Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling ...human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively. Population and single-cell RNA sequencing (RNA-seq) profiling combined with bulk assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids and modeling human interneuron migration and offers deeper insight into molecular dynamics during human brain development.
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•hMGEOs and hCOs recapitulate human brain organization and fetal brain transcriptomes•Transcriptome and chromatin accessibility distinguish hMGEOs and hCOs•hMGEOs and hCOs display activity-dependent and synchronized calcium oscillations•Interneurons migrate from hMGEOs and functionally integrate in hCOs
Xiang and colleagues report a method for generating human medial ganglionic eminence (MGE)-like organoids (hMGEOs) and cortical-like organoids (hCOs), which resemble the developing human MGE and cortex, respectively. By fusing hMGEOs and hCOs, they establish a 3D model to investigate human interneuron migration.
Tuning the optical, electromagnetic and mechanical properties of a material requires simultaneous control over its composition and shape. This is particularly challenging for complex structures at ...the nanoscale because surface-energy minimization generally causes small structures to be highly symmetric. Here we combine low-temperature shadow deposition with nanoscale patterning to realize nanocolloids with anisotropic three-dimensional shapes, feature sizes down to 20 nm and a wide choice of materials. We demonstrate the versatility of the fabrication scheme by growing three-dimensional hybrid nanostructures that contain several functional materials with the lowest possible symmetry, and by fabricating hundreds of billions of plasmonic nanohelices, which we use as chiral metafluids with record circular dichroism and tunable chiroptical properties.
We examine how commonality in liquidity varies across countries and over time in ways related to supply determinants (funding liquidity of financial intermediaries) and demand determinants ...(correlated trading behavior of international and institutional investors, incentives to trade individual securities, and investor sentiment) of liquidity. Commonality in liquidity is greater in countries with and during times of high market volatility (especially, large market declines), greater presence of international investors, and more correlated trading activity. Our evidence is more reliably consistent with demand-side explanations and challenges the ability of the funding liquidity hypothesis to help us understand important aspects of financial market liquidity around the world, even during the recent financial crisis.
Summary Background Induction of a clinical complete response with chemoradiotherapy, followed by observation via a watch-and-wait approach, has emerged as a management option for patients with rectal ...cancer. We aimed to address the shortage of evidence regarding the safety of the watch-and-wait approach by comparing oncological outcomes between patients managed by watch and wait who achieved a clinical complete response and those who had surgical resection (standard care). Methods Oncological Outcomes after Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) was a propensity-score matched cohort analysis study, that included patients of all ages diagnosed with rectal adenocarcinoma without distant metastases who had received preoperative chemoradiotherapy (45 Gy in 25 daily fractions with concurrent fluoropyrimidine-based chemotherapy) at a tertiary cancer centre in Manchester, UK, between Jan 14, 2011, and April 15, 2013. Patients who had a clinical complete response were offered management with the watch-and-wait approach, and patients who did not have a complete clinical response were offered surgical resection if eligible. We also included patients with a clinical complete response managed by watch and wait between March 10, 2005, and Jan 21, 2015, across three neighbouring UK regional cancer centres, whose details were obtained through a registry. For comparative analyses, we derived one-to-one paired cohorts of watch and wait versus surgical resection using propensity-score matching (including T stage, age, and performance status). The primary endpoint was non-regrowth disease-free survival from the date that chemoradiotherapy was started, and secondary endpoints were overall survival, and colostomy-free survival. We used a conservative p value of less than 0·01 to indicate statistical significance in the comparative analyses. Findings 259 patients were included in our Manchester tertiary cancer centre cohort, 228 of whom underwent surgical resection at referring hospitals and 31 of whom had a clinical complete response, managed by watch and wait. A further 98 patients were added to the watch-and-wait group via the registry. Of the 129 patients managed by watch and wait (median follow-up 33 months IQR 19–43), 44 (34%) had local regrowths (3-year actuarial rate 38% 95% CI 30–48); 36 (88%) of 41 patients with non-metastatic local regrowths were salvaged. In the matched analyses (109 patients in each treatment group), no differences in 3-year non-regrowth disease-free survival were noted between watch and wait and surgical resection (88% 95% CI 75–94 with watch and wait vs 78% 63–87 with surgical resection; time-varying p=0·043). Similarly, no difference in 3-year overall survival was noted (96% 88–98 vs 87% 77–93; time-varying p=0·024). By contrast, patients managed by watch and wait had significantly better 3-year colostomy-free survival than did those who had surgical resection (74% 95% CI 64–82 vs 47% 37–57; hazard ratio 0·445 95% CI 0·31–0·63; p<0·0001), with a 26% (95% CI 13–39) absolute difference in patients who avoided permanent colostomy at 3 years between treatment groups. Interpretation A substantial proportion of patients with rectal cancer managed by watch and wait avoided major surgery and averted permanent colostomy without loss of oncological safety at 3 years. These findings should inform decision making at the outset of chemoradiotherapy. Funding Bowel Disease Research Foundation.
