The isocortex and hippocampal formation (HPF) in the mammalian brain play critical roles in perception, cognition, emotion, and learning. We profiled ∼1.3 million cells covering the entire adult ...mouse isocortex and HPF and derived a transcriptomic cell-type taxonomy revealing a comprehensive repertoire of glutamatergic and GABAergic neuron types. Contrary to the traditional view of HPF as having a simpler cellular organization, we discover a complete set of glutamatergic types in HPF homologous to all major subclasses found in the six-layered isocortex, suggesting that HPF and the isocortex share a common circuit organization. We also identify large-scale continuous and graded variations of cell types along isocortical depth, across the isocortical sheet, and in multiple dimensions in hippocampus and subiculum. Overall, our study establishes a molecular architecture of the mammalian isocortex and hippocampal formation and begins to shed light on its underlying relationship with the development, evolution, connectivity, and function of these two brain structures.
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•Single-cell transcriptomics from >1.3 million cells in the mouse cortex and hippocampus•Many neuron types specific to associational cortex and hippocampal regions are identified•Parallel cell-type and laminar organization between isocortex and hippocampal formation•Large-scale continuous neuron-type variation in isocortex and hippocampus/subiculum
Single-cell transcriptomics of the entire mouse isocortex and hippocampal formation shows shared cellular and circuit organization and large-scale continuous gradients of neuron-type variation that illuminates the underlying relationship between these two critical brain structures.
Tissue regenerative potential displays striking divergence across phylogeny and ontogeny, but the underlying mechanisms remain enigmatic. Loss of mammalian cardiac regenerative potential correlates ...with cardiomyocyte cell-cycle arrest and polyploidization as well as the development of postnatal endothermy. We reveal that diploid cardiomyocyte abundance across 41 species conforms to Kleiber's law-the ¾-power law scaling of metabolism with bodyweight-and inversely correlates with standard metabolic rate, body temperature, and serum thyroxine level. Inactivation of thyroid hormone signaling reduces mouse cardiomyocyte polyploidization, delays cell-cycle exit, and retains cardiac regenerative potential in adults. Conversely, exogenous thyroid hormones inhibit zebrafish heart regeneration. Thus, our findings suggest that loss of heart regenerative capacity in adult mammals is triggered by increasing thyroid hormones and may be a trade-off for the acquisition of endothermy.
Models of thermal adaptation assume that warm‐adapted and cold‐adapted organisms can achieve the same fitness, yet recent comparative studies suggest that warm‐adapted organisms outperform ...cold‐adapted ones. We explored how this thermodynamic effect on performance might influence selective pressures on thermal physiology. In the absence of a thermodynamic effect, natural selection favors a thermal optimum for performance that closely matches the mean (or modal) body temperature. When warm‐adapted organisms outperform cold‐adapted organisms, natural selection can favor a thermal optimum that exceeds the mean body temperature. The optimal mismatch between the thermal optimum and the mean temperature increases as does the variation in body temperature within generations. This result holds regardless of whether performance affects fitness through fecundity or survivorship. The selective pressures generated by a thermodynamic effect might explain the substantial mismatch between thermoregulatory behavior and thermal physiology that has been observed in some species.
An anatomic transcriptional atlas of human glioblastoma Puchalski, Ralph B; Shah, Nameeta; Miller, Jeremy ...
Science (American Association for the Advancement of Science),
05/2018, Letnik:
360, Številka:
6389
Journal Article
Recenzirano
Odprti dostop
Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for ...diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.
Neurons are frequently classified into distinct types on the basis of structural, physiological, or genetic attributes. To better constrain the definition of neuronal cell types, we characterized the ...transcriptomes and intrinsic physiological properties of over 4,200 mouse visual cortical GABAergic interneurons and reconstructed the local morphologies of 517 of those neurons. We find that most transcriptomic types (t-types) occupy specific laminar positions within visual cortex, and, for most types, the cells mapping to a t-type exhibit consistent electrophysiological and morphological properties. These properties display both discrete and continuous variation among t-types. Through multimodal integrated analysis, we define 28 met-types that have congruent morphological, electrophysiological, and transcriptomic properties and robust mutual predictability. We identify layer-specific axon innervation pattern as a defining feature distinguishing different met-types. These met-types represent a unified definition of cortical GABAergic interneuron types, providing a systematic framework to capture existing knowledge and bridge future analyses across different modalities.
