Notes

lncRNA TRMP-S directs twin elements to control p27-mediated mobile senescence.
Complex organosulfur molecules are ubiquitous in interstellar molecular clouds, but their fundamental formation mechanisms have remained largely elusive. Olaparib These processes are of critical importance in initiating a series of elementary chemical reactions, leading eventually to organosulfur molecules-among them potential precursors to iron-sulfide grains and to astrobiologically important molecules, such as the amino acid cysteine. Here, we reveal through laboratory experiments, electronic-structure theory, quasi-classical trajectory studies, and astrochemical modeling that the organosulfur chemistry can be initiated in star-forming regions via the elementary gas-phase reaction of methylidyne radicals with hydrogen sulfide, leading to thioformaldehyde (H2CS) and its thiohydroxycarbene isomer (HCSH). The facile route to two of the simplest organosulfur molecules via a single-collision event affords persuasive evidence for a likely source of organosulfur molecules in star-forming regions. These fundamental reaction mechanisms are valuable to facilitate an understanding of the origin and evolution of the molecular universe and, in particular, of sulfur in our Galaxy.Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.Quantum mechanics/molecular mechanics (QM/MM) maturation of an immunoglobulin (Ig) powered by supercomputation delivers novel functionality to this catalytic template and facilitates artificial evolution of biocatalysts. We here employ density functional theory-based (DFT-b) tight binding and funnel metadynamics to advance our earlier QM/MM maturation of A17 Ig-paraoxonase (WTIgP) as a reactibody for organophosphorus toxins. It enables regulation of biocatalytic activity for tyrosine nucleophilic attack on phosphorus. The single amino acid substitution l-Leu47Lys results in 340-fold enhanced reactivity for paraoxon. The computed ground-state complex shows substrate-induced ionization of the nucleophilic l-Tyr37, now H-bonded to l-Lys47, resulting from repositioning of l-Lys47. Multiple antibody structural homologs, selected by phenylphosphonate covalent capture, show contrasting enantioselectivities for a P-chiral phenylphosphonate toxin. That is defined by crystallographic analysis of phenylphosphonylated reaction products for antibodies A5 and WTIgP. DFT-b analysis using QM regions based on these structures identifies transition states for the favored and disfavored reactions with surprising results. This stereoselection analysis is extended by funnel metadynamics to a range of WTIgP variants whose predicted stereoselectivity is endorsed by experimental analysis. The algorithms used here offer prospects for tailored design of highly evolved, genetically encoded organophosphorus scavengers and for broader functionalities of members of the Ig superfamily, including cell surface-exposed receptors.Our decisions often depend on multiple sensory experiences separated by time delays. The brain can remember these experiences and, simultaneously, estimate the timing between events. To understand the mechanisms underlying working memory and time encoding, we analyze neural activity recorded during delays in four experiments on nonhuman primates. To disambiguate potential mechanisms, we propose two analyses, namely, decoding the passage of time from neural data and computing the cumulative dimensionality of the neural trajectory over time. Time can be decoded with high precision in tasks where timing information is relevant and with lower precision when irrelevant for performing the task. Neural trajectories are always observed to be low-dimensional. In addition, our results further constrain the mechanisms underlying time encoding as we find that the linear "ramping" component of each neuron's firing rate strongly contributes to the slow timescale variations that make decoding time possible. These constraints rule out working memory models that rely on constant, sustained activity and neural networks with high-dimensional trajectories, like reservoir networks. Instead, recurrent networks trained with backpropagation capture the time-encoding properties and the dimensionality observed in the data.Memory is typically thought of as enabling reminiscence about past experiences. However, memory also informs and guides processing of future experiences. These two functions of memory are often at odds Remembering specific experiences from the past requires storing idiosyncratic properties that define particular moments in space and time, but by definition such properties will not be shared with similar situations in the future and thus may not be applicable to future situations. We discovered that, when faced with this conflict, the brain prioritizes prediction over encoding. Behavioral tests of recognition and source recall showed that items allowing for prediction of what will appear next based on learned regularities were less likely to be encoded into memory. Brain imaging revealed that the hippocampus was responsible for this interference between statistical learning and episodic memory. The more that the hippocampus predicted the category of an upcoming item, the worse the current item was encoded. This competition may serve an adaptive purpose, focusing encoding on experiences for which we do not yet have a predictive model.
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