Diabetes is associated with β cell failure. But it remains unclear whether the latter results from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β cell ...function. We interrogated the contribution of these two processes to β cell dysfunction, using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation, not death. Dedifferentiated β cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β cells adopted the α cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication.
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► Dedifferentiation, not apoptosis, is the main cause of β cell failure ► FoxO1 enforces the β cell fate during β cell adaptation to metabolic stress ► Dedifferentiated β cells are prone to converting into α, δ, and Pp endocrine cells
Challenging a prevalent view that pancreatic β cells undergo apoptosis in conditions that induce diabetes, this study shows that dedifferentiation is a major mechanism of β cell loss.
We review mechanisms that regulate production of glucose by the liver, focusing on areas of budding consensus, and endeavoring to provide a candid assessment of lingering controversies. We also ...attempt to reconcile data from tracer studies in humans and large animals with the growing compilation of mouse knockouts that display changes in glucose production. A clinical hallmark of diabetes, excessive glucose production remains key to its treatment. Hence, we attempt to integrate emerging pathways into the broader goal to rejuvenate the staid antidiabetic pharmacopeia.
Polychlorinated dibenzo-p-dioxins (PCDDs), as a class of persistent and highly toxic organic pollutants, have been posing a great threat to human health and the environment. The sensing of these ...compounds is important but challenging. Here, we report a highly stable zirconium-based metal-organic framework (MOF), Zr
O
(OH)
(HCOO)
(CPTTA)
(BUT-17) with one-dimensional hexagonal channels and phenyl-rich pore surfaces for the recognition and sensing of two representative PCDDs, 2,3-dichlorodibenzo-p-dioxin (BCDD) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), based on the fluorescence quenching. BUT-17 exhibits high sensing ability with the detection limits as low as 27 and 57 part per billion toward BCDD and TCDD, respectively, and is very selective as well without the interference of similar compounds. The recognition of BUT-17 toward BCDD is demonstrated by single-crystal structure of its guest-loaded phase, in which the fluorescence-quenched complexes form between the adsorbed BCDD molecules and the MOF host through π-π stacking and hydrogen bonding interactions.
Dielectric capacitors with ultrahigh power densities are fundamental energy storage components in electrical and electronic systems. However, a long-standing challenge is improving their energy ...densities. We report dielectrics with ultrahigh energy densities designed with polymorphic nanodomains. Guided by phase-field simulations, we conceived and synthesized lead-free BiFeO
-BaTiO
-SrTiO
solid-solution films to realize the coexistence of rhombohedral and tetragonal nanodomains embedded in a cubic matrix. We obtained minimized hysteresis while maintaining high polarization and achieved a high energy density of 112 joules per cubic centimeter with a high energy efficiency of ~80%. This approach should be generalizable for designing high-performance dielectrics and other functional materials that benefit from nanoscale domain structure manipulation.
In this study, we examined the Ca2+‐permeable Piezo1 channel, a newly identified mechanosensing ion channel, in human dental pulp‐derived mesenchymal stem cells (MSCs) and hypothesized that ...activation of the Piezo1 channel regulates MSC migration via inducing ATP release and activation of the P2 receptor purinergic signaling. The Piezo1 mRNA and protein were readily detected in hDP‐MSCs from multiple donors and, consistently, brief exposure to Yoda1, the Piezo1 channel‐specific activator, elevated intracellular Ca2+ concentration. Yoda1‐induced Ca2+ response was inhibited by ruthenium red or GsMTx4, two Piezo1 channel inhibitors, and also by Piezo1‐specific siRNA. Brief exposure to Yoda1 also induced ATP release. Persistent exposure to Yoda1 stimulated MSC migration, which was suppressed by Piezo1‐specific siRNA, and also prevented by apyrase, an ATP scavenger, or PPADS, a P2 generic antagonist. Furthermore, stimulation of MSC migration induced by Yoda1 as well as ATP was suppressed by PF431396, a PYK2 kinase inhibitor, or U0126, an inhibitor of the mitogen‐activated protein kinase MEK/ERK signaling pathway. Collectively, these results suggest that activation of the Piezo1 channel stimulates MSC migration via inducing ATP release and subsequent activation of the P2 receptor purinergic signaling and downstream PYK2 and MEK/ERK signaling pathways, thus revealing novel insights into the molecular and signaling mechanisms regulating MSC migration. Such findings provide useful information for evolving a full understanding of MSC migration and homing and developing strategies to improve MSC‐based translational applications.
