Human brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by ...interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture resembling late developmental stages. Here, we report the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death over long-term cultures. This method leads to sustained neurogenesis and formation of an expanded cortical plate that establishes distinct upper and deep cortical layers for neurons and astrocytes, resembling the third trimester embryonic human neocortex. Using the SNO system, we further identify a critical role of WNT/β-catenin signaling in regulating human cortical neuron subtype fate specification, which is disrupted by a psychiatric-disorder-associated genetic mutation in patient induced pluripotent stem cell (iPSC)-derived SNOs. These results demonstrate the utility of SNOs for investigating previously inaccessible human-specific, late-stage cortical development and disease-relevant mechanisms.
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•SNOs maintain growth and laminar expansion over long-term culture•SNOs exhibit separated upper and deep cortical layers•Layer-specific WNT/β-catenin signaling regulates neuronal fate specification•DISC1 mutation causes deficits in cortical neuron fate specification
Cortical organoids can be used to model human brain development and disorders. Ming and colleagues overcome the diffusion limit using a slicing method to prevent interior cell death and sustain organoid growth over long-term culture. The resulting organoids recapitulate late-stage human cortical developmental features, including formation of distinct cortical layers.
Chorea – Is Diabetes Mellitus the Cause? Phan, Tina; Klouda, Elisabeth; Jackson, Christopher D.
Journal of general internal medicine : JGIM,
06/2024
Journal Article
Recenzirano
Diabetic striatopathy (DS) is an uncommon complication of diabetes characterized by hemiballismus-hemichorea, often accompanied by reversible striatal hyperintensity on neuroimaging. Diabetes is the ...most common metabolic cause of hemiballismus and hemichorea. However, it is underreported as clinicians do not always consider it in the diagnosis of new movement abnormalities. The prognosis is generally excellent, and management involves glycemic control and anti-chorea medications. We present a case of a patient with bilateral chorea and ballismus and classic MRI findings of DS, though his history of diabetes and substance use confounds the clinical picture of DS.Diabetic striatopathy (DS) is an uncommon complication of diabetes characterized by hemiballismus-hemichorea, often accompanied by reversible striatal hyperintensity on neuroimaging. Diabetes is the most common metabolic cause of hemiballismus and hemichorea. However, it is underreported as clinicians do not always consider it in the diagnosis of new movement abnormalities. The prognosis is generally excellent, and management involves glycemic control and anti-chorea medications. We present a case of a patient with bilateral chorea and ballismus and classic MRI findings of DS, though his history of diabetes and substance use confounds the clinical picture of DS.
CpXRh(III)-catalyzed C–H functionalization reactions are a proven method for the efficient assembly of small molecules. However, rationalization of the effects of cyclopentadienyl (CpX) ligand ...structure on reaction rate and selectivity has been viewed as a black box, and a truly systematic study is lacking. Consequently, predicting the outcomes of these reactions is challenging because subtle variations in ligand structure can cause notable changes in reaction behavior. A predictive tool is, nonetheless, of considerable value to the community as it would greatly accelerate reaction development. Designing a data set in which the steric and electronic properties of the CpXRh(III) catalysts were systematically varied allowed us to apply multivariate linear regression algorithms to establish correlations between these catalyst-based descriptors and the regio-, diastereoselectivity, and rate of model reactions. This, in turn, led to the development of quantitative predictive models that describe catalyst performance. Our newly described cone angles and Sterimol parameters for CpX ligands served as highly correlative steric descriptors in the regression models. Through rational design of training and validation sets, key diastereoselectivity outliers were identified. Computations reveal the origins of the outstanding stereoinduction displayed by these outliers. The results are consistent with partial η5–η3 ligand slippage that occurs in the transition state of the selectivity-determining step. In addition to the instructive value of our study, we believe that the insights gained are transposable to other group 9 transition metals and pave the way toward rational design of C–H functionalization catalysts.
