Cardiac differentiation of human pluripotent stem cells (hPSCs) requires orchestration of dynamic gene regulatory networks during stepwise fate transitions but often generates immature cell types ...that do not fully recapitulate properties of their adult counterparts, suggesting incomplete activation of key transcriptional networks. We performed extensive single-cell transcriptomic analyses to map fate choices and gene expression programs during cardiac differentiation of hPSCs and identified strategies to improve in vitro cardiomyocyte differentiation. Utilizing genetic gain- and loss-of-function approaches, we found that hypertrophic signaling is not effectively activated during monolayer-based cardiac differentiation, thereby preventing expression of HOPX and its activation of downstream genes that govern late stages of cardiomyocyte maturation. This study therefore provides a key transcriptional roadmap of in vitro cardiac differentiation at single-cell resolution, revealing fundamental mechanisms underlying heart development and differentiation of hPSC-derived cardiomyocytes.
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•Single-cell RNA-seq during cardiac hPSC differentiation reveals cellular heterogeneity•A key cardiac regulatory gene, HOPX, is rarely expressed during in vitro differentiation•HOPX is a key in vitro regulator of cardiomyocyte hypertrophy and maturation
Friedman et al. performed single-cell transcriptional analysis over a time course of in vitro cardiac differentiation from human pluripotent stem cells. They utilized these data to identify the requirement of hypertrophic stimuli for expression of a cardiac regulatory gene, HOPX, to generate cardiomyocytes more accurately reflecting in vivo heart development.
Reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection have raised important questions about the strength and durability of the immune response to primary infection, ...which are key factors in predicting the course of the pandemic. Identifying reinfection requires detecting the virus at two different time points and using viral genomic data to distinguish reinfection from persistent viral carriage. This process is hindered by challenges of logistics and capacity, such as banking samples from primary infection and performing viral genome sequencing. These challenges may help to explain why very few cases have been described to date. In addition, reinfection may be a rare phenomenon, but detailed prospective studies are needed to rigorously assess its frequency. To provide context for future investigations of SARS-CoV-2 reinfection, we review 16 cases that have been published to date or are available in preprint. Reinfection occurred across demographic spectra and in patients whose initial infections were both asymptomatic/mild and moderate/severe. For cases in which severity could be compared between episodes, half of reinfections were less severe, raising the possibility of partial immune protection. Although many patients had a positive total immunoglobulin or IgG result at the time of reinfection, very little examination of their immune response was performed. Further work is needed to elucidate the frequency, determinants, and consequences of SARS-CoV-2 reinfection. Establishing the necessary frameworks for surveillance and investigation will rely heavily on clinical laboratories and clinical investigators, and we propose several considerations to guide the medical community in identifying and characterizing SARS-CoV-2 reinfections.
In patients with colorectal cancer (CRC) that metastasizes to the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment ...response, and accurate identification of patients at high risk for recurrence. Although new therapeutic regimens developed over the past decade have increased survival, there is substantial room for improvement in selecting targeted treatment regimens for the patients who will derive the most benefit. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem of detecting and treating the metastatic spread of CRC to the liver. Our multidisciplinary group held a state-of-the-science symposium this past year to review advances in this rapidly evolving field. Herein, we present a discussion around the issues facing treatment of patients with CRC liver metastases, including the relationship of discrete gene signatures with prognosis. We also discuss the latest advances to maximize regional and systemic therapies aimed at decreasing intrahepatic recurrence, review recent insights into the tumor microenvironment, and summarize advances in noninvasive multimodal biomarkers for early detection of primary and recurrent disease. As we continue to advance clinically and technologically in the field of colorectal tumor biology, our goal should be continued refinement of predictive and prognostic studies to decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailored multidisciplinary approach to cancer care.
Integrating the behavioral theory of the firm (the BTF) and the self-enhancement motive of managers, this paper examines how performance feedback—the discrepancy between actual performance and ...aspiration levels—affects the international expansion of emerging economy firms (EEFs). Empirical results using panel data on 876 publicly-listed Chinese manufacturing companies over a 7-year period indicate that performance relative to social aspiration (i.e., peer performance) and relative to historical aspiration (i.e., firms’ own past performance) affects EEFs’ levels of subsequent outward foreign direct investment (OFDI). Specifically, performance below social or historical aspiration enhances levels of OFDI, while the effect of performance below social aspiration is stronger than that of underperforming historical results. The results also show that performance above social aspiration enhances levels of OFDI, while performance above historical aspiration decreases levels of OFDI. Moreover, we uncover the importance of considering the joint effect of historical and social performance feedback, as receiving consistent or mixed signals about firm performance may result in risk-taking behaviors that differ from those triggered by just one performance signal on its own. These findings underscore the impact of performance feedback relative to social and historical aspirations on EEFs’ OFDI activities.