A, Exposure to Yoda1, the Piezo1 channel‐specific activator, stimulates human dental pulp mesenchymal stem cell migration in wound healing assay; B, the underlying signaling mechanisms.
Developing high-performance film dielectrics for capacitive energy storage has been a great challenge for modern electrical devices. Despite good results obtained in lead titanate-based dielectrics, ...lead-free alternatives are strongly desirable due to environmental concerns. Here we demonstrate that giant energy densities of ~70 J cm
, together with high efficiency as well as excellent cycling and thermal stability, can be achieved in lead-free bismuth ferrite-strontium titanate solid-solution films through domain engineering. It is revealed that the incorporation of strontium titanate transforms the ferroelectric micro-domains of bismuth ferrite into highly-dynamic polar nano-regions, resulting in a ferroelectric to relaxor-ferroelectric transition with concurrently improved energy density and efficiency. Additionally, the introduction of strontium titanate greatly improves the electrical insulation and breakdown strength of the films by suppressing the formation of oxygen vacancies. This work opens up a feasible and propagable route, i.e., domain engineering, to systematically develop new lead-free dielectrics for energy storage.
An easily prepared platinum nanoparticle (PtNP) probe for the sensitive and selective detection of Hg2+ ions is developed here. The PtNPs with an average size of approximately 2.5 nm were prepared by ...a reduction method with sodium borohydride and trisodium citrate serving as reductant and stabilizer, respectively. The resulting PtNPs could catalyze the reduction of Hg2+ by surface-capping citrate. The effect of Hg2+ uptake implies amalgam formation, which leads to remarkable inhibition of the peroxidase-like activity of citrate-capped PtNPs. On the basis of this effect, a colorimetric mercury sensor was established through the use of citrate-capped PtNPs to catalyze the colorimetric system of 3,3′,5,5′-tetramethylbenzidine (TMB) and H2O2. The high specificity of the Hg–Pt interaction provides the excellent selectivity for Hg2+ over interfering metal ions. The sensitivity of this smart probe to Hg2+ is extremely excellent with a limit of detection (LOD) as low as 8.5 pM. In view of these advantages, as well as the cost-effectiveness, minimized working steps, and naked-eye observation, we expect that this colorimetric sensor will be a promising candidate for the field detection of toxic Hg2+ ions in environmental, biological, and food samples.
A microporous three-dimensional (3D) hydrogen-bonded organic framework (HOF-20) has been constructed from an aromatic-rich tetratopic carboxylic acid, ...5-(2,6-bis(4-carboxyphenyl)pyridin-4-yl)isophthalic acid (H4BCPIA). The activated HOF-20a has a moderately high Brunauer–Emmett–Teller (BET) surface area of 1323 m2 g–1 and excellent stability in water and HCl aqueous solution. HOF-20 exhibits highly efficient turn-up fluorescent sensing of aniline in water with a detection limit of 2.24 μM and is selective toward aniline in the presence of aromatic interferents, owing to the hydrogen bonding and edge-to-face π–π stacking interactions between the HOF-20 host and the guest aniline molecules, as demonstrated in the single-crystal X-ray structure of HOF-20⊃aniline. Density functional theory (DFT) calculations further demonstrate that the recognition of aniline molecules by HOF-20 could restrict the rotation of the aromatic rings in H4BCPIA linkers, reducing the nonradiative decay pathways upon photoexcitation and subsequently enhancing the fluorescence intensity.