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•Patch-seq data obtained from >4,200 GABAergic interneurons with >500 morphologies•Comprehensive characterization of morphoelectric features of transcriptomic types•28 interneuron met-types with congruent properties across data modalities•Different Sst met-types preferentially innervate different cortical layers
GABAergic cortical interneurons of the mouse visual cortex can be defined into 28 types based on their morphological, electrophysiological, and transcriptomic properties and are distinguished by their layer-specific axon innervation patterns.
Surgical management of isolated tricuspid regurgitation (TR) is associated with high morbidity and mortality, thereby creating a significant need for a lower-risk transcatheter solution.
The ...single-arm, multicenter, prospective CLASP TR (Edwards PASCAL TrAnScatheter Valve RePair System in Tricuspid Regurgitation CLASP TR Early Feasibility Study) evaluated 1-year outcomes of the PASCAL transcatheter valve repair system (Edwards Lifesciences) to treat TR.
Study inclusion required a previous diagnosis of severe or greater TR and persistent symptoms despite medical treatment. An independent core laboratory evaluated echocardiographic results, and a clinical events committee adjudicated major adverse events. The study evaluated primary safety and performance outcomes, with echocardiographic, clinical, and functional endpoints. Study investigators report 1-year all-cause mortality and heart failure hospitalization rates.
Sixty-five patients were enrolled: mean age of 77.4 years; 55.4% female; and 97.0% with severe to torrential TR. At 30 days, cardiovascular mortality was 3.1%, the stroke rate was 1.5%, and no device-related reinterventions were reported. Between 30 days and 1 year, there were an additional 3 cardiovascular deaths (4.8%), 2 strokes (3.2%), and 1 unplanned or emergency reintervention (1.6%). One-year postprocedure, TR severity significantly reduced (P < 0.001), with 31 of 36 (86.0%) patients achieving moderate or less TR; 100% had at least 1 TR grade reduction. Freedom from all-cause mortality and heart failure hospitalization by Kaplan-Meier analyses were 87.9% and 78.5%, respectively. Their New York Heart Association functional class significantly improved (P < 0.001) with 92% in class I or II, 6-minute walk distance increased by 94 m (P = 0.014), and overall Kansas City Cardiomyopathy Questionnaire scores improved by 18 points (P < 0.001).
The PASCAL system demonstrated low complication and high survival rates, with significant and sustained improvements in TR, functional status, and quality of life at 1 year. (Edwards PASCAL TrAnScatheter Valve RePair System in Tricuspid Regurgitation CLASP TR Early Feasibility Study CLASP TR EFS; NCT03745313)
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Understanding the diversity of cell types in the brain has been an enduring challenge and requires detailed characterization of individual neurons in multiple dimensions. To systematically profile ...morpho-electric properties of mammalian neurons, we established a single-cell characterization pipeline using standardized patch-clamp recordings in brain slices and biocytin-based neuronal reconstructions. We built a publicly accessible online database, the Allen Cell Types Database, to display these datasets. Intrinsic physiological properties were measured from 1,938 neurons from the adult laboratory mouse visual cortex, morphological properties were measured from 461 reconstructed neurons, and 452 neurons had both measurements available. Quantitative features were used to classify neurons into distinct types using unsupervised methods. We established a taxonomy of morphologically and electrophysiologically defined cell types for this region of the cortex, with 17 electrophysiological types, 38 morphological types and 46 morpho-electric types. There was good correspondence with previously defined transcriptomic cell types and subclasses using the same transgenic mouse lines.
Seven different high-performance fuels were synthesized from bio-based monoterpenes (3-carene, sabinene, α-pinene, β-pinene, limonene, 1,6-dimethyl-1,5-cyclooctadiene, and myrcene) by Simmons-Smith ...cyclopropanation. Key fuel properties of the resulting multicyclic fuel mixtures were measured including, density, net heat of combustion (NHOC), and low-temperature viscosity. The mixtures exhibited densities 10–16% higher and volumetric NHOCs 12–16% higher than conventional jet fuel, while maintaining low temperature (−20 °C) viscosities either below or close to the specification limit. To evaluate the fuels as potential rocket propellants, heats of formation were calculated using the G4 composite method. These values were then used to calculate specific impulse (Isp) and density-specific impulse (d-Isp) for each fuel mixture. The cyclopropanated monoterpenes exhibited sea level Isp values up to 1.2% higher than conventional rocket propellant (RP-1) and d-Isp values up to 4.1% higher than RP-1. The results of this study suggest that cyclopropanated monoterpenes may have utility as high-performance jet fuel blendstocks or specialized rocket propellants, offering the ability to increase the payload capacity and enhance the mission capability of space-delivery systems. This work further highlights the potential of biosynthetic fuels for high-performance applications.
