Miracle-dz/UniFAR-FTUs huggingface dataset:
Single cell trajectory analysis of human pluripotent stem cells differentiating towards lung and hepatocyte progenitors

Understanding the development of human respiratory tissues is crucial for modeling and treating lung disorders. The molecular details for the specification of lung progenitors from human pluripotent stem cells (hPSCs) are unclear. Here, we use single cell RNA-sequencing with high temporal resolution along an optimized differentiation protocol to determine the transcriptional hierarchy of lung specification from human hPSCs and map out the underlying single cell trajectories. We show that Sonic hedgehog, TGF-β and Notch activation are required in an ISL1/NKX2-1 trajectory that gives rise to lung progenitors during the foregut endoderm stage. Induction of HHEX marks an alternative trajectory at the early definitive endoderm stage, which precedes the lung trajectory and generates a major hepatoblast population. Moreover, neither KDR+ nor mesendoderm progenitors are apparent intermediate states of lung and hepatic lineages. Our hierarchical multistep model predicts mechanisms leading to lung organogenesis, and creates a basis for studying early human lung development, as well as hPSC based disease and drug research.
A photoswitchable GPCR-based opsin for presynaptic silencing

Optical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been relatively straightforward, rapid and reversible synaptic inhibition has been far more difficult to achieve. Instead of relying on unpredictable ion manipulations or slow photoactivatable toxins at axon terminals, we took a different approach to leverage the natural ability of inhibitory presynaptic GPCRs to silence synaptic transmission. Here we characterize parapinopsin (PPO), a photoswitchable non-visual opsin from lamprey pineal gland that couples to Gi/o-signaling cascades. PPO can be rapidly activated by pulsed blue light, switched off with amber light, and is effective for repeated or prolonged inhibition. We developed viral vectors for cell-specific expression of PPO, which traffics very effectively in numerous neuron types. At presynaptic terminals, PPO can silence glutamate release and suppress dopamine-dependent reward and cocaine place preference behaviors in vivo. PPO immediately fills a significant gap in the neuroscience toolkit for rapid and reversible synaptic inhibition, and has broader utility for achieving spatiotemporal control of inhibitory GPCR signaling cascades in other biological and pharmacological applications.
Mass cytometry reveals immunological response to radiation-induced cardiac fibrosis in mice

Background Radiation-induced cardiac injury results in complex clinical presentations, unique management issues, and increased morbidity and mortality. But the underlying mechanism of radiation-induced cardiac injury is still unclear. The aim of this study is to explain the compositional alterations of innate and adaptive cells after thoracic irradiation and the relationship of macrophage with other adaptive cells. Methods C57BL/6 mice were anesthetized and performed with 20Gy single dose cardiac irradiation. We carried out mice echocardiography to examine cardiac function. Masson and immunohistochemical staining were adopted to analyze cardiac fibrosis. Blood and cardiac tissue were collected 7 days, 4 weeks and 8 weeks after irradiation and sham-irradiated mice were set as a control group. Part of blood and tissue samples were analyzed with mass cytometry. We also used remaining blood samples to measure pro-fibrotic cytokines. Results We observed reduced cardiac diastolic function and pathologically confirmed cardiac fibrosis after thoracic irradiation. Through mass cytometry, we identified that the proportion of neutrophils, macrophages and monocytes elevated. The ratio of T and B cells decreased after irradiation in the blood samples. For tissue samples, the proportion of macrophages, monocytes and neutrophils increased, endothelial cells reduced, but T and B cells also increased. The level of TGF-β, TNF-α, IL-6 climbed considerably, all of them are closely associated with the evolution of macrophage function during recovering phase of cardiac injury. In the correlation plot, we also discovered that CD4+T and CD8+T cells were strongly positively correlated with macrophages. Conclusion We illustrated the immunological response after radiation-induced cardiac fibrosis, and macrophage may play a crucial role during the process. The results might have therapeutic potential for targeting macrophages in order to reduce radiation-induced cardiac fibrosis.
Dual proteomics of Drosophila melanogaster hemolymph infected with the heritable endosymbiont Spiroplasma poulsonii