Engineered gene drives based on a homing mechanism could rapidly spread genetic alterations through a population. However, such drives face a major obstacle in the form of resistance against the ...drive. In addition, they are expected to be highly invasive. Here, we introduce the Toxin-Antidote Recessive Embryo (TARE) drive. It functions by disrupting a target gene, forming recessive lethal alleles, while rescuing drive-carrying individuals with a recoded version of the target. Modeling shows that such drives will have threshold-dependent invasion dynamics, spreading only when introduced above a fitness-dependent frequency. We demonstrate a TARE drive in Drosophila with 88-95% transmission by female heterozygotes. This drive was able to spread through a large cage population in just six generations following introduction at 24% frequency without any apparent evolution of resistance. Our results suggest that TARE drives constitute promising candidates for the development of effective, flexible, and regionally confinable drives for population modification.
Human pluripotent stem cell (hPSC) differentiation typically yields heterogeneous populations. Knowledge of signals controlling embryonic lineage bifurcations could efficiently yield desired cell ...types through exclusion of alternate fates. Therefore, we revisited signals driving induction and anterior-posterior patterning of definitive endoderm to generate a coherent roadmap for endoderm differentiation. With striking temporal dynamics, BMP and Wnt initially specified anterior primitive streak (progenitor to endoderm), yet, 24 hr later, suppressed endoderm and induced mesoderm. At lineage bifurcations, cross-repressive signals separated mutually exclusive fates; TGF-β and BMP/MAPK respectively induced pancreas versus liver from endoderm by suppressing the alternate lineage. We systematically blockaded alternate fates throughout multiple consecutive bifurcations, thereby efficiently differentiating multiple hPSC lines exclusively into endoderm and its derivatives. Comprehensive transcriptional and chromatin mapping of highly pure endodermal populations revealed that endodermal enhancers existed in a surprising diversity of “pre-enhancer” states before activation, reflecting the establishment of a permissive chromatin landscape as a prelude to differentiation.
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•Signaling roadmap for four successive lineage bifurcations during endoderm development•Highly efficient (94%) endodermal differentiation of nine diverse hPSC lines•Global mapping of endoderm enhancer dynamics across five distinct lineage transitions•H2AZ marks an endoderm “pre-enhancer” state prior to activation
Loh et al. describe an efficient protocol for the endodermal differentiation of human pluripotent stem cells by directing signals controlling lineage bifurcations, allowing precise analysis of the chromatin status of enhancers during the differentiation process.
Biological microorganisms swim with flagella and cilia that execute nonreciprocal motions for low Reynolds number (Re) propulsion in viscous fluids. This symmetry requirement is a consequence of ...Purcell's scallop theorem, which complicates the actuation scheme needed by microswimmers. However, most biomedically important fluids are non-Newtonian where the scallop theorem no longer holds. It should therefore be possible to realize a microswimmer that moves with reciprocal periodic body-shape changes in non-Newtonian fluids. Here we report a symmetric 'micro-scallop', a single-hinge microswimmer that can propel in shear thickening and shear thinning (non-Newtonian) fluids by reciprocal motion at low Re. Excellent agreement between our measurements and both numerical and analytical theoretical predictions indicates that the net propulsion is caused by modulation of the fluid viscosity upon varying the shear rate. This reciprocal swimming mechanism opens new possibilities in designing biomedical microdevices that can propel by a simple actuation scheme in non-Newtonian biological fluids.
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