In an attempt to restore the connectivity of fragmented river habitats, a variety of passage facilities have been installed at river barriers. Despite the cost of building these structures, there has ...been no quantitative evaluation of their overall success at restoring fish passage. We reviewed articles from 1960 to 2011, extracted data from 65 papers on fish passage efficiency, size and species of fish, and fishway characteristics to determine the best predictors of fishway efficiency. Because data were scarce for fishes other than salmonids (order Salmoniformes), we combined data for all non‐salmonids for our analysis. On average, downstream passage efficiency was 68.5%, slightly higher than upstream passage efficiency of 41.7%, and neither differed across the geographical regions of study. Salmonids were more successful than non‐salmonids in passing upstream (61.7 vs. 21.1%) and downstream (74.6 vs. 39.6%) through fish passage facilities. Passage efficiency differed significantly between types of fishways; pool and weir, pool and slot and natural fishways had the highest efficiencies, whereas Denil and fish locks/elevators had the lowest. Upstream passage efficiency decreased significantly with fishway slope, but increased with fishway length, and water velocity. An information‐theoretic analysis indicated that the best predictors of fish passage efficiency were order of fish (i.e. salmonids > non‐salmonids), type of fishway and length of fishway. Overall, the low efficiency of passage facilities indicated that most need to be improved to sufficiently mitigate habitat fragmentation for the complete fish community across a range of environmental conditions.
Abstract
Summary
Previous attempts in cardiac bioengineering have failed to provide tissues for cardiac regeneration. Recent advances in 3-dimensional bioprinting technology using prevascularized ...myocardial microtissues as ‘bioink’ have provided a promising way forward. This review guides the reader to understand why myocardial tissue engineering is difficult to achieve and how revascularization and contractile function could be restored in 3-dimensional bioprinted heart tissue using patient-derived stem cells.
The Coupled Model
Intercomparison Project phase 6 (CMIP6) HighResMIP is a new experimental design for global
climate model simulations that aims to assess the impact of model horizontal
resolution on ...climate simulation fidelity. We describe a hierarchy of global
coupled model resolutions based on the Hadley Centre Global Environment Model 3 – Global Coupled vn 3.1 (HadGEM3-GC3.1) model that ranges from
an atmosphere–ocean resolution of 130 km–1∘ to 25 km–1∕12∘, all using the same forcings and initial conditions. In
order to make such high-resolution simulations possible, the experiments
have a short 30-year spinup, followed by at least century-long simulations
with constant forcing to assess drift. We assess the change in model biases as a function of both atmosphere and
ocean resolution, together with the effectiveness and robustness of this new
experimental design. We find reductions in the biases in top-of-atmosphere
radiation components and cloud forcing. There are significant reductions in
some common surface climate model biases as resolution is increased,
particularly in the Atlantic for sea surface temperature and precipitation,
primarily driven by increased ocean resolution. There is also a reduction in
drift from the initial conditions both at the surface and in the deeper
ocean at higher resolution. Using an eddy-present and eddy-rich ocean
resolution enhances the strength of the North Atlantic ocean circulation
(boundary currents, overturning circulation and heat transport), while an
eddy-present ocean resolution has a considerably reduced Antarctic
Circumpolar Current strength. All models have a reasonable representation of El Niño–Southern Oscillation. In general, the biases present after 30 years of simulations do not change character markedly over longer timescales,
justifying the experimental design.
Lower Gastrointestinal Hemorrhage Imran, Hira; Alexander, Jason T; Jackson, Christopher D
JAMA : the journal of the American Medical Association,
05/2024, Letnik:
331, Številka:
19
Journal Article
A bio-based economy has the potential to provide sustainable substitutes for petroleum-based products and new chemical building blocks for advanced materials. We previously engineered Saccharomyces ...cerevisiae for industrial production of the isoprenoid artemisinic acid for use in antimalarial treatments. Adapting these strains for biosynthesis of other isoprenoids such as β-farnesene (C
H
), a plant sesquiterpene with versatile industrial applications, is straightforward. However, S. cerevisiae uses a chemically inefficient pathway for isoprenoid biosynthesis, resulting in yield and productivity limitations incompatible with commodity-scale production. Here we use four non-native metabolic reactions to rewire central carbon metabolism in S. cerevisiae, enabling biosynthesis of cytosolic acetyl coenzyme A (acetyl-CoA, the two-carbon isoprenoid precursor) with a reduced ATP requirement, reduced loss of carbon to CO
-emitting reactions, and improved pathway redox balance. We show that strains with rewired central metabolism can devote an identical quantity of sugar to farnesene production as control strains, yet produce 25% more farnesene with that sugar while requiring 75% less oxygen. These changes lower feedstock costs and dramatically increase productivity in industrial fermentations which are by necessity oxygen-constrained. Despite altering key regulatory nodes, engineered strains grow robustly under taxing industrial conditions, maintaining stable yield for two weeks in broth that reaches >15% farnesene by volume. This illustrates that rewiring yeast central metabolism is a viable strategy for cost-effective, large-scale production of acetyl-CoA-derived molecules.
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