Insects are frequently infected with heritable bacterial endosymbionts. Endosymbionts have a dramatic impact on their host physiology and evolution. Their tissue distribution is variable with some species being housed intracellularly, some extracellularly and some having a mixed lifestyle. The impact of extracellular endosymbionts on the biofluids they colonize (e.g. insect hemolymph) is however difficult to appreciate because biofluids composition can depend on the contribution of numerous tissues. Here we address the question of Drosophila hemolymph proteome response to the infection with the endosymbiont Spiroplasma poulsonii. S. poulsonii inhabits the fly hemolymph and gets vertically transmitted over generations by hijacking the oogenesis in females. Using dual proteomics on infected hemolymph, we uncovered a low level and chronic activation of the Toll immune pathway by S. poulsonii that was previously undetected by transcriptomics-based approaches. Using Drosophila genetics, we also identified candidate proteins putatively involved in controlling S. poulsonii growth. Last, we also provide a deep proteome of S. poulsonii, which, in combination with previously published transcriptomics data, improves our understanding of the post-transcriptional regulations operating in this bacterium. Summary statement We report the changes in Drosophila melanogaster hemolymph proteome upon infection with the heritable bacterial endosymbiont Spiroplasma poulsonii.
Behavioral control by depolarized and hyperpolarized states of an integrating neuron by

Coordinated transitions between mutually exclusive motor states are central to behavioral decisions. During locomotion, the nematode Caenorhabditis elegans spontaneously cycles between forward runs, reversals, and turns with complex but predictable dynamics. Here we provide insight into these dynamics by demonstrating how RIM interneurons, which are active during reversals, act in two modes to stabilize both forward runs and reversals. By systematically quantifying the roles of RIM outputs during spontaneous behavior, we show that RIM lengthens reversals when depolarized through glutamate and tyramine neurotransmitters and lengthens forward runs when hyperpolarized through its gap junctions. RIM is not merely silent upon hyperpolarization: RIM gap junctions actively reinforce a hyperpolarized state of the reversal circuit. Additionally, the combined outputs of chemical synapses and gap junctions from RIM regulate forward-to-reversal transitions. Our results indicate that multiple classes of RIM synapses create behavioral inertia during spontaneous locomotion.
A Transient Metabolic State in Melanoma Persister Cells Mediated by Chemotherapeutic Treatments

Persister cells are defined as the small fraction of quiescent cells in a bulk cancer cell population that can tolerate unusually high levels of drugs. Persistence is a transient state that poses an important health concern in cancer therapy. The mechanisms associated with persister phenotypes are highly diverse and complex, and many aspects of persister cell physiology remain to be explored. We applied a melanoma cell line and panel of chemotherapeutic agents to show that melanoma persister cells are not necessarily preexisting dormant cells or stem cells; in fact, they may be induced by cancer chemotherapeutics. Our metabolomics analysis and phenotype microarray assays further demonstrated that the levels of Krebs cycle molecules are significantly lower in the melanoma persister subpopulation than in the untreated bulk cell population due to increased utilization rates in persisters. Our data indicate that this observed metabolic remodeling is transient, as the consumption rates of Krebs cycle metabolites are significantly reduced in the progenies of persisters. Given that the mitochondrial electron transport chain (ETC) is more active in the persister subpopulation than in the bulk cancer cell population, we also verified that targeting ETC activity can reduce melanoma persistence. The reported metabolic remodeling feature seems to be a conserved characteristic of melanoma persistence, as it has been observed in various melanoma persister subpopulations derived from a diverse range of chemotherapeutics. Elucidating a global metabolic mechanism that contributes to persister survival and reversible switching will ultimately foster the development of novel cancer therapeutic strategies.
Resting-State Theta Oscillations and Reward Sensitivity in Risk Taking

Females demonstrate greater risk aversion than males on a variety of tasks, but the underlying neurobiological basis is still unclear. We studied how theta (4-7 Hz) oscillations at rest related to three different measures of risk taking. Thirty-five participants (15 females) completed the Bomb Risk Elicitation Task (BRET), which allowed us to measure risk taking during an economic game. The Domain-Specific Risk-Taking Scale (DOSPERT) was used to measure self-assessed risk attitudes as well as reward and punishment sensitivities. In addition, the Barratt Impulsiveness Scale (BIS11) was included to quantify impulsiveness. To obtain measures of frontal theta asymmetry and frontal theta power, we used magnetoencephalography (MEG) acquired prior to task completion, while participants were at rest. Frontal theta asymmetry correlated with average risk taking during the game but only in the female sample. By contrast, frontal theta power correlated with risk taking as well as with measures of reward and punishment sensitivity in the joint sample. Importantly, we showed that reward sensitivity mediated a correlation between risk taking and the power of theta oscillations localized to the anterior cingulate cortex. In addition, we observed significant sex differences in source- and sensor-space theta power, risk taking during the game, and reward sensitivity. Our findings suggest that sensitivity to rewards, associated with resting-state theta oscillations in the anterior cingulate cortex, is a trait that potentially contributes to sex differences in risk taking.
Precise Topology of Adjacent Domain-General and Sensory-Biased Regions in the Human Brain