Inferotemporal cortex (IT) has long been studied as a single pathway dedicated to object vision, but connectivity analysis reveals anatomically distinct channels, through ventral superior temporal ...sulcus (STSv) and dorsal/ventral inferotemporal gyrus (TEd, TEv). Here, we report a major functional distinction between channels. We studied individual IT neurons in monkeys viewing stereoscopic 3D images projected on a large screen. We used adaptive stimuli to explore neural tuning for 3D abstract shapes ranging in scale and topology from small, closed, bounded objects to large, open, unbounded environments (landscape-like surfaces and cave-like interiors). In STSv, most neurons were more responsive to objects, as expected. In TEd, surprisingly, most neurons were more responsive to 3D environmental shape. Previous studies have localized environmental information to posterior cortical modules. Our results show it is also channeled through anterior IT, where extensive cross-connections between STSv and TEd could integrate object and environmental shape information.
Interleukin‐12 family cytokines have emerged as critical regulators of immunity with some members (IL‐12, IL‐23) associated with disease pathogenesis while others (IL‐27, IL‐35) mitigate autoimmune ...diseases. Each IL‐12 family member is comprised of an α and a β chain, and chain‐sharing is a key feature. Although four bona fide members have thus far been described, promiscuous chain‐pairing between alpha (IL‐23p19, IL‐27p28, IL‐12/IL‐35p35) and beta (IL‐12/IL‐23p40, IL‐27/IL‐35Ebi3) subunits, predicts six possible heterodimeric IL‐12 family cytokines. Here, we describe a new IL‐12 member composed of IL‐23p19 and Ebi3 heterodimer (IL‐39) that is secreted by LPS‐stimulated B cells and GL7+ activated B cells of lupus‐like mice. We further show that IL‐39 mediates inflammatory responses through activation of STAT1/STAT3 in lupus‐like mice. Taken together, our results show that IL‐39 might contribute to immunopathogenic mechanisms of systemic lupus erythematosus, and could be used as a possible target for its treatment.
Promiscuous chain‐pairing of IL‐12 subunit proteins predicts six possible IL‐12 family members. We have discovered IL‐39 (IL‐23p19/Ebi3) as newest IL‐12 member that signals through its cognate receptor (IL‐23R/gp130) and STAT1/STAT3 pathways. IL‐39 is secreted by activated B cells of Lupus‐like mice and might therefore contribute to immune‐pathogenic mechanisms of Lupus
.
Capture and conversion of sunlight into the storable energy carrier H
can be achieved through photoelectrochemical water splitting using light-absorbing cathodes and anodes bearing H
and O
evolving ...catalysts. Here, we report on the development of a dye-sensitised p-type nickel oxide (NiO) photocathode with a hexaphosphonated Ru(2,2'-bipyridine)
based dye (
) and a tetraphosphonated molecular Ni(P
N
)
type proton reduction catalyst (
) for the photoreduction of aqueous protons to H
. A layer-by-layer deposition approach was employed, using Zr
ions to link the phosphonate units in
and
in a supramolecular assembly on the NiO photocathode. This approach keeps the dye in close proximity to the catalyst and semiconductor surface, but spatially separates
from NiO for advantageous electron transfer dynamics. The NiO|
-Zr
-
electrodes generate higher photocurrents and are more stable than photocathodes with
and
co-immobilised on the NiO surface in the absence of Zr
cations linking dye and catalyst. The generation of H
with the NiO|
-Zr
-
hybrid electrode in pH 3 aqueous electrolyte solution during irradiation with a UV-filtered solar light simulator (
> 400 nm, 100 mW cm
, AM1.5G) has been confirmed by gas chromatography at an underpotential of 300 mV (
= +0.3 V
RHE), demonstrating the potential of these electrodes to store solar energy in the chemical bond of H
.
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