Transient receptor potential melastatin 2 (TRPM2) channel activation by reactive oxygen species (ROS) plays a critical role in delayed neuronal cell death, responsible for postischemia brain damage ...via altering intracellular Zn2+ homeostasis, but a mechanistic understanding is still lacking. Here, we showed that H2O2 induced neuroblastoma SH‐SY5Y cell death with a significant delay, dependently of the TRPM2 channel and increased Zn2+i, and therefore used this cell model to investigate the mechanisms underlying ROS‐induced TRPM2‐mediated delayed cell death. H2O2 increased concentration‐dependently the Zn2+i and caused lysosomal dysfunction and Zn2+ loss and, furthermore, mitochondrial Zn2+ accumulation, fragmentation, and ROS generation. Such effects were suppressed by preventing poly(adenosine diphosphate ribose, ADPR) polymerase‐1‐dependent TRPM2 channel activation with PJ34 and 3,3′,5,5′‐tetra‐tert‐butyldiphenoquinone, inhibiting the TRPM2 channel with 2‐aminoethoxydiphenyl borate (2‐APB) and N‐(p‐amylcinnamoyl)anthranilic acid, or chelating Zn2+ with N,N,N,N‐tetrakis(2‐pyridylmethyl)‐ethylenediamine (TPEN). Bafilomycin‐induced lysosomal dysfunction also resulted in mitochondrial Zn2+ accumulation, fragmentation, and ROS generation that were inhibited by PJ34 or 2‐APB, suggesting that these mitochondrial events are TRPM2 dependent and sequela of lysosomal dysfunction. Mitochondrial TRPM2 expression was detected and exposure to ADPR‐induced Zn2+ uptake in isolated mitochondria, which was prevented by TPEN. H2O2‐induced delayed cell death was inhibited by apocynin and diphenyleneiodonium, nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase (NOX) inhibitors, GKT137831, an NOX1/4‐specific inhibitor, or Gö6983, a protein kinase C (PKC) inhibitor. Moreover, inhibition of PKC/NOX prevented H2O2‐induced ROS generation, lysosomal dysfunction and Zn2+ release, and mitochondrial Zn2+ accumulation, fragmentation and ROS generation. Collectively, these results support a critical role for the TRPM2 channel in coupling PKC/NOX‐mediated ROS generation, lysosomal Zn2+ release, and mitochondrial Zn2+ accumulation, and ROS generation to form a vicious positive feedback signaling mechanism for ROS‐induced delayed cell death.
Transient receptor potential melastatin 2 (TRPM2) channel activation by reactive oxygen species (ROS) is critically responsible for delayed neuronal cell death, responsible for postischemia brain damage via altering intracellular Zn2+ homeostasis. In this study, we provide evidence to support that the TRPM2 channel plays a critical role in forming a vicious positive feedback signaling mechanism for ROS‐induced delayed cell death.
To guarantee system stability, proportional capacitor-current-feedback (CCF) active damping control has been widely used in LCL -type grid-connected inverter. However, when digital control is adopted ...in a grid-side current-controlled inverter, proportional CCF active damping will show negative damping characteristic in frequency band higher than one-sixth of the sampling frequency ( f s /6), causing poor robustness in weak grid. In this article, an unstable second-order phase lead compensator is proposed to insert into the CCF path for eliminating the negative effect resulting from the digital control delay. In doing so, the positive damping region is extended to almost Nyquist frequency ( f s /2), which achieves high robustness against grid impedance variation. To ensure system stability, the discrete rule is investigated for the proposed compensator and system performance is analyzed when the LCL resonance frequency changes in the range of (0, f s /2) in discrete domain, a particularly simple and practical design is further presented for the proposed compensator and the current regulator. Finally, the effectiveness of the proposed strategy and parameters design is verified by the experimental results.
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