Recent functional MRI studies identified sensory-biased regions across much of the association cortices and cerebellum. However, their anatomical relationship to multiple-demand (MD) regions, characterized as domain-general due to their co-activation during multiple cognitive demands, remains unclear. For a better anatomical delineation, we used multimodal MRI techniques of the Human Connectome Project to scan subjects performing visual and auditory versions of a working memory (WM) task. The contrast between hard and easy WM showed strong domain generality, with essentially identical patterns of cortical, subcortical and cerebellar MD activity for visual and auditory materials. In contrast, modality preferences were shown by contrasting easy WM with baseline; most MD regions showed visual preference while immediately adjacent to cortical MD regions, there were interleaved regions of both visual and auditory preference. The results may exemplify a general motif whereby domain-specific regions feed information into and out of an adjacent, integrative MD core.
Broad Influence of Mutant Ataxin-3 on the Proteome of the Adult Brain, Young Neurons, and Axons Reveals Central Molecular Processes and Biomarkers in SCA3/MJD Using Knock-In Mouse Model

Spinocerebellar ataxia type 3 (SCA3/MJD) has a polyQ etiology but, the current knowledge on molecular processes and proteins involved in pathogenesis is not sufficient to fully determine the disease mechanism and find drug targets. Proteases and deubiquitinases, such as Ataxin-3, often have a profound impact on other proteins, yet the global model picture of SCA3 disease progression on the protein level, showing the most crucial proteins and pathways in the brain, and neurons, was not investigated previously. Here, we investigated molecular SCA3 mechanism using interdisciplinary research paradigm combining SCA3 knock-in model, behavior, MRI, brain proteomics, precise axonal proteomics, neuronal energy recordings, labeling of vesicles, and inclusions and focusing in axonal compartment. We have demonstrated that altered metabolic and mitochondrial proteins in the brain and the lack of weight gain in Ki91 SCA3/MJD mice is reflected by the failure of energy metabolism recorded in neonatal SCA3 cerebellar neurons. We have determined that further, during disease progression, proteins responsible for metabolism, cytoskeletal architecture, vesicular and axonal transport proteins are disturbed, revealing axons as one of the essential cell compartments in SCA3 pathogenesis. Therefore we focus on SCA3 pathogenesis in axonal and somatodendritic compartments revealing highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport, and mitochondria was decreased. We demonstrate the accumulation of axonal vesicles in neonatal SCA3 cerebellar neurons and increased phosphorylation of SMI-312 positive adult cerebellar axons, which indicate axonal dysfunction in SCA3. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of protein synthetic machinery in axons.
Novel SERS-Active Optical Fibers Prepared by the Immobilization of Silver Colloidal Particles

A novel sensor based upon surface-enhanced Raman scattering (SERS) has been constructed by immobilizing colloidal silver particles onto the distal end of an optical fiber. This same single fiber was then used to both transport the exciting laser radiation and collect the Raman scattering from analytes sorbed onto the colloidal particles. The colloidal particles were immobilized by functionalization of the end of the optical fiber with (3-aminopropyl)trimethoxysilane prior to immersion of the fiber in silver colloid. Spectra were obtained from both 4-(5′-azobenzotriazol)3,5-dimethoxyphenylamine and crystal violet. The within-batch variation of a set of five fibers has been measured as approximately 10%. Raman imaging experiments demonstrated that the effects due to spatial variations in the intensity of the SERS recorded over the distal end of the fiber are removed by the use of a multimode fiber.
Effects of adding basic oxides of La and/or Ce to SiO2-supported Co catalysts for ethanol steam reforming

In this study, cobalt catalysts supported on La2O3–CeO2–SiO2 were synthesized by the method of impregnation of the support with aqueous solution of the active phase precursor. These materials were tested in ethanol steam reforming (ESR). The catalysts were characterized by in situ X-ray diffraction (XRD), temperature-programmed reduction (H2-TPR), temperature-programmed hydrogen desorption (H2-TPD), temperature-programmed oxidation (O2-TPO), adsorption–desorption of nitrogen (BET) and energy-dispersive X-ray spectroscopy (EDS). After reaction, the spent materials were characterized by XRD, SEM and elemental analysis. The in situ XRD analysis showed the formation of the solid solution CexLa1−xO2−δ and identified cobalt oxide in the spinel structure (Co3O4) and metallic cobalt (Co0). The H2-TPR analysis showed the reduction of cobalt oxide, and it was observed that the peaks of cobalt oxide shifted to lower temperatures as the content of lanthanum increased. The H2-TPD analysis showed that metal surface area and metal dispersion decreased as the percentage of lanthanum oxide in the supports increased. The O2-TPO analysis showed that La2%Ce48%Si50% consumed the most oxygen. The SEM analysis identified filamentous carbon after reaction. The catalysts were active for H2 and CO2 production. The best catalytic performance was shown by Co10%La2%Ce48%Si50%, which gave the highest H2 yield.
Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure

Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor–mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.
Small-scale patterns of sulfate aerosol climate forcing simulated with a high-resolution regional climate model

Abstract A high-resolution, regional climate model (RCA2) is employed to evaluate direct and indirect radiative forcing patterns due to man-made sulfate aerosols over Europe and to examine the sensitivity of the results to the choice of model resolution. A simulation encompassing the whole year of 1993 is performed. The model includes an explicit parameterization of the atmospheric sulfur cycle where predicted cloud and precipitation parameters are utilized at each time step. The overall pattern of the monthly mean direct climate effect simulated by the regional climate model is similar to that obtained using global climate models. Calculations over 0.4 and 4.0° spatial resolution indicate that, for the climatic conditions simulated by the RCA2, correlations between small-scale variations of relative humidity and aerosol loading do not contribute substantially to the magnitude of the monthly mean optical thickness. For the monthly mean indirect climate effect, the finer grid spacing in the RCA2 results in a pronounced spatial variability, not visible in global climate model simulations. An interesting question is whether this variability affects the estimated magnitude of the indirect climate effect. Calculations of the effective droplet radius (re) for 0.4 and 4° spatial resolution indicate a minor importance over the RCA2 model domain (the difference in re is less than 7%). The model generally underestimates the sulfate concentration within the boundary layer, whereas the magnitude of the simulated CDNC and re agrees well with aircraft measurements. Despite an underestimate of the absolute magnitude, the regional pattern of the modeled re resembles that observed by satellite. A number of sensitivity simulations demonstrate that the magnitude of the indirect radiative forcing is highly uncertain. In order to reduce the uncertainty, different parameterizations of the indirect effect should be evaluated in more detail versus measurements of, e.g., aerosol concentration and properties, CDNC, and re at various locations.
CHARGE SCREENING AND THE DIELECTRIC CONSTANT OF PROTEINS : INSIGHTS FROM MOLECULAR DYNAMICS

The dielectric constants of myoglobin, apomyoglobin, the B fragment of staphylococcal protein A, and the immunoglobulin-binding domain of streptococcal protein G are calculated from 1−2 ns molecular dynamics simulations in water, using the Frohlich−Kirkwood theory of dielectrics. This dielectric constant is a direct measure of the polarizability of the protein medium and is the appropriate macroscopic quantity to measure its relaxation properties in response to a charged perturbation, such as electron transfer, photoexcitation, or ion binding. In each case the dielectric constant is low (2−3) in the protein interior, then rises to 11−21 for the whole molecule. The large overall dielectric constant is almost entirely due to the charged protein side chains, located at the protein surface, which have significant flexibility. If these are viewed instead as part of the outer solvent medium, then the remainder of the protein has a low dielectric constant of 3−6 (depending on the protein), comparable to that of .
Quantitative comparisons of structures

Abstract Diagrams of the shortest selected non-bonding distances illustrating and measuring the structural differences have been employed for analysing polymorphs, isostructural crystals, and crystal structures at varied thermodynamical conditions. The diagrams efficiently compare the interatomic, intermolecular or interionic distances, describe quantitatively the crystal packings, and facilitate finding the molecular or ionic features responsible for the formation of polymorphs, isostructural crystals, or strains induced by changes of temperature or pressure. It appears as an immediate conclusion from comparing the interactions in a series of polymorphs and isostructural crystals, that the close packing rule plays the crucial role for the formation of these structures.
Prediction of Coke CSR from Ash Chemistry of Coal Blend

Coke reactivity index (CRI) and coke strength after reaction (CSR) are the most important parameters used to assess the blast-furnace coke quality. The present work describes the possibility of estimating CSR for coke from ash chemistry of coal blends. For development and validation of the regression model, data obtained from the Tata Steel's coke oven battery numbers 8 and 9 were utilized. It was found that CSR is greatly influenced by coal ash chemistry.
Preparation and Characterization of Electrochemical Glucose Sensor Based on Nickel Electrodes Supported by Silicon Microchannel Plates

A novel nickel nanocomposite electrode supported by 3D ordered silicon microchannel plates (MCP) had been reported and its electrocatalytic toward the oxidation of glucose for sensor had been studied. The 3D ordered Si MCP electrodes were first fabricated by electrochemical etching and then Nickel nanoparticles were deposited onto the sidewall of the MCP via electroless deposition followed by annealing at 300°C for 300 s under argon to stabilize the structure. The morphology of the Ni/Si-MCP electrode was characterized by Scanning electron microscope (SEM) and X-ray diffraction (XRD). The electrochemical methods were employed to investigate the Ni/Si-MCP materials. The Ni/Si-MCP nanocomposites exhibit superior electrocatalytic properties towards glucose electro-oxidation in alkaline solutions, in addition to showing excellent long-term stability and good reproducibility.