperatures to desired levels, but the model indicates that trading ratios, used to account for uncertainty, lead programs to decrease water temperatures below those produced through conventional regulation.

This paper describes several simulation techniques [1] for ACC antenna integration in complex environments (radomes, bumpers) at 76–77 GHz. The first step exposes the antenna architecture. The second step follows with the antenna equivalent model techniques. Starting with the antenna design, one can replace the antenna by an equivalent source (near fields, spherical modes,…) to perform the ACC radar integration steps. Due to the high frequency ACC application, and due to the large electrical size of the complex structures, fast simulation techniques (MLFMM, RL-GO, MoM-GF,…) are used. The aim is to end up with a good trade off between simulation runtime and memory consumption, with accurate results compared to classical full wave techniques. Two integration scenarios are presented: The first one with a monolayer bumper structure and the second scenario with a multilayer bumper assembly taking into account the painting layers.

The first human space flight, in the early 1960s, was aimed primarily at determining whether humans could indeed survive and function in micro-gravity. Would eating and sleeping be possible? What mental and physical tasks could be performed? Subsequent programs increased the complexity of the tasks the crew performed. Table 1 summarizes the history of U.S. space flight, showing the projects, their dates, crew sizes, and mission durations. With over forty years of experience with human space flight, the emphasis now is on how to design space vehicles, habitats, and missions to produce the greatest returns to human knowledge. What are the roles of the humans in space flight in low earth orbit, on the moon, and in exploring Mars?

Three paramagnetic heterobimetallic lantern complexes of the form [PtM(tba)4(OH2)] (M = Fe, 1; Co, 2; Ni, 3; tba = thiobenzoate) have been prepared in a single-step, bench-top procedure. In all three cases, a lantern structure with Pt–M bonding is observed in solution and in the solid state. Compound 1 is a monomer whereas 3 exists as a dimer in the solid state via a Pt⋯Pt metallophilic interaction. Compound 2 has been characterized in forms with (2a, purple) and without (2b, yellow) Pt⋯Pt metallophilic interactions. The dimers 2a (J = −10 cm−1, based on the spin Hamiltonian Ĥ = −2J(SA·SB)) and 3 (J = −60 cm−1) exhibit antiferromagnetic coupling between the two first-row metal ions in the solid state via a Pt⋯Pt non-covalent metallophilic interaction. The electronic structure of C4v [PtM(tba)4], C2 [PtM(tba)4(OH2)], (M = Fe, Co, Ni) and D2 symmetry [PtM(tba)4(OH2)]2 M = Co, Ni, units have been studied with DFT calculations, confirming the relative spin-state energies observed and the antiferromagnetic exchange pathway through four dz2 orbitals. The compounds 2a and 3 are the first examples of antiferromagnetic coupling through an unbridged M⋯M contact.