•Biosynthetic fuel mixtures were prepared by cyclopropanation of terpene substrates.•Fuel properties were evaluated and structure-property relationships determined.•Fuels exhibited volumetric heats of combustion up to 16% higher than Jet-A.•ΔHf and specific impulse (Isp) values were calculated for the fuel molecules.•Fuels had d-Isp values up to 4.1% higher compared to RP-1.
CD4(+) Foxp3(+) regulatory T cells (Tregs) are an independent cell lineage, and their developmental progression during thymic development depends on IL-2R signaling. However, the role of IL-2R ...signaling during thymic Treg development remains only partially understood. The current study assessed the contribution of IL-2 to the expansion and functional programming of developing Tregs. In the absence of IL-2Rβ signaling, predominantly CD4(+) CD25(-) Foxp3(lo) T cells were found, and these cells exhibited somewhat lower expression of the proliferative marker Ki67. These immature Tregs, which represent products of failed development, were also found in normal mice and were characterized by markedly lower expression of several Treg functional molecules. Therefore, IL-2R is required for the progression, functional programming, and expansion of Tregs during thymic development. An IL-2R-signaling mutant that lowers STAT5 activation readily supported Treg functional programming, but Treg proliferation remained somewhat impaired. The requirement for IL-2 during thymic Treg expansion was best illustrated in mixed chimeras where the Tregs with mutant IL-2Rs were forced to compete with wild-type Tregs during their development. Tregs with impaired IL-2R signaling were more prevalent in the thymus than spleen in these competitive experiments. The general effectiveness of mutant IL-2Rs to support thymic Treg development is partially accounted for by a heightened capacity of thymic Tregs to respond to IL-2. Overall, our data support a model in which limiting IL-2R signaling is amplified by thymic Tregs to readily support their development and functional programming, whereas these same conditions are not sufficient to support peripheral Treg homeostasis.
The TRISCEND study (Edwards EVOQUE Tricuspid Valve Replacement: Investigation of Safety and Clinical Efficacy after Replacement of Tricuspid Valve with Transcatheter Device) is evaluating the safety ...and performance of transfemoral transcatheter tricuspid valve replacement in patients with clinically significant tricuspid regurgitation (TR) and elevated surgical risk.
Transcatheter valve replacement could lead to a paradigm shift in treating TR and improving patient quality of life.
In the prospective, single-arm, multicenter TRISCEND study, patients with symptomatic moderate or greater TR, despite medical therapy, underwent percutaneous transcatheter tricuspid valve replacement with the EVOQUE system. A composite rate of major adverse events, echocardiographic parameters, and clinical, functional, and quality-of-life measures were assessed at 30 days.
Fifty-six patients (mean age of 79.3 years, 76.8% female, 91.1% TR severe or greater, 91.1% atrial fibrillation, and 87.5% New York Heart Association functional class III or IV) were treated. At 30 days, TR was reduced to mild or less in 98%. The composite major adverse events rate was 26.8% at 30 days caused by 1 cardiovascular death in a patient with a failed procedure, 2 reinterventions after device embolization, 1 major access site or vascular complication, and 15 severe bleeds, of which none were life-threatening or fatal. No myocardial infarction, stroke, renal failure, major cardiac structural complications, or device-related pulmonary embolism were observed. New York Heart Association significantly improved to functional class I or II (78.8%; P < 0.001), 6-minute walk distance improved 49.8 m (P < 0.001), and Kansas City Cardiomyopathy Questionnaire score improved 19 points (P < 0.001).
Early experience with the transfemoral EVOQUE system in patients with clinically significant TR demonstrated technical feasibility, acceptable safety, TR reduction, and symptomatic improvement at 30 days. The TRISCEND II randomized trial (NCT04482062) is underway.
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